0000874015-22-000079 | 10-K | XBRL Viewer | Ionis Pharmaceuticals INC

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CONSOLIDATED BALANCE SHEETS - USD ($) $ in Thousands	Dec. 31, 2021	Dec. 31, 2020
Current assets:
Cash and cash equivalents	$ 869,191	$ 397,664
Short-term investments	1,245,782	1,494,711
Contracts receivable	61,896	76,204
Inventories	24,806	21,965
Other current assets	143,374	140,163
Total current assets	2,345,049	2,130,707
Property, plant and equipment, net	178,069	181,077
Patents, net	29,005	27,937
Deposits and other assets	59,567	50,034
Total assets	2,611,690	2,389,755
Current liabilities:
Accounts payable	11,904	17,199
Accrued compensation	38,810	65,728
Accrued liabilities	88,560	90,161
Income taxes payable	36	1,324
1 percent convertible senior notes, net	0	308,809
Current portion of long-term obligations	3,526	7,301
Current portion of deferred contract revenue	97,714	108,376
Total current liabilities	240,550	598,898
Long-term deferred contract revenue	351,879	424,046
Long-term obligations, less current portion	26,378	23,409
Long-term mortgage debt	59,713	59,984
Total liabilities	1,839,953	1,646,473
Stockholders' equity:
Common stock, $0.001 par value; 300,000,000 shares authorized, 141,210,015 and 140,365,594 shares issued and outstanding at December 31, 2021 and December 31, 2020, respectively	141	140
Additional paid-in capital	1,964,167	1,895,519
Accumulated other comprehensive loss	(32,668)	(21,071)
Accumulated deficit	(1,159,903)	(1,131,306)
Total stockholders' equity	771,737	743,282
Total liabilities and stockholders' equity	2,611,690	2,389,755
0 Percent Convertible Senior Notes [Member]
Current liabilities:
Convertible senior notes, net	619,119	0
0.125 Percent Convertible Senior Notes [Member]
Current liabilities:
Convertible senior notes, net	$ 542,314	$ 540,136

CONSOLIDATED BALANCE SHEETS (Parenthetical) - $ / shares	Dec. 31, 2021	Dec. 31, 2020
Stockholders' equity:
Common stock, par value (in dollars per share)	$ 0.001	$ 0.001
Common stock, shares authorized (in shares)	300,000,000	300,000,000
Common stock, shares issued (in shares)	141,210,015	140,365,594
Common stock, shares outstanding (in shares)	141,210,015	140,365,594
1 Percent Convertible Senior Notes [Member]
LIABILITIES AND STOCKHOLDERS' EQUITY
Interest rate on convertible senior notes	1.00%	1.00%
0 Percent Convertible Senior Notes [Member]
LIABILITIES AND STOCKHOLDERS' EQUITY
Interest rate on convertible senior notes	0.00%
0.125 Percent Convertible Senior Notes [Member]
LIABILITIES AND STOCKHOLDERS' EQUITY
Interest rate on convertible senior notes	0.125%	0.125%

CONSOLIDATED STATEMENTS OF OPERATIONS - USD ($) shares in Thousands, $ in Thousands	12 Months Ended
	Dec. 31, 2021	Dec. 31, 2020	Dec. 31, 2019
Revenue:
Revenue	$ 810,456	$ 729,264	$ 1,122,599
Expenses:
Cost of sales	10,842	11,947	4,384
Research, development and patent	643,453	535,077	465,688
Selling, general and administrative	186,347	354,322	286,644
Total operating expenses	840,642	901,346	756,716
Income (loss) from operations	(30,186)	(172,082)	365,883
Other income (expense):
Investment income	10,044	30,562	52,013
Interest expense	(9,349)	(9,510)	(12,440)
Gain on investments	10,103	16,540	192
Loss on early retirement of debt	(8,627)	0	(66,196)
Other expenses	(1,133)	(62)	(686)
Income (loss) before income tax benefit (expense)	(29,148)	(134,552)	338,766
Income tax benefit (expense)	551	(345,191)	(51,507)
Net income (loss)	(28,597)	(479,743)	287,259
Net (income) loss attributable to noncontrolling interest in Akcea Therapeutics, Inc.	0	35,480	(9,116)
Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders	$ (28,597)	$ (444,263)	$ 278,143
Basic net income (loss) per share (in dollars per share)	$ (0.20)	$ (3.18)	$ 2.00
Shares used in computing basic net income (loss) per share (in shares)	141,021	139,612	139,998
Diluted net income (loss) per share (in dollars per share)	$ (0.20)	$ (3.18)	$ 1.90
Shares used in computing diluted net income (loss) per share (in shares)	141,021	139,612	153,164
Commercial Revenue [Member]
Revenue:
Revenue	$ 342,395	$ 364,699	$ 352,450
SPINRAZA Royalties [Member]
Revenue:
Revenue	267,776	286,583	292,992
TEGSEDI and WAYLIVRA Revenue, Net [Member]
Revenue:
Revenue	55,500	69,999	42,253
Licensing and Other Royalty Revenue [Member]
Revenue:
Revenue	19,119	8,117	17,205
Research and Development Revenue Under Collaborative Agreements [Member]
Revenue:
Revenue	$ 468,061	$ 364,565	$ 770,149

CONSOLIDATED STATEMENTS OF COMPREHENSIVE INCOME (LOSS) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2021	Dec. 31, 2020	Dec. 31, 2019
CONSOLIDATED STATEMENTS OF COMPREHENSIVE INCOME (LOSS) [Abstract]
Net income (loss)	$ (28,597)	$ (479,743)	$ 287,259
Unrealized gains (losses) on investments, net of tax	(11,486)	3,729	6,633
Currency translation adjustment	(111)	617	93
Adjustments to other comprehensive loss from purchase of noncontrolling interest of Akcea Therapeutics, Inc.	0	(127)	0
Comprehensive income (loss)	(40,194)	(475,524)	293,985
Comprehensive income (loss) attributable to noncontrolling interest in Akcea Therapeutics, Inc.	0	(35,480)	9,116
Comprehensive income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders	$ (40,194)	$ (440,044)	$ 284,869

- Definition

Amount after tax of increase (decrease) in equity from transactions and other events and circumstances from net income (loss) and other comprehensive income (loss), attributable to noncontrolling interests. Excludes changes in equity resulting from investments by owners and distributions to owners.

+ References + Details

- Definition

Amount after tax of increase (decrease) in equity from transactions and other events and circumstances from net income and other comprehensive income. Excludes changes in equity resulting from investments by owners and distributions to owners.

+ References + Details

- Definition

The consolidated profit or loss for the period, net of income taxes, including the portion attributable to the noncontrolling interest.

+ References

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CONSOLIDATED STATEMENTS OF STOCKHOLDERS' EQUITY - USD ($) shares in Thousands, $ in Thousands	Common Stock [Member]	Additional Paid In Capital [Member]	Accumulated Other Comprehensive Loss [Member]	Accumulated Deficit [Member]	Total Ionis Stockholders' Equity [Member]	Noncontrolling Interest in Akcea Therapeutics, Inc. [Member]	Total
Balance at Dec. 31, 2018	$ 138	$ 1,833,668	$ (32,016)	$ (840,251)	$ 961,539	$ 139,084	$ 1,100,623
Balance (in shares) at Dec. 31, 2018	137,929
Increase (Decrease) in Stockholders' Equity [Roll Forward]
Net loss	$ 0	0	0	278,143	278,143	0	278,143
Change in unrealized gains (losses), net of tax	0	0	6,633	0	6,633	0	6,633
Foreign currency translation	0	0	93	0	93	0	93
Issuance of common stock in connection with employee stock plans	$ 3	119,654	0	0	119,657	0	119,657
Issuance of common stock in connection with employee stock plans (in shares)	3,100
Issuance of warrants	$ 0	56,110	0	0	56,110	0	56,110
Purchase of note hedges, net of tax	0	(85,860)	0	0	(85,860)	0	(85,860)
Repurchases and retirements of common stock	$ (1)	0	0	(34,387)	(34,388)	0	(34,388)
Repurchases and retirements of common stock (in shares)	(535)
Stock-based compensation expense	$ 0	146,574	0	0	146,574	0	146,574
Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options	$ 0	(19,242)	0	0	(19,242)	0	(19,242)
Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options (in shares)	(154)
Noncontrolling interest in Akcea Therapeutics, Inc.	$ 0	(65,254)	0	0	(65,254)	74,370	9,116
Balance at Dec. 31, 2019	$ 140	1,985,650	(25,290)	(596,495)	1,364,005	213,454	1,577,459
Balance (in shares) at Dec. 31, 2019	140,340
Increase (Decrease) in Stockholders' Equity [Roll Forward]
Net loss	$ 0	0	0	(444,263)	(444,263)	0	(444,263)
Change in unrealized gains (losses), net of tax	0	0	3,729	0	3,729	0	3,729
Foreign currency translation	0	0	617	0	617	0	617
Issuance of common stock in connection with employee stock plans	$ 1	52,033	0	0	52,034	0	52,034
Issuance of common stock in connection with employee stock plans (in shares)	1,721
Purchase of noncontrolling interest of Akcea Therapeutics, Inc., including cash payments for cancellation of Akcea Therapeutics, Inc. equity awards	$ 0	(324,022)	301	0	(323,721)	(220,965)	(544,686)
Repurchases and retirements of common stock	$ (1)	0	0	(90,548)	(90,549)	0	(90,549)
Repurchases and retirements of common stock (in shares)	(1,478)
Stock-based compensation expense	$ 0	230,117	0	0	230,117	0	230,117
Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options	$ 0	(13,410)	0	0	(13,410)	0	(13,410)
Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options (in shares)	(217)
Deferred tax liability adjustment due to purchase of noncontrolling interest of Akcea Therapeutics, Inc.	$ 0	7,714	0	0	7,714	0	7,714
Noncontrolling interest in Akcea Therapeutics, Inc.	0	(42,563)	(428)	0	(42,991)	7,511	(35,480)
Balance at Dec. 31, 2020	$ 140	1,895,519	(21,071)	(1,131,306)	743,282	0	743,282
Balance (in shares) at Dec. 31, 2020	140,366
Increase (Decrease) in Stockholders' Equity [Roll Forward]
Net loss	$ 0	0	0	(28,597)	(28,597)	0	(28,597)
Change in unrealized gains (losses), net of tax	0	0	(11,486)	0	(11,486)	0	(11,486)
Foreign currency translation	0	0	(111)	0	(111)	0	(111)
Issuance of common stock in connection with employee stock plans	$ 1	11,563	0	0	11,564	0	11,564
Issuance of common stock in connection with employee stock plans (in shares)	1,132
Issuance of warrants	$ 0	89,752	0	0	89,752	0	89,752
Purchase of note hedges, net of tax	0	(136,620)	0	0	(136,620)	0	(136,620)
Stock-based compensation expense	0	120,678	0	0	120,678	0	120,678
Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options	$ 0	(16,725)	0	0	(16,725)	0	(16,725)
Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options (in shares)	(288)
Balance at Dec. 31, 2021	$ 141	$ 1,964,167	$ (32,668)	$ (1,159,903)	$ 771,737	$ 0	$ 771,737
Balance (in shares) at Dec. 31, 2021	141,210

CONSOLIDATED STATEMENTS OF CASH FLOWS - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2021	Dec. 31, 2020	Dec. 31, 2019
Operating activities:
Net income (loss)	$ (28,597)	$ (479,743)	$ 287,259
Adjustments to reconcile net income (loss) to net cash used in operating activities:
Depreciation	15,487	13,365	12,540
Amortization of right-of-use operating lease assets	1,721	1,731	1,542
Amortization of patents	2,352	2,064	1,912
Amortization of premium (discount) on investments, net	17,776	11,521	(7,485)
Amortization of debt issuance costs	4,958	3,255	2,945
Stock-based compensation expense	120,678	230,117	146,574
Loss on early retirement of debt	8,627	0	66,196
Gain on investments	(1,092)	(16,540)	(192)
Deferred income taxes, including changes in valuation allowance	0	341,729	911
Non-cash losses related to patents	2,707	1,948	2,226
Changes in operating assets and liabilities:
Contracts receivable	14,308	(13,170)	(47,674)
Inventories	(2,841)	(1,261)	(5,411)
Other current and long-term assets	(877)	(9,975)	(44,659)
Long-term income taxes receivable (payable)	1,008	(89)	8,418
Accounts payable	(6,000)	(2,755)	(16,343)
Income taxes	(1,288)	(31,190)	31,656
Accrued compensation	(26,918)	28,371	8,089
Accrued liabilities and other current liabilities	(8,381)	32,424	16,406
Deferred contract revenue	(82,829)	(75,910)	(119,283)
Net cash used in operating activities	30,799	35,892	345,627
Investing activities:
Purchases of short-term investments	(1,124,193)	(1,570,410)	(1,946,726)
Proceeds from sale of short-term investments	1,344,185	1,885,935	1,951,734
Purchases of property, plant and equipment	(11,955)	(35,120)	(30,905)
Acquisition of licenses and other assets, net	(5,946)	(5,928)	(5,377)
Purchases of strategic investments	(7,185)	0	(10,000)
Net cash provided by (used in) investing activities	194,906	274,477	(41,274)
Financing activities:
Proceeds from equity, net	11,565	52,036	119,657
Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options	(16,725)	(13,411)	(19,242)
Repurchase of $247.9 million principal amount of 1 percent convertible senior notes	(256,963)	0	0
Repayment of remaining principal amount of 1 percent convertible senior notes at maturity	(61,967)	0	0
Proceeds from issuance of warrants	89,752	0	56,110
Purchase of note hedges	(136,620)	0	(108,684)
Repurchases and retirements of common stock	0	(90,548)	(34,392)
Purchase of noncontrolling interest of Akcea Therapeutics, Inc., including cash payments for cancellation of Akcea Therapeutics, Inc. equity awards	0	(544,686)	0
Principal payments on line of credit	0	0	(12,500)
Net cash provided by (used in) financing activities	245,933	(596,609)	100,021
Effects of exchange rates on cash	(111)	617	93
Net increase (decrease) in cash and cash equivalents	471,527	(285,623)	404,467
Cash and cash equivalents at beginning of year	397,664	683,287	278,820
Cash and cash equivalents at end of year	869,191	397,664	683,287
Supplemental disclosures of cash flow information:
Interest paid	4,778	6,247	9,870
Income taxes paid	38	25,855	9,041
Supplemental disclosures of non-cash investing and financing activities:
Right-of-use assets obtained in exchange for lease liabilities	6,641	2,149	14,178
Amounts accrued for capital and patent expenditures	705	4,059	3,126
0.125 percent convertible senior notes principal issued related to our December 2019 debt exchange/issuance	0	0	439,326
1 percent convertible senior notes principal extinguished related to our December 2019 debt exchange	0	0	375,590
0 Percent Convertible Senior Notes [Member]
Financing activities:
Proceeds from the issuance of convertible senior notes	632,500	0	0
Convertible senior notes issuance costs	(15,609)	0	0
0.125 Percent Convertible Senior Notes [Member]
Financing activities:
Proceeds from the issuance of convertible senior notes	0	0	109,500
Convertible senior notes issuance costs	$ 0	$ 0	$ (10,428)

CONSOLIDATED STATEMENTS OF CASH FLOWS (Parenthetical) - USD ($) $ in Millions	Dec. 31, 2021	Nov. 30, 2021	Apr. 30, 2021	Dec. 31, 2020	Dec. 31, 2019	Dec. 31, 2016	Nov. 30, 2014
0 Percent Convertible Senior Notes [Member]
Consolidated Statements of Cash Flows [Abstract]
Interest rate on convertible senior notes	0.00%		0.00%		0.00%
0.125 Percent Convertible Senior Notes [Member]
Consolidated Statements of Cash Flows [Abstract]
Interest rate on convertible senior notes	0.125%			0.125%	0.125%
1 Percent Convertible Senior Notes [Member]
Consolidated Statements of Cash Flows [Abstract]
Interest rate on convertible senior notes	1.00%	1.00%	1.00%	1.00%	1.00%	1.00%	1.00%
Principal amount repurchased	$ 247.9		$ 247.9		$ 375.6

Organization and Significant Accounting Policies

12 Months Ended

Dec. 31, 2021

Organization and Significant Accounting Policies [Abstract]

Organization and Significant Accounting Policies

1. Organization and Significant Accounting Policies

Basis of Presentation

In our consolidated financial statements we included the accounts of Ionis Pharmaceuticals, Inc. and the consolidated results of our subsidiary, Akcea Therapeutics, Inc. and its wholly owned subsidiaries (“we”, “us” or “our”). We formed Akcea in December 2014. In July 2017, Akcea completed an initial public offering, or IPO, which reduced our ownership of Akcea’s common stock below 100 percent. In October 2020, we completed a merger transaction with Akcea such that following the completion of the merger, Akcea became our wholly owned subsidiary. We will refer to this transaction as the Akcea Merger throughout the remainder of this document. We reflected changes in our ownership percentage in our financial statements as an adjustment to noncontrolling interest in the period the changes occurred.

Organization and Business Activity

We incorporated in California on January 10, 1989. In conjunction with our IPO, we reorganized as a Delaware corporation in April 1991. We were organized principally to develop human therapeutic medicines using antisense technology. In December 2015, we changed our name from Isis Pharmaceuticals, Inc. to Ionis Pharmaceuticals, Inc.

Basic and Diluted Net Income (Loss) per Share

Basic net income (loss) per share

We compute basic net income (loss) per share by dividing the total net income (loss) attributable to our common stockholders by our weighted-average number of common shares outstanding during the period. For the year ended December 31, 2021, we did not have to consider Akcea results separately in our calculation because we owned 100 percent of Akcea for the entire period. Our basic net loss per share for the year ended December 31, 2021 was $0.20.

For the years ended December 31, 2020 and 2019, we calculated total net income (loss) attributable to our common stockholders for each year using our net income (loss) for Ionis on a stand-alone basis plus our share of Akcea’s net income (loss) for the period. To calculate the portion of Akcea’s net income (loss) attributable to our ownership for each year, we multiplied Akcea’s income (loss) per share by the weighted average shares we owned in Akcea during the period. As a result of this calculation, our total net income (loss) available to Ionis common stockholders for the calculation of net income (loss) per share is different than net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders in our consolidated statements of operations for each year.

We calculated our basic net loss per share for the year ended December 31, 2020 as follows (in thousands, except per share amounts):

Year Ended December 31, 2020	Weighted Average Shares Owned in Akcea		Akcea’s Net Loss Per Share			Basic Net Loss Per Share Calculation
Akcea’s net loss in the pre-merger period attributable to our ownership		77,095	$	(1.45	)	$	(111,775	)
Akcea’s net loss in the post-merger period attributable to our ownership							(85,987	)
Akcea’s total net loss attributable to our ownership						$	(197,762	)
Ionis’ stand-alone net loss							(246,702	)
Net loss available to Ionis common stockholders						$	(444,464	)
Weighted average shares outstanding							139,612
Basic net loss per share						$	(3.18	)

We calculated our basic net income per share for the year ended December 31, 2019 as follows (in thousands, except per share amounts):

Year Ended December 31, 2019	Weighted Average Shares Owned in Akcea		Akcea’s Net Income Per Share		Basic Net Income Per Share Calculation
Common shares		70,100	$	0.49	$	34,073
Akcea’s net income attributable to our ownership					$	34,073
Ionis’ stand-alone net income						246,487
Net income available to Ionis common stockholders					$	280,560
Weighted average shares outstanding						139,998
Basic net income per share					$	2.00

Diluted net income (loss) per share

For the years ended December 31, 2021 and 2020, we incurred a net loss; therefore, we did not include dilutive common equivalent shares in the computation of diluted net loss per share because the effect would have been anti-dilutive. Common stock underlying the following would have had an anti-dilutive effect on net loss per share:

●

0.125 percent convertible senior notes, or 0.125% Notes;

●

Note hedges related to the 0.125% Notes;

●

1 percent convertible senior notes, or 1% Notes;

●

Dilutive stock options;

●

Unvested restricted stock units, or RSUs;

●

Unvested performance restricted stock units, or PRSUs; and

●

Employee Stock Purchase Plan, or ESPP.

For the year ended December 31, 2021, common stock underlying the following would also have had an anti-dilutive effect on net loss per share:

●

0 percent convertible senior notes, or 0% Notes; and

●

Note hedges related to the 0% Notes.

Additionally as of December 31, 2021, we had warrants related to our 0 percent and 0.125 percent Notes outstanding. We will include the shares issuable under these warrants in our calculation of diluted earnings per share when the average market price per share of our common stock for the reporting period exceeds the strike price of the warrants.

For the year ended December 31, 2019, we reported net income available to Ionis common stockholders. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during each period. We calculated our diluted net income per share as follows (in thousands except per share amounts):

Year Ended December 31, 2019	Net Income Available to Ionis Common Stockholders (Numerator)		Shares (Denominator)		Per-Share Amount
Net income available to Ionis common stockholders	$	280,560		139,998	$	2.00
Effect of dilutive securities:
Shares issuable upon exercise of stock options		—		2,090
Shares issuable upon restricted stock award issuance		—		766
Shares issuable related to our ESPP		—		18
Shares issuable related to our 0.125 percent convertible notes		860		217
Shares issuable related to our 1 percent convertible notes		9,527		10,075
	$	290,947		153,164	$	1.90

Revenue Recognition

Our Revenue Sources

We generally recognize revenue when we have satisfied all contractual obligations and are reasonably assured of collecting the resulting receivable. We are often entitled to bill our customers and receive payment from our customers in advance of recognizing the revenue. In the instances in which we have received payment from our customers in advance of recognizing revenue, we include the amounts in deferred revenue on our consolidated balance sheet.

At contract inception, we analyze our collaboration arrangements to assess whether such arrangements involve joint operating activities performed by parties that are both active participants in the activities and exposed to significant risks and rewards dependent on the commercial success of such activities and therefore within the scope of ASC Topic 808, Collaborative Arrangements (ASC 808). For collaboration arrangements within the scope of ASC 808 that contain multiple elements, we first determine which elements of the collaboration reflect a vendor-customer relationship and therefore within the scope of ASC 606. When we determine elements of a collaboration do not reflect a vendor-customer relationship, we consistently apply the reasonable and rational policy election we made by analogizing to authoritative accounting literature.

We evaluate the income statement classification for presentation of amounts due from or owed to other participants associated with multiple activities in a collaboration arrangement based on the nature of each separate activity. For example, in our eplontersen collaboration with AstraZeneca, we recognize funding received from AstraZeneca for co-development activities as revenue. While, we recognize cost sharing payments to and from AstraZeneca associated with co-commercialization activities and co-medical affairs activities as SG&A expense and research and development expense, respectively.

Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue

We earn commercial revenue primarily in the form of royalty payments on net sales of SPINRAZA. We will also recognize as commercial revenue sales milestone payments and royalties we earn under our other partnerships.

Commercial Revenue: TEGSEDI and WAYLIVRA revenue, net

We began commercializing TEGSEDI and WAYLIVRA in Europe in January 2021 and TEGSEDI in North America in April 2021 through distribution agreements with Swedish Orphan Biovitrum AB, or Sobi. Under our agreements, we are responsible for supplying finished goods inventory to Sobi and Sobi is responsible for selling each medicine to the end customer. As a result of these agreements, we earn a distribution fee on net sales from Sobi for each medicine.

Prior to the second quarter of 2021 in North America, we sold TEGSEDI through exclusive distribution agreements with third-party logistics companies, or 3PLs, that took title to TEGSEDI. The 3PLs then distributed TEGSEDI to a specialty pharmacy and a specialty distributor, which we collectively refer to as wholesalers, who then distributed TEGSEDI to health care providers and patients. In the United States, or U.S., we had a single 3PL as our sole customer and in Canada we also had a single 3PL as our sole customer. Prior to 2021 in Europe, we sold TEGSEDI and WAYLIVRA to hospitals and pharmacies, which were our customers, using 3PLs as distributors.

Under our collaboration agreement with PTC Therapeutics International Limited, or PTC, PTC is responsible for commercializing TEGSEDI and WAYLIVRA in Latin America and Caribbean countries. In the third quarter of 2021, we earned a $4 million milestone payment from PTC when WAYLIVRA was approved in Brazil, which we included in TEGSEDI and WAYLIVRA revenue in our consolidated statement of operations. Under our agreement, we started receiving royalties from PTC for TEGSEDI sales beginning in December 2021.

Research and development revenue under collaborative agreements

We often enter into collaboration agreements to license and sell our technology on an exclusive or non-exclusive basis. Our collaboration agreements typically contain multiple elements, or performance obligations, including technology licenses or options to obtain technology licenses, research and development, or R&D, services, and manufacturing services.

We provide details about our collaboration agreements in Note 6, Collaborative Arrangements and Licensing Agreements. For each collaboration, we discuss our specific revenue recognition conclusions, including our significant performance obligations under each collaboration.

Steps to Recognize Revenue

We use a five-step process to determine the amount of revenue we should recognize and when we should recognize it. The five step process is as follows:

Identify the contract

Accounting rules require us to first determine if we have a contract with our partner, including confirming that we have met each of the following criteria:

●

We and our partner approved the contract and we are both committed to perform our obligations;

●

We have identified our rights, our partner’s rights and the payment terms;

●

We have concluded that the contract has commercial substance, meaning that the risk, timing, or amount of our future cash flows is expected to change as a result of the contract; and

●

We believe collectability of the consideration is probable.

Identify the performance obligations

We next identify our performance obligations, which represent the distinct goods and services we are required to provide under the contract.

Often we enter into a collaboration agreement in which we provide our partner with an option to license a medicine in the future. We may also provide our partner with an option to request that we provide additional goods or services in the future, such as active pharmaceutical ingredient, or API. We evaluate whether these options are material rights at the inception of the agreement. If we determine an option is a material right, we will consider the option a separate performance obligation. Historically, we have concluded that the options we grant to license a medicine in the future or to provide additional goods and services as requested by our partner are not material rights because these items are contingent upon future events that may not occur and are not priced at a significant discount. When a partner exercises its option to license a medicine or requests additional goods or services, then we identify a new performance obligation for that item.

In some cases, we deliver a license at the start of an agreement. If we determine that our partner has full use of the license and we do not have any additional material performance obligations related to the license after delivery, then we consider the license to be a separate performance obligation. For example, in the fourth quarter of 2021, we received a $200 million upfront payment when we entered into an agreement with AstraZeneca to jointly develop and commercialize eplontersen. We recognized the upfront payment in full in the fourth quarter of 2021 because we did not have any remaining performance obligations after we delivered the license to AstraZeneca.

Determine the transaction price

We then determine the transaction price by reviewing the amount of consideration we are eligible to earn under the collaboration agreement, including any variable consideration. Under our collaboration agreements, consideration typically includes fixed consideration in the form of an upfront payment and variable consideration in the form of potential milestone payments, license fees and royalties. At the start of an agreement, our transaction price usually consists of only the upfront payment. We do not typically include any payments we may receive in the future in our initial transaction price because the payments are not probable and are contingent on certain future events. We reassess the total transaction price at each reporting period to determine if we should include additional payments in the transaction price.

Milestone payments are our most common type of variable consideration. We recognize milestone payments using the most likely amount method because we will either receive the milestone payment or we will not, which makes the potential milestone payment a binary event. The most likely amount method requires us to determine the likelihood of earning the milestone payment. We include a milestone payment in the transaction price once it is probable we will achieve the milestone event. Most often, we do not consider our milestone payments probable until we or our partner achieve the milestone event because the majority of our milestone payments are contingent upon events that are not within our control and/ or are usually based on scientific progress which is inherently uncertain. For example, in the fourth quarter of 2021, we earned a $10 million milestone payment from AstraZeneca when AstraZeneca advanced a target for a metabolic disease. We did not consider the milestone payment probable until AstraZeneca achieved the milestone event because advancing the target was contingent on AstraZeneca initiating a Phase 1 study and was not within our control. We recognized the milestone payment in full in the period the milestone event was achieved because we did not have any remaining performance obligations related to the milestone payment.

Allocate the transaction price

Next, we allocate the transaction price to each of our performance obligations. When we have to allocate the transaction price to more than one performance obligation, we make estimates of the relative stand-alone selling price of each performance obligation because we do not typically sell our goods or services on a stand-alone basis. We then allocate the transaction price to each performance obligation based on the relative stand-alone selling price. We do not reallocate the transaction price after the start of an agreement to reflect subsequent changes in stand-alone selling prices.

We may engage a third party, independent valuation specialist to assist us with determining a stand-alone selling price for collaborations in which we deliver a license at the start of an agreement. We estimate the stand-alone selling price of these licenses using valuation methodologies, such as the relief from royalty method. Under this method, we estimate the amount of income, net of taxes, for the license. We then discount the projected income to present value. The significant inputs we use to determine the projected income of a license could include:

●

Estimated future product sales;

●

Estimated royalties we may receive from future product sales;

●

Estimated contractual milestone payments we may receive;

●

Expenses we expect to incur;

●

Estimated income taxes; and

●

A discount rate.

We typically estimate the selling price of R&D services by using our internal estimates of the cost to perform the specific services. The significant inputs we use to determine the selling price of our R&D services include:

●

The number of internal hours we estimate we will spend performing these services;

●

The estimated cost of work we will perform;

●

The estimated cost of work that we will contract with third parties to perform; and

●

The estimated cost of API we will use.

For purposes of determining the stand-alone selling price of the R&D services we perform and the API we will deliver, accounting guidance requires us to include a markup for a reasonable profit margin.

Recognize revenue

We recognize revenue in one of two ways, over time or at a point in time. We recognize revenue over time when we are executing on our performance obligation over time and our partner receives benefit over time. For example, we recognize revenue over time when we provide R&D services. We recognize revenue at a point in time when our partner receives full use of an item at a specific point in time. For example, we recognize revenue at a point in time when we deliver a license or API to a partner.

For R&D services that we recognize over time, we measure our progress using an input method. The input methods we use are based on the effort we expend or costs we incur toward the satisfaction of our performance obligation. We estimate the amount of effort we expend, including the time we estimate it will take us to complete the activities, or costs we incur in a given period, relative to the estimated total effort or costs to satisfy the performance obligation. This results in a percentage that we multiply by the transaction price to determine the amount of revenue we recognize each period. This approach requires us to make numerous estimates and use significant judgement. If our estimates or judgements change over the course of the collaboration, they may affect the timing and amount of revenue that we recognize in the current and future periods. Refer to Note 6, Collaborative Arrangements and Licensing Agreements, for further discussion of the cumulative catch up adjustment we made.

The following are examples of when we typically recognize revenue based on the types of payments we receive.

Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue

We recognize royalty revenue, including royalties from SPINRAZA sales, in the period in which the counterparty sells the related product and recognizes the related revenue, which in certain cases may require us to estimate our royalty revenue.

Commercial Revenue: TEGSEDI and WAYLIVRA revenue, net

Under our distribution agreements with Sobi we concluded that our performance obligation is to provide services to Sobi over the term of the agreement, which includes supplying finished goods inventory to Sobi and because we retained the marketing authorization for TEGSEDI and WAYLIVRA we are responsible for leading the global commercial strategy for each medicine. We view this performance obligation as a series of distinct activities that are substantially the same. Therefore, we recognize as revenue the price Sobi pays us for the inventory when we deliver the finished goods inventory to Sobi. We also recognize distribution fee revenue based on Sobi’s net sales of TEGSEDI and WAYLIVRA in the period in which the sales occurred. Under our agreements with Sobi, Sobi does not generally have a right of return.

Prior to our distribution agreements with Sobi, we recognized TEGSEDI and WAYLIVRA commercial revenue in the period when our customer obtained control of our products, which occurred at a point in time upon transfer of title to the customer. We classified payments to customers or other parties in the distribution channel for services that were distinct and priced at fair value as selling, general and administrative, or SG&A, expenses in our consolidated statements of operations. We classified payments to customers or other parties in the distribution channel that did not meet those criteria as a reduction of revenue, as discussed further below. We excluded from revenues taxes collected from customers relating to TEGSEDI and WAYLIVRA commercial revenue and remitted these amounts to governmental authorities.

Reserves for TEGSEDI and WAYLIVRA commercial revenue

Prior to our distribution agreements with Sobi, we recorded TEGSEDI and WAYLIVRA commercial revenue at our net sales price, or transaction price. We included in our transaction price estimated reserves for discounts, returns, chargebacks, rebates and other allowances that we offered within contracts between us and our customers, wholesalers, distributors, health care providers and other indirect customers. We estimated our reserves using the amounts we have earned or we could claim on the associated sales. We classified our reserves as a reduction of accounts receivable when we were not required to make a payment or as a current liability when we were required to make a payment. In certain cases, our estimates included a range of possible outcomes that were probability weighted for relevant factors such as our historical experience, current contractual and statutory requirements, specific known market events and trends, industry data and forecasted customer buying and payment patterns. Overall, our reserves reflected our best estimates under the terms of our respective contracts. When calculating our reserves and related TEGSEDI and WAYLIVRA commercial revenue, we only recognized amounts to the extent that we considered it probable that we would not have to reverse a significant amount of the cumulative sales we previously recognized in a future period. Under our agreements with Sobi, we transferred all reserves to Sobi.

The following were the components of variable consideration related to TEGSEDI and WAYLIVRA product sales prior to our agreements with Sobi:

Chargebacks: In the U.S., we estimated obligations resulting from contractual commitments with the government and other entities to sell products to qualified healthcare providers at prices lower than the list prices charged to our U.S. customer. Our U.S. customer charged us for the difference between what it paid for the product and the selling price to the qualified healthcare providers. We also estimated the amount of chargebacks related to our estimated product remaining in the distribution channel at the end of the reporting period that we expected our customer to sell to healthcare providers in future periods. We recorded these reserves as a reduction to contracts receivable on our consolidated balance sheet.

Government rebates: We were subject to discount obligations under government programs, including Medicaid and Medicare programs in the U.S. and we recorded reserves for government rebates based on statutory discount rates and estimated utilization. We estimated Medicaid and Medicare rebates based on a range of possible outcomes that were probability weighted for the estimated payer mix. We recorded these reserves as an accrued liability on our consolidated balance sheet with a corresponding offset reducing our product sales in the same period we recognized the related sale. For Medicare, we also estimated the number of patients in the prescription drug coverage gap for whom we would owe an additional liability under the Medicare Part D program. On a quarterly basis, we updated our estimates and recorded any adjustments in the period that we identified the adjustments.

Managed care rebates: We were subject to rebates in connection with agreements with certain contracted commercial payers. We recorded these rebates as a liability on our consolidated balance sheet in the same period we recognized the related revenue. We estimated our managed care rebates based on our estimated payer mix and the applicable contractual rebate rate.

Trade discounts: We provided customary invoice discounts on product sales to our U.S. customer for prompt payment. We recorded this discount as a reduction of product sales in the period in which we recognized the related product revenue.

Distribution services: We received and paid for various distribution services from our U.S. and European customers (prior to our agreement with Sobi) and wholesalers in the U.S. We classified the costs for services we received that are either not distinct from the sale of the product or for which we could not reasonably estimate the fair value as a reduction of product sales. To the extent that the services we received are distinct from the sale of the product, we classified the costs for such services as SG&A expenses.

Product returns: Our U.S. customer had return rights and the wholesalers had limited return rights primarily related to the product’s expiration date. We estimated the amount of product sales that our customer may return. We recorded our return estimate as an accrued refund liability on our consolidated balance sheet with a corresponding offset reducing our product sales in the same period we recognized the related sale. Based on our distribution model for product sales, contractual inventory limits with our customer and wholesalers and the price of the product, we had minimal returns. Our European customers generally only took title to the product after they received an order and therefore they did not maintain excess inventory levels of our products. Accordingly, we had limited return risk in Europe and we did not estimate returns in Europe.

Research and development revenue under collaboration agreements:

Upfront payments

When we enter into a collaboration agreement with an upfront payment, we typically record the entire upfront payment as deferred revenue if our only performance obligation is for R&D services we will provide in the future. We amortize the upfront payment into revenue as we perform the R&D services. For example, under our collaboration agreement with Roche to develop IONIS-FB-L_Rx for the treatment of complement-mediated diseases, we received a $75 million upfront payment in the fourth quarter of 2018. We allocated the upfront payment to our single performance obligation, R&D services. We are amortizing the $75 million upfront payment using an input method over the estimated period of time we are providing R&D services.

Milestone payments

We are required to include additional consideration in the transaction price when it is probable. We typically include milestone payments for R&D services in the transaction price when they are achieved. We include these milestone payments when they are achieved because typically there is considerable uncertainty in the research and development processes that trigger these payments. Similarly, we include approval milestone payments in the transaction price once the medicine is approved by the applicable regulatory agency. We will recognize sales-based milestone payments in the period in which we achieve the milestone under the sales-based royalty exception allowed under accounting rules.

We recognize milestone payments that relate to an ongoing performance obligation over our period of performance. For example, in the fourth quarter of 2021, we achieved a $7.5 million milestone payment from Biogen when we advanced a target under our 2018 strategic collaboration. We added this payment to the transaction price and allocated it to our R&D services performance obligation. We are recognizing revenue related to this milestone payment over our estimated period of performance.

Conversely, we recognize in full those milestone payments that we earn based on our partners’ activities when our partner achieves the milestone event and we do not have a performance obligation. For example, in the fourth quarter of 2021, we recognized $15 million in milestone payments when Biogen advanced two targets under our 2018 strategic collaboration. We concluded that the milestone payments were not related to our R&D services performance obligation. Therefore, we recognized the milestone payments in full in the fourth quarter of 2021.

License fees

We generally recognize as revenue the total amount we determine to be the relative stand-alone selling price of a license when we deliver the license to our partner. This is because our partner has full use of the license and we do not have any additional performance obligations related to the license after delivery. For example, in the fourth quarter of 2021, we earned a $60 million license fee from Biogen when Biogen licensed ION306, an investigational medicine in development to treat SMA.

Sublicense fees

We recognize sublicense fee revenue in the period in which a party, who has already licensed our technology, further licenses the technology to another party because we do not have any performance obligations related to the sublicense. For example, in the fourth quarter of 2020, we earned a $41.2 million sublicense fee from Alnylam Pharmaceuticals for its sublicense of our technology to Sanofi Genzyme.

Amendments to Agreements

From time to time we amend our collaboration agreements. When this occurs, we are required to assess the following items to determine the accounting for the amendment:

If the additional goods and/or services are distinct from the other performance obligations in the original agreement; and

If the goods and/or services are at a stand-alone selling price.

If we conclude the goods and/or services in the amendment are distinct from the performance obligations in the original agreement and at a stand-alone selling price, we account for the amendment as a separate agreement. If we conclude the goods and/or services are not distinct and are sold at a stand-alone selling price, we then assess whether the remaining goods or services are distinct from those already provided. If the goods and/or services are distinct from what we have already provided, then we allocate the remaining transaction price from the original agreement and the additional transaction price from the amendment to the remaining goods and/or services. If the goods and/or services are not distinct from what we have already provided, we update the transaction price for our single performance obligation and recognize any change in our estimated revenue as a cumulative adjustment.

For example, in May 2015, we entered into an exclusive license agreement with Bayer to develop and commercialize IONIS-FXI_Rx for the prevention of thrombosis. As part of the agreement, Bayer paid us a $100 million upfront payment. At the onset of the agreement, we were responsible for completing a Phase 2 study of IONIS-FXI_Rx in people with end-stage renal disease on hemodialysis and for providing an initial supply of API. In February 2017, we amended our agreement with Bayer to advance IONIS-FXI_Rx and to initiate development of fesomersen, which Bayer licensed. As part of the 2017 amendment, Bayer paid us $75 million. We are also eligible to receive milestone payments and tiered royalties on gross margins of IONIS-FXI_Rx and fesomersen. Under the 2017 amendment, we concluded we had a new agreement with three performance obligations. These performance obligations were to deliver the license of fesomersen, to provide R&D services and to deliver API. We allocated the $75 million transaction price to these performance obligations. Refer to Note 6, Collaborative Arrangements and Licensing Agreements, for further discussion of the Bayer collaboration.

Multiple agreements

From time to time, we may enter into separate agreements at or near the same time with the same partner. We evaluate such agreements to determine whether we should account for them individually as distinct arrangements or whether the separate agreements should be combined and accounted for together. We evaluate the following to determine the accounting for the agreements:

●

Whether the agreements were negotiated together with a single objective;

●

Whether the amount of consideration in one contract depends on the price or performance of the other agreement; or

●

Whether the goods and/or services promised under the agreements are a single performance obligation.

Our evaluation involves significant judgment to determine whether a group of agreements might be so closely related that accounting guidance requires us to account for them as a combined arrangement.

For example, in the second quarter of 2018, we entered into two separate agreements with Biogen at the same time: a new strategic neurology collaboration agreement and a stock purchase agreement, or SPA. We evaluated the Biogen agreements to determine whether we should treat the agreements separately or combine them. We considered that the agreements were negotiated concurrently and in contemplation of one another. Based on these facts and circumstances, we concluded that we should evaluate the provisions of the agreements on a combined basis.

Contracts Receivable

Our contracts receivable balance represents the amounts we have billed our partners or customers and that are due to us unconditionally for goods we have delivered or services we have performed. When we bill our partners or customers with payment terms based on the passage of time, we consider the contracts receivable to be unconditional. We typically receive payment within one quarter of billing our partner or customer.

As of December 31, 2021, approximately 93.8 percent of our contracts receivables were from two significant customers. As of December 31, 2020, approximately 99.5 percent of our contracts receivables were from two significant customers.

Unbilled SPINRAZA Royalties

Our unbilled SPINRAZA royalties represent our right to receive consideration from Biogen in advance of when we are eligible to bill Biogen for SPINRAZA royalties. We include these unbilled amounts in other current assets on our consolidated balance sheet.

Deferred Revenue

We are often entitled to bill our customers and receive payment from our customers in advance of our obligation to provide services or transfer goods to our partners. In these instances, we include the amounts in deferred revenue on our consolidated balance sheet. During the years ended December 31, 2021 and 2020, we recognized $98.1 million and $100.4 million of revenue from amounts that were in our beginning deferred revenue balance for each respective period. For further discussion, refer to our revenue recognition policy above.

Cost of Sales

Our cost of sales includes manufacturing costs, transportation and freight costs and indirect overhead costs associated with the manufacturing and distribution of our products. We also may include certain period costs related to manufacturing services and inventory adjustments in cost of sales. We also may include certain period costs related to manufacturing services and inventory adjustments in cost of sales.

Research, Development and Patent Expenses

Our research and development expenses include wages, benefits, facilities, supplies, external services, clinical trial and manufacturing costs and other expenses that are directly related to our research and development operations. We expense research and development costs as we incur them. When we make payments for research and development services prior to the services being rendered, we record those amounts as prepaid assets on our consolidated balance sheet and we expense them as the services are provided. For the years ended December 31, 2021, 2020 and 2019, research and development expenses were $638.2 million, $531.0 million and $461.5 million, respectively. A portion of the costs included in research and development expenses are costs associated with our partner agreements.

We capitalize costs consisting principally of outside legal costs and filing fees related to obtaining patents. We amortize patent costs over the useful life of the patent, beginning with the date the U.S. Patent and Trademark Office, or foreign equivalent, issues the patent. The weighted average remaining amortizable life of our issued patents was 10.2 years at December 31, 2021.

The cost of our patents capitalized on our consolidated balance sheet at December 31, 2021 and 2020 was $38.4 million and $37.0 million, respectively. Accumulated amortization related to patents was $9.4 million and $9.1 million at December 31, 2021 and 2020, respectively.

Based on our existing patents, we estimate amortization expense related to patents in each of the next five years to be the following:

Year Ending December 31,	Amortization (in millions)
2022	$	2.2
2023	$	2.1
2024	$	1.9
2025	$	1.8
2026	$	1.8

We review our capitalized patent costs regularly to ensure that they include costs for patents and patent applications that have future value. When we identify patents and patent applications that we are not actively pursuing, we write off any associated costs. In 2021, 2020 and 2019, patent expenses were $5.3 million, $4.1 million and $4.2 million, respectively, and included non-cash charges related to the write-down of our patent costs to their estimated net realizable values of $2.7 million, $1.9 million and $2.2 million, respectively.

Accrued Liabilities

Our accrued liabilities consisted of the following (in thousands):

	December 31,
	2021		2020
Clinical expenses	$	65,730	$	39,477
In-licensing expenses		8,044		8,264
Commercial expenses		2,471		11,559
Other miscellaneous expenses		12,315		30,861
Total accrued liabilities	$	88,560	$	90,161

Estimated Liability for Clinical Development Costs

We have numerous medicines in preclinical studies and/or clinical trials at clinical sites throughout the world. On at least a quarterly basis, we estimate our liability for preclinical and clinical development costs we have incurred and services that we have received but for which we have not yet been billed and maintain an accrual to cover these costs. These costs primarily relate to third-party clinical management costs, laboratory and analysis costs, toxicology studies and investigator grants. We estimate our liability using assumptions about study and patient activities and the related expected expenses for those activities determined based on the contracted fees with our service providers. The assumptions we use represent our best estimates of the activity and expenses at the time of our accrual and involve inherent uncertainties and the application of our judgment. Upon settlement, these costs may differ materially from the amounts accrued in our consolidated financial statements. Our historical accrual estimates have not been materially different from our actual amounts.

Noncontrolling Interest in Akcea Therapeutics, Inc.

Since Akcea’s IPO in July 2017 and prior to the Akcea Merger in October 2020, the shares of Akcea’s common stock third parties owned represented an interest in Akcea’s equity that we did not control. During this period our ownership ranged from 68 percent to 77 percent. However, as we maintained overall control of Akcea through our voting interest, we reflected the assets, liabilities and results of operations of Akcea in our consolidated financial statements. Since Akcea’s IPO in July 2017 and through the closing of the Akcea Merger, we reflected the noncontrolling interest attributable to other owners of Akcea’s common stock on a separate line on our statement of operations and a separate line within stockholders’ equity in our consolidated balance sheet. In addition, through the closing of the Akcea Merger, we recorded a noncontrolling interest adjustment to account for the stock options Akcea granted, which if exercised, would have diluted our ownership in Akcea. This adjustment was a reclassification within stockholders’ equity from additional paid-in capital to noncontrolling interest in Akcea equal to the amount of stock-based compensation expense Akcea had recognized. Additionally, we reflected changes in our ownership percentage in our financial statements as an adjustment to noncontrolling interest in the period the change occurred.

Concentration of Credit Risk

Financial instruments that potentially subject us to concentrations of credit risk consist primarily of cash equivalents, short-term investments and receivables. We place our cash equivalents and short-term investments with reputable financial institutions. We primarily invest our excess cash in commercial paper and debt instruments of the U.S. Treasury, financial institutions, corporations, and U.S. government agencies with strong credit ratings and an investment grade rating at or above A-1, P-1 or F-1 by Moody’s, Standard & Poor’s, or S&P, or Fitch, respectively. We have established guidelines relative to diversification and maturities that maintain safety and liquidity. We periodically review and modify these guidelines to maximize trends in yields and interest rates without compromising safety and liquidity.

Cash, Cash Equivalents and Investments

We consider all liquid investments with maturities of three months or less when we purchase them to be cash equivalents. Our short-term investments have initial maturities of greater than three months from date of purchase. We classify our short-term debt investments as “available-for-sale” and carry them at fair market value based upon prices on the last day of the fiscal period for identical or similar items. We record unrealized gains and losses on debt securities as a separate component of comprehensive income (loss) and include net realized gains and losses in gain (loss) on investments in our consolidated statement of operations. We use the specific identification method to determine the cost of securities sold.

We also have equity investments of less than 20 percent ownership in publicly and privately held biotechnology companies that we received as part of a technology license or partner agreement. At December 31, 2021, we held equity investments in three publicly held companies, Antisense Therapeutics Limited, or ATL, Bicycle Therapeutics plc, or Bicycle, and ProQR Therapeutics N.V., or ProQR. We also held equity investments in seven privately-held companies, Aro Biotherapeutics, Atlantic Pharmaceuticals Limited, Dynacure SAS, Empirico, Inc., Flamingo Therapeutics BV, YourBio Health, Inc. (formerly Seventh Sense Biosystems) and Suzhou-Ribo Life Science Co, Ltd.

We are required to measure and record our equity investments at fair value and to recognize the changes in fair value in our consolidated statement of operations. We account for our equity investments in privately held companies at their cost minus impairments, plus or minus changes resulting from observable price changes in orderly transactions for the identical or similar investment of the same issuer. For example, during 2020, we revalued our investments in three privately held companies, Dynacure, Suzhou-Ribo and Aro Biotherapeutics because the companies sold additional equity securities that were similar to the equity we own. As a result of these observable price changes, we recognized a $6.3 million gain on our investment in Dynacure, a $3.0 million gain on our investment in Suzhou-Ribo and a $5.5 million gain on our investment in Aro Biotherapeutics in our consolidated statement of operations during 2020 because the sales were at higher prices compared to our recorded value.

Inventory Valuation

We reflect our inventory on our consolidated balance sheet at the lower of cost or net realizable value under the first-in, first-out method, or FIFO. We capitalize the costs of raw materials that we purchase for use in producing our medicines because until we use these raw materials, they have alternative future uses, which we refer to as clinical raw materials. We include in inventory raw material costs for medicines that we manufacture for our partners under contractual terms and that we use primarily in our clinical development activities and drug products. We can use each of our raw materials in multiple products and, as a result, each raw material has future economic value independent of the development status of any single medicine. For example, if one of our medicines failed, we could use the raw materials for that medicine to manufacture our other medicines. We expense these costs as R&D expenses when we begin to manufacture API for a particular medicine if the medicine has not been approved for marketing by a regulatory agency. Our raw materials- commercial inventory includes API for our commercial medicines. We capitalize material, labor and overhead costs as part of our raw materials- commercial inventory.

We review our inventory periodically and reduce the carrying value of items we consider to be slow moving or obsolete to their estimated net realizable value based on forecasted demand compared to quantities on hand. We consider several factors in estimating the net realizable value, including shelf life of our inventory, alternative uses for our medicines in development and historical write-offs. We recorded an insignificant amount of inventory write-offs during the years ended December 31, 2021 and 2020.

Our inventory consisted of the following (in thousands):

	December 31,
	2021		2020
Raw materials:
Raw materials- clinical	$	14,507	$	9,206
Raw materials- commercial		4,139		7,502
Total raw materials		18,646		16,708
Work in process		5,770		2,252
Finished goods		390		3,005
Total inventory	$	24,806	$	21,965

Property, Plant and Equipment

We carry our property, plant and equipment at cost and depreciate it on the straight-line method over its estimated useful life, which consists of the following (in thousands):

	Estimated Useful	December 31,
	Lives (in years)	2021			2020
Computer software, laboratory, manufacturing and other equipment	3 to 10	$	72,802		$	68,990
Building, building improvements and building systems	15 to 40		144,046			137,879
Land improvements	20		10,077			8,391
Leasehold improvements	5 to 15		20,144			17,263
Furniture and fixtures	5 to 10		10,591			12,871
			257,660			245,394
Less accumulated depreciation			(102,653	)		(87,379	)
			155,007			158,015
Land			23,062			23,062
Total		$	178,069		$	181,077

We depreciate our leasehold improvements using the shorter of the estimated useful life or remaining lease term.

Fair Value of Financial Instruments

We have estimated the fair value of our financial instruments. The amounts reported for cash, accounts receivable, accounts payable and accrued expenses approximate the fair value because of their short maturities. We report our investment securities at their estimated fair value based on quoted market prices for identical or similar instruments.

Leases

We determine if an arrangement contains a lease at inception. We currently only have operating leases. We recognize a right-of-use operating lease asset and associated short- and long-term operating lease liability on our consolidated balance sheet for operating leases greater than one year. Our right-of-use assets represent our right to use an underlying asset for the lease term and our lease liabilities represent our obligation to make lease payments arising from the lease arrangement. We recognize our right-of-use operating lease assets and lease liabilities based on the present value of the future minimum lease payments we will pay over the lease term. We determine the lease term at the inception of each lease, and in certain cases our lease term could include renewal options if we concluded we were reasonably certain that we will exercise the renewal option. When we exercise a lease option that was not previously included in the initial lease term, we reassess our right-of-use asset and lease liabilities for the new lease term.

As our leases do not provide an interest rate implicit in the lease, we used our incremental borrowing rate, based on the information available on the date we adopted Topic 842 (January 2019), as of the lease inception date or at the lease option extension date in determining the present value of future payments. We recognize rent expense for our minimum lease payments on a straight-line basis over the expected term of our lease. We recognize period expenses, such as common area maintenance expenses, in the period we incur the expense.

Long-Lived Assets

We evaluate long-lived assets, which include property, plant and equipment and patent costs, for impairment on at least a quarterly basis and whenever events or changes in circumstances indicate that we may not be able to recover the carrying amount of such assets. We recorded charges of $2.7 million, $1.9 million and $2.2 million for the years ended December 31, 2021, 2020 and 2019, respectively, related to the write-down of patents.

Use of Estimates

We prepare our consolidated financial statements in conformity with accounting principles generally accepted in the U.S. that require us to make estimates and assumptions that affect the amounts reported in our consolidated financial statements and accompanying notes. Actual results could differ from our estimates.

Stock-Based Compensation Expense

We measure stock-based compensation expense for equity-classified awards, principally related to stock options, RSUs, PRSUs and stock purchase rights under our ESPP based on the estimated fair value of the award on the date of grant. We recognize the value of the portion of the award that we ultimately expect to vest as stock-based compensation expense over the requisite service period in our consolidated statements of operations. We reduce stock-based compensation expense for estimated forfeitures at the time of grant and revise in subsequent periods if actual forfeitures differ from those estimates. We use the Black-Scholes model to estimate the fair value of stock options granted and stock purchase rights under our ESPP.

On the grant date, we use our stock price and assumptions regarding a number of variables to determine the estimated fair value of stock-based payment awards. These variables include, but are not limited to, our expected stock price volatility over the term of the awards, and actual and projected employee stock option exercise behaviors. The expected term of stock options granted represents the period of time that we expect them to be outstanding. We estimate the expected term of options granted based on historical exercise patterns.

We recognize compensation expense for stock options granted, RSUs, PRSUs and stock purchase rights under the ESPP using the accelerated multiple-option approach. Under the accelerated multiple-option approach (also known as the graded-vesting method), we recognize compensation expense over the requisite service period for each separately vesting tranche of the award as though the award were in substance multiple awards, which results in the expense being front-loaded over the vesting period.

In December 2020, we amended and restated the Akcea 2015 equity plan, including renaming the plan as the Ionis Pharmaceuticals, Inc. 2020 Equity Incentive Plan, or 2020 Plan. As a result, all employees are now under an Ionis stock plan and subject to the same Black-Scholes assumptions.

RSU’s:

The fair value of RSUs is based on the market price of our common stock on the date of grant. The RSUs we have granted to employees vest annually over a four-year period. The RSUs we granted to our board of directors prior to June 2020 vest annually over a four-year period. RSUs granted to our board of directors after June 2020 fully vest after one year.

PRSU’s:

Beginning in 2020, we added PRSU awards to the compensation for our Chief Executive Officer, Dr. Brett Monia. Under the terms of the grants, one third of the PRSUs may vest at the end of three separate performance periods spread over the three years following the date of grant (i.e., the one-year period commencing on the date of grant and ending on the first anniversary of the date of grant; the two-year period commencing on the date of grant and ending on the second anniversary of the date of grant; and the three-year period commencing on the date of grant and ending on the third anniversary of the date of grant) based on our relative total shareholder return, or TSR, as compared to a peer group of companies, and as measured, in each case, at the end of the applicable performance period. Under the terms of the grants no number of PRSUs is guaranteed to vest and the actual number of PRSUs that will vest at the end of each performance period may be anywhere from zero to 150 percent of the target number depending on our relative TSR.

We determined the fair value of Dr. Monia’s PRSUs using a Monte Carlo model because the performance target is based on our relative TSR, which represents a market condition. We are recognizing the grant date fair value of these awards as stock-based compensation expense using the accelerated multiple-option approach over the vesting period. The weighted-average grant date fair value of PRSUs granted to Dr. Monia for the years ended December 31, 2021 and 2020 were $77.17 and $93.09 per share, respectively.

See Note 4, Stockholders’ Equity, for additional information regarding our stock-based compensation plans.

Accumulated Other Comprehensive Loss

Accumulated other comprehensive loss is comprised of unrealized gains and losses on investments, net of taxes and currency translation adjustments. The following table summarizes changes in accumulated other comprehensive loss for the years ended December 31, 2021, 2020 and 2019 (in thousands):

	Year Ended December 31,
	2021			2020			2019
Beginning balance accumulated other comprehensive loss	$	(21,071	)	$	(25,290	)	$	(32,016	)
Unrealized gains (losses) on securities, net of tax (1)		(11,486	)		3,729			6,633
Currency translation adjustment		(111	)		617			93
Adjustments to other comprehensive loss from purchase of noncontrolling interest of Akcea Therapeutics, Inc.		—			(127	)		—
Net other comprehensive loss for the period		(11,597	)		4,219			6,726
Ending balance accumulated other comprehensive loss	$	(32,668	)	$	(21,071	)	$	(25,290	)

________________

(1)	We did not have tax expense included in our other comprehensive loss for the years ended December 31, 2021 and 2020. For the year ended December 31, 2019, we had a tax benefit of $1.4 million included in other comprehensive loss.

Convertible Debt

Adoption of ASU 2020-06

In August 2020, the FASB issued ASU 2020-06, which simplifies the accounting for convertible debt instruments, amends the guidance on derivative scope exceptions for contracts in an entity’s own equity, and modifies the guidance on diluted earnings per share calculations. We adopted ASU 2020-06 on January 1, 2021 under the full retrospective approach, which required us to revise our prior period financial statements. This guidance impacted our accounting for outstanding convertible debt. At January 1, 2021, we had two outstanding convertible notes, our 0.125% Notes, which mature in December 2024, and our 1% Notes, which matured in November 2021. In April 2021, we completed a $632.5 million offering of 0% Notes primarily to repurchase a majority of our 1% Notes. We accounted for our 0% Notes under ASU 2020-06 at issuance. Refer to Note 3, Long-Term Obligations and Commitments, for further information.

The updated guidance eliminates the cash conversion accounting model we previously followed in Accounting Standard Codification, or ASC, 470-20, which required us to separate each of our convertible debt instruments at issuance into two units of accounting, a liability component, based on our nonconvertible debt borrowing rate at issuance, and an equity component. Under ASU 2020-06, we now account for each of our convertible debt instruments as a single unit of accounting, a liability, because we concluded that the conversion features do not require bifurcation as a derivative under ASC 815-15 and we did not issue our convertible debt instruments at a substantial premium. Since we adopted ASU 2020-06 using the full retrospective approach, we were required to apply the guidance to all convertible debt instruments we had outstanding as of January 1, 2019. We recomputed the basis of each convertible debt instrument as if we accounted for each as a single unit of accounting at issuance. This update included recalculating the amortization of debt issuance costs using an updated effective interest rate. As a result of adopting ASU 2020-06, we recorded a cumulative adjustment to decrease our additional paid in capital and our accumulated deficit at January 1, 2019. We have updated these financial statements to reflect the cumulative adjustment for the periods presented. We have labeled our prior period financial statements “as revised” to indicate the change required under the new accounting guidance. Below is a summary of the change in our balance sheet at December 31, 2020 and statement of operations from the years ended December 31, 2020 and 2019 under the ASC 470-20 legacy guidance compared to the new ASU 2020-06 guidance we adopted:

The following table summarizes the adjustments we made to the consolidated balance sheet we originally reported at December 31, 2020 to adopt ASU 2020-06 (in thousands):

	December 31, 2020
	As Previously Reported			ASU 2020-06 Adjustment			As Revised
1 percent convertible senior notes	$	293,161		$	15,648		$	308,809
0.125 percent convertible senior notes	$	455,719		$	84,417		$	540,136
Additional paid-in-capital	$	2,113,646		$	(218,127	)	$	1,895,519
Accumulated deficit	$	(1,249,368	)	$	118,062		$	(1,131,306	)

Under ASU 2020-06, our revised ending balances for our 1% Notes and 0.125% Notes as of December 31, 2020 represent the principal balance of each convertible debt instrument less debt issuance costs. Additionally, because we have deferred tax assets related to our convertible debt instruments, we also adjusted these amounts as part of our adoption of ASU 2020-06. However, because we have a full valuation allowance on our deferred tax assets, there was no impact to our consolidated balance sheet related to our deferred tax assets.

The following tables summarize the adjustments we made to the consolidated statement of operations we originally reported for the years ended December 31, 2020 and 2019 to adopt ASU 2020-06 (in thousands):

	Year Ended December 31, 2020
	As Previously Reported			ASU 2020-06 Adjustment			As Revised
Interest expense	$	(44,990	)	$	35,480		$	(9,510	)
Loss before income tax expense	$	(170,032	)	$	35,480		$	(134,552	)
Income tax expense	$	(316,734	)	$	(28,457	)	$	(345,191	)
Net loss	$	(486,766	)	$	7,023		$	(479,743	)
Net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders	$	(451,286	)	$	7,023		$	(444,263	)
Basic and diluted net loss per share	$	(3.23	)	$	0.05		$	(3.18	)

	Year Ended December 31, 2019
	As Previously Reported			ASU 2020-06 Adjustment			As Revised
Interest expense	$	(48,768	)	$	36,328		$	(12,440	)
Loss on early retirement of debt		(21,865	)		(44,331	)		(66,196	)
Income before income tax benefit (expense)	$	346,769		$	(8,003	)	$	338,766
Income tax expense	$	(43,507	)	$	(8,000	)	$	(51,507	)
Net income	$	303,262		$	(16,003	)	$	287,259
Net income attributable to Ionis Pharmaceuticals, Inc. common stockholders	$	294,146		$	(16,003	)	$	278,143
Basic net income per share		2.12			(0.12	)		2.00
Diluted net income per share	$	2.08		$	(0.18	)	$	1.90

Under ASU 2020-06, our revised interest expense is lower because we are no longer recording non-cash interest expense related to a debt discount. This decrease was partially offset by the increase in interest expense related to the amortization of debt issuance costs because we no longer allocate a portion of our debt issuance costs to stockholders’ equity at issuance. Instead, the entire debt issuance costs were recorded as a contra-liability on our consolidated balance sheet at issuance and we are amortizing them over the contractual term using an updated effective interest rate. Our updated effective interest rates for our 1% Notes and 0.125% Notes were 1.4 percent and 0.5 percent, respectively.

The following tables summarize the adjustments we made to our consolidated statements of stockholders’ equity we originally reported at December 31, 2020 and 2019 to adopt ASU 2020-06 (in thousands):

	December 31, 2020
	As Previously Reported			ASU 2020-06 Adjustment			As Revised
Additional paid-in-capital	$	2,113,646		$	(218,127	)	$	1,895,519
Accumulated deficit	$	(1,249,368	)	$	118,062		$	(1,131,306	)
Total stockholders’ equity	$	843,347		$	(100,065	)	$	743,282

	December 31, 2019
	As Previously Reported			ASU 2020-06 Adjustment			As Revised
Additional paid-in-capital	$	2,203,778		$	(218,128	)	$	1,985,650
Accumulated deficit	$	(707,534	)	$	111,039		$	(596,495	)
Total stockholders’ equity	$	1,684,547		$	(107,088	)	$	1,577,459

Call Spread

In conjunction with the issuance of our 0% Notes and 0.125% Notes in April 2021 and December 2019, respectively, we entered into call spread transactions, which were comprised of purchasing note hedges and selling warrants. We account for the note hedges and warrants as separate freestanding financial instruments and treat each instrument as a separate unit of accounting. We determined that the note hedges and warrants do not meet the definition of a liability using the guidance contained in ASC Topic 480; therefore, we account for the note hedges and warrants using the Derivatives and Hedging – Contracts in Entity’s Own Equity accounting guidance contained in ASC Topic 815. We determined that the note hedges and warrants meet the definition of a derivative, are indexed to our stock and meet the criteria to be classified in shareholders’ equity. We recorded the aggregate amount paid for the note hedges and the aggregate amount received for the warrants as additional paid-in capital in our consolidated balance sheet. We reassess our ability to continue to classify the note hedges and warrants in shareholders’ equity at each reporting period.

Segment Information

In 2021, we began operating as a single segment, Ionis operations, because our chief decision maker reviews operating results on an aggregate basis and manages our operations as a single operating segment. Previously, we had operated as two operating segments, Ionis Core and Akcea Therapeutics. We completed the Akcea Merger in October 2020 and fully integrated Akcea’s operations into ours as of January 1, 2021.

Fair Value Measurements

We use a three-tier fair value hierarchy to prioritize the inputs used in our fair value measurements. These tiers include: Level 1, defined as observable inputs such as quoted prices in active markets for identical assets, which includes our money market funds and treasury securities classified as available-for-sale securities and our investment in equity securities in publicly held biotechnology companies; Level 2, defined as inputs other than quoted prices in active markets that are either directly or indirectly observable, which includes our fixed income securities and commercial paper classified as available-for-sale securities; and Level 3, defined as unobservable inputs in which little or no market data exists, therefore requiring us to develop our own assumptions. We classify most of our securities as Level 2. We obtain the fair value of our Level 2 investments from our custodian bank or from a professional pricing service. We validate the fair value of our Level 2 investments by understanding the pricing model used by the custodian banks or professional pricing service provider and comparing that fair value to the fair value based on observable market prices.

The following tables present the major security types we held at December 31, 2021 and 2020 that we regularly measure and carry at fair value. As of December 31, 2021, our Bicycle investment was subject to trading restrictions that extend to the third quarter of 2022; as a result, we included a lack of marketability discount in valuing this investment, which is a Level 3 input. As of December 31, 2020, we did not have any investments that we valued using Level 3 inputs. The following tables segregate each security type by the level within the fair value hierarchy of the valuation techniques we utilized to determine the respective securities’ fair value (in thousands):

	At December 31, 2021		Quoted Prices in Active Markets (Level 1)		Significant Other Observable Inputs (Level 2)		Significant Unobservable Inputs (Level 3)
Cash equivalents (1)	$	541,199	$	541,199	$	—	$	—
Corporate debt securities (2)		764,059		—		764,059		—
Debt securities issued by U.S. government agencies (2)		120,868		—		120,868		—
Debt securities issued by the U.S. Treasury (2)		182,634		182,634		—		—
Debt securities issued by states of the U.S. and political subdivisions of the states (3)		174,464		—		174,464		—
Other municipal debt securities (2)		6,099		—		6,099		—
Investment in Bicycle Therapeutics plc (4)		14,330		—		—		14,330
Investment in ProQR Therapeutics N.V. (4)		3,875		3,875		—		—
Total	$	1,807,528	$	727,708	$	1,065,490	$	14,330

	At December 31, 2020		Quoted Prices in Active Markets (Level 1)		Significant Other Observable Inputs (Level 2)
Cash equivalents (1)	$	221,125	$	221,125	$	—
Corporate debt securities (5)		846,315		—		846,315
Debt securities issued by U.S. government agencies (2)		174,861		—		174,861
Debt securities issued by the U.S. Treasury (6)		358,497		358,497		—
Debt securities issued by states of the U.S. and political subdivisions of the states (2)		136,309		—		136,309
Other municipal debt securities (2)		6,225		—		6,225
Investment in ProQR Therapeutics N.V. (4)		2,031		2,031		—
Total	$	1,745,363	$	581,653	$	1,163,710

________________

(1)	Included in cash and cash equivalents on our consolidated balance sheet.

(2)	Included in short-term investments.

(3)	$2.3 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.

(4)	Included in other current assets on our consolidated balance sheet.

(5)	$10.0 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.

(6)	$17.5 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.

Convertible Notes

Our 0.125% Notes and 0% Notes had a fair value of $495.4 million and $559.2 million at December 31, 2021, respectively. We determine the fair value of our notes based on quoted market prices for these notes, which are Level 2 measurements because the notes do not trade regularly.

Income Taxes

We account for income taxes using the asset and liability method, which requires the recognition of deferred tax assets and liabilities for the expected future tax consequences of events that have been recognized in our financial statements or tax returns. In addition, deferred tax assets are recorded for the future benefit of utilizing net operating losses and research and development credit carryforwards. We record a valuation allowance when necessary to reduce our net deferred tax assets to the amount expected to be realized.

We apply the authoritative accounting guidance prescribing a threshold and measurement attribute for the financial recognition and measurement of a tax position taken or expected to be taken in a tax return. We recognize liabilities for uncertain tax positions based on a two-step process. The first step is to evaluate the tax position for recognition by determining if the weight of available evidence indicates that it is more likely than not that the position will be sustained on audit, including resolution of related appeals or litigation processes, if any. The second step requires us to estimate and measure the tax benefit as the largest amount that is more than 50 percent likely to be realized upon ultimate settlement.

We are required to use significant judgment in evaluating our uncertain tax positions and determining our provision for income taxes. Although we believe our reserves are reasonable, no assurance can be given that the final tax outcome of these matters will not be different from that which is reflected in our historical income tax provisions and accruals. We adjust these reserves for changing facts and circumstances, such as the closing of a tax audit or the refinement of an estimate. To the extent that the final tax outcome of these matters is different than the amounts recorded, such differences may impact the provision for income taxes in the period in which such determination is made.

We are also required to use significant judgment in determining any valuation allowance recorded against our deferred tax assets. In assessing the need for a valuation allowance, we consider all available evidence, including scheduled reversal of deferred tax liabilities, past operating results, the feasibility of tax planning strategies and estimates of future taxable income. We base our estimates of future taxable income on assumptions that are consistent with our plans. The assumptions we use represent our best estimates and involve inherent uncertainties and the application of our judgment. Should actual amounts differ from our estimates, the amount of our tax expense and liabilities we recognize could be materially impacted. We record a valuation allowance to reduce the balance of our net deferred tax assets to the amount we believe is more-likely-than-not to be realized.

We do not provide for a U.S. income tax liability and foreign withholding taxes on undistributed foreign earnings of our foreign subsidiaries.

Impact of Recently Issued Accounting Standards

As disclosed in the “Convertible Debt” policy above within this footnote, we adopted the simplified accounting for convertible debt instrument guidance (ASU 2020-06) on January 1, 2021. Refer to the section above for the impact of adoption. We do not expect any other recently issued accounting standards to have a material impact to our financial results.

Investments

12 Months Ended

Dec. 31, 2021

Investments [Abstract]

Investments

2. Investments

The following table summarizes the contract maturity of the available-for-sale securities we held as of December 31, 2021:

One year or less	51	%
After one year but within two years	34	%
After two years but within three and a half years	15	%
Total	100	%

As illustrated above, at December 31, 2021, 85 percent of our available-for-sale securities had a maturity of less than two years.

All of our available-for-sale securities are available to us for use in our current operations. As a result, we categorize all of these securities as current assets even though the stated maturity of some individual securities may be one year or more beyond the balance sheet date.

At December 31, 2021, we had an ownership interest of less than 20 percent in seven private companies and three public companies with which we conduct business. The privately-held companies are Aro Biotherapeutics, Atlantic Pharmaceuticals Limited, Dynacure SAS, Empirico, Inc., Flamingo Therapeutics BV, YourBio Health, Inc. and Suzhou-Ribo Life Science Co, Ltd. The publicly traded companies are Antisense Therapeutics Ltd., Bicycle and ProQR.

The following is a summary of our investments (in thousands):

	Amortized		Gross Unrealized					Estimated
December 31, 2021	Cost		Gains		Losses			Fair Value
Available-for-sale securities:
Corporate debt securities (1)	$	383,870	$	728	$	(226	)	$	384,372
Debt securities issued by U.S. government agencies		48,493		19		(18	)		48,494
Debt securities issued by the U.S. Treasury (1)		45,424		—		(64	)		45,360
Debt securities issued by states of the U.S. and political subdivisions of the states		134,770		45		(37	)		134,778
Total securities with a maturity of one year or less		612,557		792		(345	)		613,004
Corporate debt securities		382,000		331		(2,644	)		379,687
Debt securities issued by U.S. government agencies		72,935		—		(561	)		72,374
Debt securities issued by the U.S. Treasury		137,635		139		(500	)		137,274
Debt securities issued by states of the U.S. and political subdivisions of the states		39,909		1		(224	)		39,686
Other municipal debt securities		6,136		—		(37	)		6,099
Total securities with a maturity of more than one year		638,615		471		(3,966	)		635,120
Total available-for-sale securities	$	1,251,172	$	1,263	$	(4,311	)	$	1,248,124
Equity securities:
Total equity securities included in other current assets (2)	$	11,897	$	7,145	$	(837	)	$	18,205
Total equity securities included in deposits and other assets (3)		15,615		16,707		—			32,322
Total equity securities	$	27,512	$	23,852	$	(837	)	$	50,527
Total available-for-sale and equity securities	$	1,278,684	$	25,115	$	(5,148	)	$	1,298,651

	Amortized		Gross Unrealized					Estimated
December 31, 2020	Cost		Gains		Losses			Fair Value
Available-for-sale securities:
Corporate debt securities (1)	$	514,182	$	2,194	$	(41	)	$	516,335
Debt securities issued by U.S. government agencies		94,234		354		(2	)		94,586
Debt securities issued by the U.S. Treasury (1)		307,576		233		(9	)		307,800
Debt securities issued by states of the U.S. and political subdivisions of the states		104,271		196		(12	)		104,455
Other municipal debt securities		5,191		—		(7	)		5,184
Total securities with a maturity of one year or less		1,025,454		2,977		(71	)		1,028,360
Corporate debt securities		325,079		4,941		(40	)		329,980
Debt securities issued by U.S. government agencies		80,099		185		(9	)		80,275
Debt securities issued by the U.S. Treasury		50,318		383		(4	)		50,697
Debt securities issued by states of the U.S. and political subdivisions of the states		31,779		91		(16	)		31,854
Other municipal debt securities		1,041		—		—			1,041
Total securities with a maturity of more than one year		488,316		5,600		(69	)		493,847
Total available-for-sale securities	$	1,513,770	$	8,577	$	(140	)	$	1,522,207
Equity securities:
Total equity securities included in other current assets (2)	$	4,712	$	—	$	(2,681	)	$	2,031
Total equity securities included in deposits and other assets (3)		15,062		15,938		—			31,000
Total equity securities	$	19,774	$	15,938	$	(2,681	)	$	33,031
Total available-for-sale and equity securities	$	1,533,544	$	24,515	$	(2,821	)	$	1,555,238

________________

(1)	Includes investments classified as cash equivalents on our consolidated balance sheet.

(2)	Our equity securities included in other current assets consisted of our investments in publicly traded companies. We recognize publicly traded equity securities at fair value.

(3)

Our equity securities included in deposits and other assets consisted of our investments in privately held companies. We recognize our private company equity securities at cost minus impairments, plus or minus changes resulting from observable price changes in orderly transactions for the identical or similar investment of the same issuer on our consolidated balance sheet.

The following is a summary of our investments we considered to be temporarily impaired at December 31, 2021 (in thousands). All of these investments have less than 12 months of temporary impairment. We believe that the decline in value of these securities is temporary and is primarily related to the change in market interest rates since purchase. We believe it is more likely than not that we will be able to hold our debt securities to maturity. Therefore, we anticipate full recovery of our debt securities’ amortized cost basis at maturity.

	Number of Investments		Estimated Fair Value		Unrealized Losses
Corporate debt securities		272	$	552,966	$	(2,870	)
Debt securities issued by U.S. government agencies		15		114,338		(579	)
Debt securities issued by the U.S. Treasury		13		134,987		(564	)
Debt securities issued by states of the U.S. and political subdivisions of the states		425		126,401		(261	)
Other municipal debt securities		2		6,099		(37	)
Total temporarily impaired securities		727	$	934,791	$	(4,311	)

Long-Term Obligations and Commitments

12 Months Ended

Dec. 31, 2021

Long-Term Obligations and Commitments [Abstract]

Long-Term Obligations and Commitments

3. Long-Term Obligations and Commitments

The carrying value of our long-term obligations was as follows (in thousands):

	December 31,
	2021			2020
				(as revised*)
0.125 percent convertible senior notes	$	542,314		$	540,136
1 percent convertible senior notes (1)		—			308,809
0 percent convertible senior notes		619,119			—
Long-term mortgage debt		59,713			59,984
Leases and other obligations		29,904			30,710
Total	$	1,251,050		$	939,639
Less: current portion (1)		(3,526	)		(316,110	)
Total Long-Term Obligations	$	1,247,524		$	623,529

________________

(1)	We classified the carrying value of our 1% Notes as a current liability on our consolidated balance sheet at December 31, 2020 because it matured in November 2021.

*	We revised our 2020 amounts to reflect the simplified convertible instruments accounting guidance, which we adopted retrospectively. Refer to Note 1, Organization and Significant Accounting Policies, for further information.

Convertible Debt and Call Spread

0 Percent Convertible Senior Notes and Call Spread

In April 2021, we completed a $632.5 million offering of convertible senior notes. We used a portion of the net proceeds from the issuance of the 0% Notes to repurchase $247.9 million in principal of our 1% Notes for $257.0 million.

At December 31, 2021, we had the following 0% Notes outstanding (amounts in millions except interest rate and price per share data):

	0% Notes
Outstanding principal balance	$	632.5
Unamortized debt issuance costs	$	13.4
Maturity date	April 2026
Interest rate	0 percent
Effective interest rate	0.5 percent
Conversion price per share	$	57.84
Effective conversion price per share with call spread	$	76.39
Total shares of common stock subject to conversion		10.9

In conjunction with the April 2021 offering, we entered into a call spread transaction, which was comprised of purchasing note hedges and selling warrants, to minimize the impact of potential economic dilution upon conversion of our 0% Notes by increasing the effective conversion price on our 0% Notes. We increased our effective conversion price to $76.39 with the same number of underlying shares as our 0% Notes. The call spread cost us $46.9 million, of which $136.7 million was for the note hedge purchase, offset by $89.8 million we received for selling the warrants. Similar to our 0% Notes, our note hedges are subject to adjustment. Additionally, our note hedges are exercisable upon conversion of the 0% Notes. The note hedges will expire upon maturity of the 0% Notes, or April 2026. The note hedges and warrants are separate transactions and are not part of the terms of our 0% Notes. The holders of the 0% Notes do not have any rights with respect to the note hedges and warrants.

We recorded the amount we paid for the note hedges and the amount we received for the warrants in additional paid-in capital in our consolidated balance sheet. See our Call Spread accounting policy in Note 1, Organization and Significant Accounting Policies, in the Notes to the Consolidated Financial Statements. We reassess our ability to continue to classify the note hedges and warrants in shareholders’ equity at each reporting period.

0.125 Percent Convertible Senior Notes and Call Spread

In December 2019, we entered into privately negotiated exchange and/or subscription agreements with certain new investors and certain holders of our existing 1% Notes to exchange $375.6 million of our 1% Notes for $439.3 million of our 0.125% Notes, and to issue $109.5 million of our 0.125% Notes.

At December 31, 2021, we had the following 0.125% Notes outstanding with interest payable semi-annually (amounts in millions except interest rate and price per share data):

	0.125% Notes
Outstanding principal balance	$	548.8
Unamortized debt issuance costs	$	6.5
Maturity date	December 2024
Interest rate	0.125 percent
Effective interest rate	0.5 percent
Conversion price per share	$	83.28
Effective conversion price per share with call spread	$	123.38
Total shares of common stock subject to conversion		6.6

In conjunction with the issuance of our 0.125% Notes in December 2019, we entered into a call spread transaction, which was comprised of purchasing note hedges and selling warrants, to minimize the impact of potential economic dilution upon conversion of our 0.125% Notes by increasing the effective conversion price on our 0.125% Notes. We increased our effective conversion price to $123.38 with the same number of underlying shares as our 0.125% Notes. The call spread cost us $52.6 million, of which $108.7 million was for the note hedge purchase, offset by $56.1 million we received for selling the warrants. Similar to our 0.125% Notes, our note hedges are subject to adjustment. Additionally, our note hedges are exercisable upon conversion of the 0.125% Notes. The note hedges will expire upon maturity of the 0.125% Notes, or December 2024. The note hedges and warrants are separate transactions and are not part of the terms of our 0.125% Notes. The holders of the 0.125% Notes do not have any rights with respect to the note hedges and warrants.

1 Percent Convertible Senior Notes

In November 2014, we completed a $500 million offering of convertible senior notes, which matured in 2021 and beared interest at 1 percent with interest payable semi-annually. In December 2016, we issued an additional $185.5 million of 1% Notes in exchange for the redemption of a portion of our previously outstanding 2.75% convertible senior notes, or 2.75% Notes. In December 2019, we exchanged a portion of our 1% Notes for new 0.125% Notes. As a result, the principal balance of 1% Notes was $309.9 million. Additionally, we recorded a $66.2 million non-cash loss on the early retirement of debt, reflecting the early retirement of a significant portion of our 1% Notes in December 2019. The non-cash loss on the early retirement of our debt is the difference between the amount paid to exchange our 1% Notes and the net carrying balance of the liability at the time that we completed the debt exchange.

In April 2021, we repurchased $247.9 million in aggregate principal amount of our 1% Notes in privately negotiated transactions. As a result of the repurchase, we recognized an $8.6 million loss on early retirement of debt, reflecting the early retirement of a significant portion of our 1% Notes. The loss on the early retirement of our debt is the difference between the amount paid to retire our 1% Notes and the net carrying balance of the liability at the time that we retired the debt. We paid the remaining principal balance of our 1% Notes with $62.0 million of cash at maturity in November 2021.

Other Terms of Convertible Senior Notes

The 0% and 0.125% Notes are convertible under certain conditions, at the option of the note holders. We can settle conversions of the notes, at our election, in cash, shares of our common stock or a combination of both. We may not redeem the notes prior to maturity, and we do not have to provide a sinking fund for them. Holders of the notes may require us to purchase some or all of their notes upon the occurrence of certain fundamental changes, as set forth in the indentures governing the notes, at a purchase price equal to 100 percent of the principal amount of the notes to be purchased, plus any accrued and unpaid interest. The 1% Notes were subject to similar terms.

Our total interest expense for our outstanding senior convertible notes for the years ended December 31, 2021, 2020 and 2019 included $4.9 million, $3.2 million and $2.9 million, respectively, of non-cash interest expense related to the amortization of debt issuance costs for our convertible notes.

Financing Arrangements

Research and Development and Manufacturing Facilities

In July 2017, we purchased the building that houses our primary R&D facility for $79.4 million and our manufacturing facility for $14.0 million. We financed the purchase of these two facilities with mortgage debt of $60.4 million in total. Our primary R&D facility mortgage has an interest rate of 3.88 percent. Our manufacturing facility mortgage has an interest rate of 4.20 percent. During the first five years of both mortgages, we are only required to make interest payments. We will begin making principal payments in 2022. Both mortgages mature in August 2027.

Maturity Schedules

Annual debt and other obligation maturities, including fixed and determinable interest, at December 31, 2021 are as follows (in thousands):

2022	$	3,498
2023		4,180
2024		4,180
2025		1,184,820
2026		3,494
Thereafter		57,439
Subtotal	$	1,257,611
Less: current portion		(3,526	)
Less: fixed and determinable interest		(15,498	)
Less: debt issuance costs		(20,302	)
Plus: lease liabilities		22,058
Plus: other liabilities		7,181
Total long-term debt	$	1,247,524

Long-Term Obligations and Commitments

Operating Leases

Carlsbad Leases

We lease a facility adjacent to our manufacturing facility that has laboratory and office space that we use to support our manufacturing facility. We lease this space under a non-cancelable operating lease. In May 2020, we exercised our option to extend our lease, extending our lease term from June 2021 to August 2026. We have one remaining option to extend the lease for an additional five-year period.

We also lease additional office spaces in Carlsbad. We lease these spaces under non-cancelable operating leases with initial terms ending in 2023 with options to extend each of the leases for one five-year period.

Boston Leases

We entered into an operating lease agreement for office space located in Boston, Massachusetts in the second quarter of 2018. The lease commencement date was in August 2018 and we took occupancy in September 2018. We are leasing this space under a non-cancelable operating lease with an initial term ending after 123 months and an option to extend the lease for an additional five-year term. Under the lease agreement, we received a three-month free rent period, which commenced on August 15, 2018, and a tenant improvement allowance up to $3.8 million.

In January 2022, we entered into a sublease agreement for our office space located in Boston, Massachusetts. The sublease commencement date was in January 2022 when the office space was ready for our tenant’s occupancy. We are subleasing this space under a non-cancelable operating sublease with a sublease term ending 83 months following the sublease commencement date with no option to extend the sublease. Under the sublease agreement we provided a seven-month free rent period, which commenced on January 6, 2022. We will receive lease payments over the sublease term totaling $9.6 million.

In September 2021, we entered into an operating lease agreement for another office space located in Boston, Massachusetts. The lease commencement date was in November 2021 when the office space was ready for our occupancy. We are leasing this space under a non-cancelable operating lease with an initial term ending 91 months following the lease commencement date and an option to extend the lease for an additional five-year term. Under the lease agreement, we will receive a seven-month free rent period, which commenced on November 1, 2021. Our lease payments over the initial term total $6.8 million. We recognized a right-of-use lease asset and lease liability in the fourth quarter of 2021 upon the lease commencement date.

When we determined our lease term for our operating lease right-of-use assets and lease liabilities for these leases, we did not include the extension options for these leases in the original lease term.

Amounts related to our operating leases were as follows (dollar amounts in millions):

	At December 31, 2021
Right-of-use operating lease assets (1)	$	18.0
Operating lease liabilities (2)	$	22.1
Weighted average remaining lease term	6.6 years
Weighted average discount rate		6.0	%

________________

(1)	Included in deposits and other assets on our consolidated balance sheet.

(2)	Current portion of $2.6 million was included in current portion of long-term obligations on our consolidated balance sheet, with the difference included in long-term obligations.

During the years ended December 31, 2021, 2020, and 2019 we paid $3.3 million, $3.8 million and $3.9 million of lease payments, which were included in operating activities in our consolidated statements of cash flows.

As of December 31, 2021, the future payments for our operating lease liabilities are as follows (in thousands):

	Operating Leases
Year ending December 31,	$
2022		4,075
2023		4,314
2024		4,223
2025		4,062
2026		3,778
Thereafter		7,035
Total minimum lease payments		27,487
Less:
Imputed interest		(5,429	)
Total operating lease liabilities	$	22,058

Rent expense was $3.4 million, $3.7 million and $3.6 million for the years ended December 31, 2021, 2020 and 2019, respectively.

- Definition

The entire disclosure for information about short-term and long-term debt arrangements, which includes amounts of borrowings under each line of credit, note payable, commercial paper issue, bonds indenture, debenture issue, own-share lending arrangements and any other contractual agreement to repay funds, and about the underlying arrangements, rationale for a classification as long-term, including repayment terms, interest rates, collateral provided, restrictions on use of assets and activities, whether or not in compliance with debt covenants, and other matters important to users of the financial statements, such as the effects of refinancing and noncompliance with debt covenants.

+ References

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+ Details

Stockholders' Equity

12 Months Ended

Dec. 31, 2021

Stockholders' Equity [Abstract]

Stockholders' Equity

4. Stockholders’ Equity

Preferred Stock

We are authorized to issue up to 15 million shares of “blank check” Preferred Stock. As of December 31, 2021, there were no shares of Preferred Stock outstanding. We have designated Series C Junior Participating Preferred Stock but have no issued or outstanding shares as of December 31, 2021.

Common Stock

At December 31, 2021 and 2020, we had 300 million shares of common stock authorized, of which 141.2 million and 140.4 million were issued and outstanding, respectively. As of December 31, 2021, total common shares reserved for future issuance were 46.2 million.

During the years ended December 31, 2021, 2020 and 2019, we issued 1.1 million, 1.7 million and 3.1 million shares of common stock, respectively, for stock option exercises, vesting of restricted stock units, and ESPP purchases. We received net proceeds from these transactions of $11.6 million, $52.0 million and $119.7 million in 2021, 2020 and 2019, respectively.

Share Repurchase Program

In September 2019, our board of directors approved a share repurchase program of up to $125 million of our common stock. In 2019, we repurchased 535,000 shares for $34.4 million. In the first quarter of 2020, we repurchased an additional 1.5 million shares for $90.5 million.

Stock Plans

1989 Stock Option Plan

In June 1989, our Board of Directors adopted, and the stockholders subsequently approved, a stock option plan that, as amended, provides for the issuance of non-qualified and incentive stock options for the purchase of up to 20.0 million shares of common stock to our employees, directors, and consultants. The plan expires in January 2024. The 1989 Plan does not allow us to grant stock bonuses or restricted stock awards and prohibits us from repricing any options outstanding under the plan unless our stockholders approve the repricing. Options vest over a four-year period, with 25percent exercisable at the end of one year from the date of the grant and the balance vesting ratably, on a monthly basis, thereafter and have a term of seven years. At December 31, 2021, a total of 28 thousand options were outstanding, of which options to purchase 28 thousand shares were exercisable, and 49 thousand shares were available for future grant under the 1989 Plan.

2011 Equity Incentive Plan

In March 2011, our Board of Directors adopted, and the stockholders subsequently approved, a stock option plan that provides for the issuance of stock options, stock appreciation rights, restricted stock awards, restricted stock unit awards, and performance cash awards to our employees, directors, and consultants. In June 2015, May 2017 and June 2019, after receiving approval from our stockholders, we amended our 2011 Equity Incentive Plan, or 2011 Plan, to increase the total number of shares reserved for issuance. We increased the shares available under our 2011 Equity Incentive Plan from 5.5 million to 11.0 million in June 2015, from 11.0 million to 16.0 million in May 2017 and from 16.0 million to 23.0 million in June 2019. In the second quarter of 2021, after receiving approval from our stockholders, we amended our 2011 Plan. The amendment increased the total number of shares of common stock authorized for issuance under the 2011 Plan from 23.0 million to 29.7 million and added a fungible share counting ratio whereby the share reserve will be reduced by 1.7 shares for each share of common stock issued pursuant to a full value award (i.e., RSU or PRSU) and increased by 1.7 shares for each share of common stock returning from a full value award. The plan expires in June 2031. The 2011 Plan does not allow us to reduce the exercise price of any outstanding stock options or stock appreciation rights or cancel any outstanding stock options or stock appreciation rights that have an exercise price or strike price greater than the current fair market value of the common stock in exchange for cash or other stock awards unless our stockholders approve such action. Currently we anticipate awarding only stock options, RSU and PRSU awards to our employees, directors and consultants. Options vest over a four-year period, with 25 percent exercisable at the end of one year from the date of the grant and the balance vesting ratably, on a monthly basis, thereafter and have a term of seven years. Options granted after December 31, 2021 have a term of ten years. We have granted restricted stock unit awards to our employees under the 2011 Plan which vest annually over a four-year period. At December 31, 2021, a total of 12.8 million options were outstanding, of which 8.3 million were exercisable, 2.5 million restricted stock unit awards were outstanding, and 8.5 million shares were available for future grant under the 2011 Plan.

Under the 2011 Plan, we may issue a stock award with additional acceleration of vesting and exercisability upon or after a change in control. In the absence of such provisions, no such acceleration will occur. The stock options and restricted stock unit awards we issued to Dr. Stanley T. Crooke in his former role as chief executive officer and certain stock options and restricted stock unit awards we issued to B. Lynne Parshall in her former role as chief operating officer have accelerated vesting upon a change of control, as defined in the 2011 Plan. In addition, we implemented a change of control and severance benefit plan that provides for change of control and severance benefits to our executive officers, including our chief executive officer and chief financial officer. If we terminate one of our executive officers or if an executive officer resigns for good reason during the period that begins three months before and ends twelve months following a change in control of the company, the impacted executive officers’ stock options and RSUs vesting will accelerate for options and RSUs outstanding as of the termination date.

2020 Equity Incentive Plan

In connection with the Akcea Merger in October 2020, we assumed the unallocated portion of the available share reserve under the Akcea 2015 Equity Incentive Plan. In December 2020, we amended and restated the Akcea 2015 equity plan, including renaming the plan as the Ionis Pharmaceuticals, Inc. 2020 Equity Incentive Plan, or 2020 Plan. The 2020 Plan provided for the issuance of up to 2.6 million shares of our Common Stock to our employees, directors and consultants who were employees of Akcea prior to the Akcea Merger. In the second quarter of 2021, our Compensation Committee approved an amendment to the 2020 Plan. The amendment decreased the total number of shares of common stock authorized for issuance under the 2020 Plan from approximately 2.6 million to 1.6 million. We assumed the 2020 Plan in connection with Ionis’ reacquisition of all of the outstanding shares of Akcea Therapeutics, Inc. as part of the Akcea Merger.

The plan expires in December 2025. The 2020 Plan does not allow us to reduce the exercise price of any outstanding stock options or stock appreciation rights or cancel any outstanding stock options or stock appreciation rights that have an exercise price or strike price greater than the current fair market value of the common stock in exchange for cash or other stock awards unless our stockholders approve such action. Currently we anticipate awarding only stock options and RSU awards to our eligible employees, directors and consultants. Options vest over a four-year period, with 25 percent exercisable at the end of one year from the date of the grant and the balance vesting ratably, on a monthly basis, thereafter and have a term of seven years. Options granted after December 31, 2021 have a term of ten years. We have granted restricted stock unit awards to our employees under the 2020 Plan which vest annually over a four-year period. At December 31, 2021, a total of 0.2 million options were outstanding, of which none were exercisable, 0.1 million restricted stock unit awards were outstanding, and 1.3 million shares were available for future grant under the 2020 Plan.

Under the 2020 Plan, we may issue a stock award with additional acceleration of vesting and exercisability upon or after a change in control. In the absence of such provisions, no such acceleration will occur.

Corporate Transactions and Change in Control under 2011 and 2020 Plans

In the event of certain significant corporate transactions, our Board of Directors has the discretion to take one or more of the following actions with respect to outstanding stock awards under the 2011 and 2020 Plans:

●

arrange for assumption, continuation, or substitution of a stock award by a surviving or acquiring entity (or its parent company);

●

arrange for the assignment of any reacquisition or repurchase rights applicable to any shares of our common stock issued pursuant to a stock award to the surviving or acquiring corporation (or its parent company);

●

accelerate the vesting and exercisability of a stock award followed by the termination of the stock award;

●

arrange for the lapse of any reacquisition or repurchase rights applicable to any shares of our common stock issued pursuant to a stock award;

●

cancel or arrange for the cancellation of a stock award, to the extent not vested or not exercised prior to the effective date of the corporate transaction, in exchange for cash consideration, if any, as the Board, in its sole discretion, may consider appropriate; and

●

arrange for the surrender of a stock award in exchange for a payment equal to the excess of (a) the value of the property the holder of the stock award would have received upon the exercise of the stock award, over (b) any exercise price payable by such holder in connection with such exercise.

2002 Non-Employee Directors’ Stock Option Plan

In September 2001, our Board of Directors adopted, and the stockholders subsequently approved, an amendment and restatement of the 1992 Non-Employee Directors’ Stock Option Plan, which provides for the issuance of non-qualified stock options and restricted stock units to our non-employee directors. The name of the resulting plan is the 2002 Non-Employee Directors’ Stock Option Plan, or the 2002 Plan. In June 2015, after receiving approval from our stockholders, we amended our 2002 Plan to increase the total number of shares reserved for issuance from 1.2 million to 2.0 million. In June 2020, after receiving approval from our stockholders, we further amended our 2002 Plan. The amendments included:

●

An increase to the total number of shares reserved for issuance under the plan from 2.0 million to 2.8 million shares;

●

A reduction to the amount of the automatic awards under the plan;

●

A revision to the vesting schedule of new awards granted; and

●

An extension of the term of the plan.

Options under this plan expire 10 years from the date of grant. At December 31, 2021, a total of 1.0 million options were outstanding, of which 0.8 million were exercisable, 0.1 million restricted stock unit awards were outstanding, and 0.7 million shares were available for future grant under the 2002 Plan.

Employee Stock Purchase Plan

In June 2009, our Board of Directors adopted, and the stockholders subsequently approved, the amendment and restatement of the ESPP and we reserved an additional 150,000 shares of common stock for issuance thereunder. In each of the subsequent years until 2019, we reserved an additional 150,000 shares of common stock for the ESPP resulting in a total of 3.2 million shares authorized under the plan as of December 31, 2021. The ESPP permits full-time employees to purchase common stock through payroll deductions (which cannot exceed 10percent of each employee’s compensation) at the lower of 85percent of fair market value at the beginning of the purchase period or the end of each purchase period. Under the amended and restated ESPP, employees must hold the stock they purchase for a minimum of six months from the date of purchase. During 2021, employees purchased and we issued to employees 0.07 million shares under the ESPP at a weighted average price of $39.26 per share. At December 31, 2021, there were 0.6 million shares available for purchase under the ESPP.

Stock Option Activity

The following table summarizes the stock option activity under our stock plans for the year ended December 31, 2021 (in thousands, except per share and contractual life data):

	Number of Shares			Weighted Average Exercise Price Per Share		Average Remaining Contractual Term (Years)		Aggregate Intrinsic Value
Outstanding at December 31, 2020		12,439		$	54.11
Granted		3,382		$	53.07
Exercised		(219	)	$	38.69
Cancelled/forfeited/expired		(1,513	)	$	54.65
Outstanding at December 31, 2021		14,089		$	54.04		3.89	$	1,131
Exercisable at December 31, 2021		9,175		$	53.65		2.94	$	1,067

The weighted-average estimated fair values of options granted were $24.35, $29.43 and $28.76 for the years ended December 31, 2021, 2020 and 2019, respectively. The total intrinsic value of options exercised during the years ended December 31, 2021, 2020 and 2019 were $2.5 million, $15.5 million and $83.8 million, respectively, which we determined as of the date of exercise. The amount of cash received from the exercise of stock options was $8.5 million, $43.7 million and $105.9 million for the years ended December 31, 2021, 2020 and 2019, respectively. For the year ended December 31, 2021, the weighted-average fair value of options exercised was $50.13. As of December 31, 2021, total unrecognized compensation cost related to non-vested stock options was $49.6 million. We expect to recognize this cost over a weighted average period of 1.1 years. We will adjust the total unrecognized compensation cost for future changes in estimated forfeitures.

Restricted Stock Unit Activity

The following table summarizes the RSU activity for the year ended December 31, 2021 (in thousands, except per share data):

	Number of Shares			Weighted Average Grant Date Fair Value Per Share
Non-vested at December 31, 2020		2,374		$	58.81
Granted		1,548		$	57.69
Vested		(834	)	$	57.47
Cancelled/forfeited		(411	)	$	59.24
Non-vested at December 31, 2021		2,677		$	58.51

For the years ended December 31, 2021, 2020 and 2019, the weighted-average grant date fair value of RSUs granted was $57.69, $60.86 and $60.23 per RSU, respectively. As of December 31, 2021, total unrecognized compensation cost related to RSUs was $57.0 million. We expect to recognize this cost over a weighted average period of 1.2 years. We will adjust the total unrecognized compensation cost for future changes in estimated forfeitures.

Stock-based Compensation Expense and Valuation Information

The following table summarizes stock-based compensation expense for the years ended December 31, 2021, 2020 and 2019 (in thousands):

	Year Ended December 31,
	2021		2020		2019
Cost of sales	$	456	$	1,991	$	438
Research, development and patent		87,522		115,584		95,348
Selling, general and administrative		32,700		112,542		50,788
Total	$	120,678	$	230,117	$	146,574

In October 2020, as part of the Akcea Merger, Akcea’s outstanding equity awards vested under Akcea’s Plan. As a result, in the fourth quarter of 2020, we recognized all unrecognized stock-based compensation ($59.3 million) under Akcea’s Plan. See Note 7, Akcea Merger, in the Notes to the Consolidated Financial Statements for further details.

In the third quarter of 2019, three Akcea executive officers terminated their employment and entered into separation agreements with Akcea. As a result, in the third quarter of 2019, Akcea reversed $19.1 million of stock-based compensation expense it had previously recognized related to the executive officers’ stock options and RSUs that were no longer going to vest.

Determining Fair Value

Valuation. We measure stock-based compensation expense for equity-classified awards, principally related to stock options, RSUs, PRSUs and stock purchase rights under the ESPP at the grant date, based on the estimated fair value of the award and we recognize the expense over the employee’s requisite service period. We value RSUs based on the market price of our common stock on the date of grant. See Note 1, Organization and Significant Accounting Policies, in the Notes to the Consolidated Financial Statements for further details on how we determine the fair value of PRSUs.

We use the Black-Scholes model to estimate the fair value of stock options granted and stock purchase rights under our ESPP. The expected term of stock options granted represents the period of time that we expect them to be outstanding. We estimate the expected term of stock options granted based on actual and projected exercise patterns. We recognize compensation expense for stock options granted, RSUs, PRSUs and stock purchase rights under the ESPP using the accelerated multiple-option approach. Under the accelerated multiple-option approach (also known as the graded-vesting method), we recognize compensation expense over the requisite service period for each separately vesting tranche of the award as though the award were in substance multiple awards, which results in the expense being front-loaded over the vesting period.

For the years ended December 31, 2021, 2020 and 2019, we used the following weighted-average assumptions in our Black-Scholes calculations:

Ionis Employee Stock Options:

	Year Ended December 31,
	2021			2020			2019
Risk-free interest rate		0.6	%		1.5	%		2.3	%
Dividend yield		0.0	%		0.0	%		0.0	%
Volatility		54.0	%		58.6	%		60.3	%
Expected life	4.9 years			4.7 years			4.8 years

Ionis Board of Director Stock Options:

	Year Ended December 31,
	2021			2020			2019
Risk-free interest rate		1.2	%		0.5	%		1.9	%
Dividend yield		0.0	%		0.0	%		0.0	%
Volatility		55.9	%		57.6	%		60.7	%
Expected life	7.3 years			6.7 years			6.6 years

Ionis ESPP:

	Year Ended December 31,
	2021			2020			2019
Risk-free interest rate		0.1	%		0.8	%		2.4	%
Dividend yield		0.0	%		0.0	%		0.0	%
Volatility		42.4	%		47.9	%		45.6	%
Expected life	6 months			6 months			6 months

Risk-Free Interest Rate. We base the risk-free interest rate assumption on observed interest rates appropriate for the term of our stock option plans or ESPP.

Dividend Yield. We base the dividend yield assumption on our history and expectation of dividend payouts. We have not paid dividends in the past and do not expect to in the future.

Volatility. We use an average of the historical stock price volatility of our stock for the Black-Scholes model. We computed the historical stock volatility based on the expected term of the awards.

Expected Life. The expected term of stock options we have granted represents the period of time that we expect them to be outstanding. We estimated the expected term of options we have granted based on actual and projected exercise patterns.

Forfeitures. We reduce stock-based compensation expense for estimated forfeitures. We estimate forfeitures at the time of grant and revise, if necessary, in subsequent periods if actual forfeitures differ from those estimates. We estimate forfeitures based on historical experience.

- Definition

The entire disclosure for shareholders' equity comprised of portions attributable to the parent entity and noncontrolling interest, including other comprehensive income. Includes, but is not limited to, balances of common stock, preferred stock, additional paid-in capital, other capital and retained earnings, accumulated balance for each classification of other comprehensive income and amount of comprehensive income.

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+ Details

Income Taxes

12 Months Ended

Dec. 31, 2021

Income Taxes [Abstract]

Income Taxes

5. Income Taxes

Income (loss) before income taxes is comprised of (in thousands):

	Year Ended December 31,
	2021			2020			2019
				(as revised*)			(as revised*)

United States	$	(29,966	)	$	(137,222	)	$	336,277
Foreign		818			2,670			2,489
Income (loss) before income taxes	$	(29,148	)	$	(134,552	)	$	338,766

Our income tax expense (benefit) was as follows (in thousands):

	Year Ended December 31,
	2021			2020			2019
				(as revised*)			(as revised*)

Current:
Federal	$	(200	)	$	(837	)	$	35,861
State		(690	)		3,782			14,329
Foreign		339			518			413
Total current income tax expense (benefit)		(551	)		3,463			50,603

Deferred:
Federal		—			341,728			904
State		—			—			—
Total deferred income tax benefit		—			341,728			904
Total income tax expense (benefit)	$	(551	)	$	345,191		$	51,507

Our expense (benefit) for income taxes differs from the amount computed by applying the U.S. federal statutory rate to income (loss) before taxes. The sources and tax effects of the differences are as follows (in thousands):

	Year Ended December 31,
	2021					2020					2019
						(as revised*)					(as revised*)

Pre-tax income (loss)	$	(29,148	)			$	(134,552	)			$	338,766

Statutory rate		(6,121	)	21.0	%		(28,256	)	21.0	%		71,141		21.0	%
State income tax net of federal benefit		4,278		(14.7	)%		(37,705	)	28.0	%		49,000		14.5	%
Foreign		143		(0.5	)%		49		0.0	%		340		0.1	%
Net change in valuation allowance		2,885		(9.9	)%		460,898		(342.5	)%		(37,314	)	(11.0	)%
Loss on debt transactions		262		(0.9	)%		—		—			9,911		2.9	%
Impact from outside basis differences		—		—			—		—			(16,344	)	(4.8	)%
Tax credits		(23,198	)	79.6	%		(18,774	)	14.0	%		(22,296	)	(6.6	)%
Deferred tax true-up		(24	)	0.1	%		(206	)	0.2	%		646		0.2	%
Tax rate change		12,838		(44.0	)%		(32,951	)	24.5	%		1,248		0.4	%
Non-deductible compensation		5,085		(17.4	)%		7,931		(5.9	)%		3,361		1.0	%
Other non-deductible items		84		(0.3	)%		193		(0.1	)%		329		0.1	%
Stock-based compensation		4,720		(16.2	)%		17,435		(13.0	)%		(4,837	)	(1.4	)%
Foreign-derived intangible income benefit		—		—			—		—			(2,071	)	(0.6	)%
Impacts from Akcea Merger		—		—			(22,032	)	16.4	%		—		—
Other		(1,503	)	5.1	%		(1,391	)	0.9	%		(1,607	)	(0.6	)%
Effective rate	$	(551	)	1.9	%	$	345,191		(256.5	)%	$	51,507		15.2	%

Deferred income taxes reflect the net tax effects of temporary differences between the carrying amounts of assets and liabilities for financial reporting purposes and the amounts used for income tax purposes.

Significant components of our deferred tax assets and liabilities as of December 31, 2021 and 2020 are as follows (in thousands):

	Year Ended December 31,
	2021			2020
				(as revised*)

Deferred Tax Assets:
Net operating loss carryovers	$	85,600		$	83,681
Tax credits		269,538			245,746
Deferred revenue		104,330			124,452
Stock-based compensation		86,611			80,055
Intangible and capital assets		92,542			98,443
Convertible debt		45,681			22,395
Interest expense limitation		6,996			—
Other		15,048			13,402
Total deferred tax assets	$	706,346		$	668,174

Deferred Tax Liabilities:
Fixed assets		(3,303	)		(3,611	)
Other		(5,270	)		(5,808	)
Net deferred tax asset	$	697,773		$	658,755
Valuation allowance		(697,773	)		(658,755	)
Total net deferred tax assets and liabilities	$	—		$	—

*	We revised our 2020 and 2019 amounts to reflect the simplified convertible instruments accounting guidance, which we adopted retrospectively. Refer to Note 1, Organization and Significant Accounting Policies, for further information.

We evaluate our deferred tax assets regularly to determine whether adjustments to the valuation allowance are appropriate due to changes in facts or circumstances, such as changes in expected future pre-tax earnings, tax law, interactions with taxing authorities and developments in case law. In making this evaluation, we rely on our recent history of pre-tax earnings. Our material assumptions are our forecasts of future pre-tax earnings and the nature and timing of future deductions and income represented by the deferred tax assets and liabilities, all of which involve the exercise of significant judgment. Although we believe our estimates are reasonable, we are required to use significant judgment in determining the appropriate amount of valuation allowance recorded against our deferred tax assets.

Ionis and Akcea filed separate U.S. federal income tax returns from the date of Akcea’s IPO in 2017 through October 12, 2020, the date on which we completed the Akcea Merger. As a result of the Akcea Merger, Ionis and Akcea now file a consolidated U.S. federal income tax return, and we now assess our U.S. federal and state valuation allowance requirements on a consolidated basis.

We assessed our valuation allowance requirements and recorded a valuation allowance of $341 million against all of Ionis’ U.S. federal net deferred tax assets in the fourth quarter of 2020, due to uncertainties related to our ability to realize the tax benefits associated with these assets. We based this determination largely on Akcea rejoining the Ionis consolidated U.S. federal tax group in the fourth quarter of 2020. Due to Akcea’s historical and projected financial statement losses, and the expected negative impact this will have on Ionis’ consolidated taxable income, we are uncertain if we will generate sufficient consolidated pre-tax income in future periods to realize the Ionis deferred tax benefits. We also expect that Ionis’ pre-tax income in future periods will be lower due to significant investments in research and development associated with our pipeline of wholly owned medicines. We now maintain a valuation allowance against all our consolidated U.S. federal and state net deferred tax assets.

Our valuation allowance increased by $39 million from December 31, 2020 to December 31, 2021. The increase was primarily related to increases in our deferred tax assets for tax credits and convertible debt offset against a decrease in our deferred tax asset for deferred revenue.

At December 31, 2021, we had federal and state, primarily California, tax net operating loss carryforwards of $271.5 million and $333.8 million, respectively. Our federal tax loss carryforwards are available indefinitely. Our California tax loss carryforwards will begin to expire in 2031. At December 31, 2021, we also had federal and California research and development tax credit carryforwards of $225.5 million and $99.7 million, respectively. Our federal research and development tax credit carryforwards will begin to expire in 2034. Our California research and development tax credit carryforwards are available indefinitely.

Utilization of the net operating loss and tax credit carryforwards may be subject to an annual limitation due to the ownership change limitations provided by the Internal Revenue Code of 1986, as amended, and similar state provisions. The annual limitation may result in the expiration of net operating losses and credits before utilization.

We analyze filing positions in all U.S. federal, state and foreign jurisdictions where we file income tax returns, and all open tax years in these jurisdictions to determine if we have any uncertain tax positions on any of our income tax returns. We recognize the impact of an uncertain tax position on an income tax return at the largest amount that the relevant taxing authority is more-likely-than not to sustain upon audit. We do not recognize uncertain income tax positions if they have less than 50 percent likelihood of the applicable tax authority sustaining our position.

The following table summarizes our gross unrecognized tax benefits (in thousands):

	Year Ended December 31,
	2021			2020			2019
Beginning balance of unrecognized tax benefits	$	54,163		$	69,784		$	68,301
Decrease for prior period tax positions		(695	)		(24,154	)		(867	)
Increase for prior period tax positions		263			7,023			736
Increase for current period tax positions		1,354			1,510			1,614
Ending balance of unrecognized tax benefits	$	55,085		$	54,163		$	69,784

Included in the balance of unrecognized tax benefits at December 31, 2021, 2020 and 2019 was $6.2 million, $6.4 million and $0.4 million respectively, that if we recognized, could impact our effective tax rate, subject to our remaining valuation allowance.

We do not foresee any material changes to our gross unrecognized tax benefits within the next twelve months.

We recognize interest and/or penalties related to income tax matters in income tax expense. During the year ended December 31, 2021 and 2020, we recognized $0.5 million and $0.3 million, respectively, of accrued interest and penalties related to gross unrecognized tax benefits. We did not record any accrued interest and penalties for the years ended December 31, 2019.

We are subject to taxation in the U.S. and various state and foreign jurisdictions. Our tax years for 1999 through 2020 are subject to examination by the U.S. federal, state and foreign tax authorities.

We do not provide for a U.S. income tax liability and foreign withholding taxes on undistributed foreign earnings of our foreign subsidiaries as we consider those earnings to be permanently reinvested. It is not practicable for us to calculate the amount of unrecognized deferred tax liabilities associated with these earnings.

- Definition

The entire disclosure for income taxes. Disclosures may include net deferred tax liability or asset recognized in an enterprise's statement of financial position, net change during the year in the total valuation allowance, approximate tax effect of each type of temporary difference and carryforward that gives rise to a significant portion of deferred tax liabilities and deferred tax assets, utilization of a tax carryback, and tax uncertainties information.

+ References

Reference 1: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
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Reference 3: http://www.xbrl.org/2003/role/disclosureRef
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Reference 4: http://www.xbrl.org/2003/role/disclosureRef
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Reference 5: http://www.xbrl.org/2003/role/disclosureRef
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-Name Accounting Standards Codification
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Reference 6: http://www.xbrl.org/2003/role/disclosureRef
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Reference 7: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
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Reference 8: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
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Reference 9: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
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-Subparagraph (SX 210.4-08(h)(2))
-URI http://asc.fasb.org/extlink&oid=120395691&loc=d3e23780-122690

+ Details

Collaborative Arrangements and Licensing Agreements

12 Months Ended

Dec. 31, 2021

Collaborative Arrangements and Licensing Agreements [Abstract]

Collaborative Arrangements and Licensing Agreements

6. Collaborative Arrangements and Licensing Agreements

Strategic Partnership

Biogen

We have several strategic collaborations with Biogen focused on using antisense technology to advance the treatment of neurological disorders. These collaborations combine our expertise in creating antisense medicines with Biogen’s expertise in developing therapies for neurological disorders. We developed and licensed to Biogen SPINRAZA, our approved medicine to treat people with spinal muscular atrophy, or SMA. We and Biogen are currently developing nine investigational medicines to treat neurodegenerative diseases under these collaborations, including medicines in development to treat people with ALS, SMA, AS, Alzheimer’s diseaseand Parkinson’s disease. In addition to these medicines, our collaborations with Biogen include a substantial research pipeline that addresses a broad range of neurological diseases. From inception through December 2021, we have received more than $3.1 billion from our Biogen collaborations.

Spinal Muscular Atrophy Collaborations

SPINRAZA

In January 2012, we entered into a collaboration agreement with Biogen to develop and commercialize SPINRAZA, an RNA-targeted therapy for the treatment of SMA. From inception through December 2021, we earned more than $1.6 billion in total revenue under our SPINRAZA collaboration, including nearly $1.2 billion in revenue from SPINRAZA royalties and more than $435 million in R&D revenue. We are receiving tiered royalties ranging from 11 percent to 15 percent on net sales of SPINRAZA. We have exclusively in-licensed patents related to SPINRAZA from Cold Spring Harbor Laboratory and the University of Massachusetts. We pay Cold Spring Harbor Laboratory and the University of Massachusetts a low single digit royalty on net sales of SPINRAZA. Biogen is responsible for all global development, regulatory and commercialization activities and costs for SPINRAZA. We completed our performance obligations under our collaboration in 2016.

New antisense medicines for the treatment of SMA

In December 2017, we entered into a collaboration agreement with Biogen to identify new antisense medicines for the treatment of SMA. Biogen has the option to license therapies arising out of this collaboration following the completion of preclinical studies. Upon licensing, Biogen will be responsible for global development, regulatory and commercialization activities and costs for such therapies. Under the collaboration agreement, we received a $25 million upfront payment in the fourth quarter of 2017. In December 2021, we earned a $60 million license fee payment when Biogen exercised its option to license ION306. We will receive development and regulatory milestone payments from Biogen if new medicines advance towards marketing approval. In total over the term of our collaboration, we are eligible to receive up to $1.2 billion in license fees, milestone payments and other payments, including up to $555 million in payments if Biogen advances ION306, which includes up to $45 million for the achievement of development milestones, up to $110 million for the achievement of regulatory milestones and up to $400 million for the achievement of sales milestones. In addition, we are eligible to receive tiered royalties from the mid-teens to mid-20 percent range on net sales. We will achieve the next payment of up to $45 millionfor the initiation of a Phase 3 trial under this collaboration.

At the commencement of this collaboration, we identified one performance obligation, which was to perform R&D services for Biogen. We determined the transaction price to be the $25 million upfront payment we received when we entered into the collaboration. We allocated the transaction price to our single performance obligation. In the fourth quarter of 2019, we completed our R&D services performance obligation under this collaboration. We recognized revenue as we performed services based on our effort to satisfy our performance obligation relative to the total effort expected to satisfy our performance obligation. We completed our performance obligation earlier than we previously estimated, as a result, we recognized $8.3 million of additional revenue in the fourth quarter of 2019.

In the fourth quarter of 2021, we identified another performance obligation upon Biogen’s license of ION306 because the license we granted to Biogen is distinct from our other performance obligations. We recognized the $60 million license fee for ION306 as revenue at that time because Biogen had full use of the license without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the license after we delivered it to Biogen. Biogen is solely responsible for the costs and expenses related to the development, manufacturing and potential future commercialization of ION306 following the option exercise. We do not have any remaining performance obligations under this collaboration.

Neurology Collaborations

2018 Strategic Neurology

In April 2018, we and Biogen entered into a strategic collaboration to develop novel antisense medicines for a broad range of neurological diseases and entered into a SPA. As part of the collaboration, Biogen gained exclusive rights to the use of our antisense technology to develop therapies for these diseases for 10 years. We are responsible for the identification of antisense drug candidates based on selected medicines. Biogen is responsible for conducting IND-enabling toxicology studies for the selected medicine. Biogen will have the option to license the selected medicine after it completes the IND-enabling toxicology study. If Biogen exercises its option to license a medicine, it will assume global development, regulatory and commercialization responsibilities and costs for that medicine.

In the second quarter of 2018, we received $1 billion from Biogen, comprised of $625 million to purchase our stock at an approximately 25 percent cash premium and $375 million in an upfront payment. We are eligible to receive up to $270 million in milestone payments for each medicine that achieves marketing approval. In addition, we are eligible to receive tiered royalties up to the 20 percent range on net sales. We are currently advancing nine programs under this collaboration and from inception through December 2021, we have received nearly $1.1 billion in payments under this collaboration. We will achieve the next payment of $7.5 million if Biogen designates or advances another programunder this collaboration.

At the commencement of this collaboration, we identified one performance obligation, which was to perform R&D services for Biogen. We determined our transaction price to be $552 million, comprised of $375 million from the upfront payment and $177 million for the premium paid by Biogen for its purchase of our common stock. We determined the fair value of the premium we received by using the stated premium in the SPA and applying a lack of marketability discount. We included a lack of marketability discount in our valuation of the premium because Biogen received restricted shares of our common stock. We allocated the transaction price to our single performance obligation.

From inception through December 2021, we have included $616 million in payments in the transaction price for our R&D services performance obligation under this collaboration, including $23 million of milestone payments we achieved in 2021 and $11 million of milestone payments we achieved in 2020. These milestone payments did not create new performance obligations because they are part of our original R&D services performance obligation. Therefore, we included these amounts in our transaction price for our R&D services performance obligation in the period we achieved the milestone payment. We are recognizing revenue for our R&D services performance obligation as we perform services based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. We currently estimate we will satisfy our performance obligation at the end of the contractual term in June 2028.

2013 Strategic Neurology

In September 2013, we and Biogen entered into a long-term strategic relationship focused on applying antisense technology to advance the treatment of neurodegenerative diseases. As part of the collaboration, Biogen gained exclusive rights to the use of our antisense technology to develop therapies for neurological diseases and has the option to license medicines resulting from this collaboration. We will usually be responsible for drug discovery and early development of antisense medicines and Biogen has the option to license antisense medicines after Phase 2 proof-of-concept. In October 2016, we expanded our collaboration to include additional research activities we will perform. If Biogen exercises its option to license a medicine, it will assume global development, regulatory and commercialization responsibilities and costs for that medicine. We are currently advancing six investigational medicines in development under this collaboration, including a medicine for Parkinson’s disease (ION859), three medicines for ALS (tofersen, IONIS-C9_Rx and ION541), a medicine for multiple system atrophy (ION464) and a medicine for an undisclosed target. In the fourth quarter of 2018, Biogen exercised its option to license our most advanced ALS medicine, tofersen, our medicine in Phase 3 development for SOD1 ALS. As a result, Biogen is now responsible for global development, regulatory and commercialization activities and costs for tofersen.

Under the terms of the agreement, we received an upfront payment of $100 million and are eligible to receive milestone payments, license fees and royalty payments for all medicines developed under this collaboration, with the specific amounts dependent upon the modality of the molecule advanced by Biogen. For each antisense molecule that is chosen for drug discovery and development under this collaboration, we are eligible to receive up to approximately $260 million in a license fee and milestone payments per program. The $260 million per program consists of approximately $60 million in development milestones, including amounts related to the cost of clinical trials, and up to $130 million in milestone payments if Biogen achieves pre-specified regulatory milestones. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales from any antisense medicines developed under this collaboration. From inception through December 2021, we have received over $280 million in upfront fees, milestone payments and other payments under this collaboration. We will achieve the next payment of up to $70 million if Biogen licenses a medicine under this collaboration.

At the commencement of our 2013 strategic neurology collaboration, we identified one performance obligation, which was to perform R&D services for Biogen. At inception, we determined the transaction price to be the $100 million upfront payment we received and allocated it to our single performance obligation. As we achieve milestone payments for our R&D services, we include these amounts in our transaction price for our R&D services performance obligation. We recognized revenue for our R&D services performance obligation based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. In the third quarter of 2019, we updated our estimate of the total effort we expect to expend to satisfy our performance obligation. As a result, we recorded a cumulative catch up adjustment of $16.5 million to decrease revenue in the third quarter of 2019. During 2020, we completed our remaining research and development services and recognized the remaining revenue related to this performance obligation. From inception through the completion of our R&D services performance obligation in 2020, we included $145 million in total payments in the transaction price for our R&D services performance obligation.

Under this collaboration, we have also generated additional payments that we concluded were not part of our R&D services performance obligation. We recognized each of these payments in full in the respective quarter we generated the payment because we did not have any performance obligations for the respective payment. For example, in the second quarter of 2021, we earned a $10 million milestone payment when Biogen advanced ION541, which we recognized in full because we did not have any performance obligations related to this milestone payment.

2012 Neurology

In December 2012, we and Biogen entered into a collaboration agreement to develop and commercialize novel antisense medicines to treat neurodegenerative diseases. We are responsible for the development of each of the medicines through the completion of the initial Phase 2 clinical study for such medicine. Biogen has the option to license a medicine from each of the programs through the completion of the first Phase 2 study for each program. Under this collaboration, we are currently advancing IONIS-MAPT_Rx for Alzheimer’s disease and ION582 for AS. If Biogen exercises its option to license a medicine, it will assume global development, regulatory and commercialization responsibilities and costs for that medicine. In the fourth quarter of 2019, Biogen exercised its option to license IONIS-MAPT_Rx. We are responsible for completing the Phase 1/2 in study patients with mild AD and a one-year long-term extension study. Biogen will have responsibility for global development, regulatory and commercialization activities and costs for IONIS-MAPT_Rx.

Under the terms of the agreement, we received an upfront payment of $30 million. Over the term of the collaboration, we are eligible to receive up to $210 million in a license fee and milestone payments per program, plus a mark-up on the cost estimate of the Phase 1 and 2 studies. The $210 million per program consists of up to $10 million in development milestone payments, plus a mark-up on the cost estimate of the Phase 1 and 2 studies and up to $130 million in milestone payments if Biogen achieves pre-specified regulatory milestones. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales of any medicines resulting from each of the three programs. From inception through December 2021, we have received $155 million in payments under this collaboration, including $19.5 million we received from Biogen for achieving milestones for advancing IONIS-MAPT_Rxduring 2020. We will achieve the next payment of $25 million if Biogen advances a medicine under this collaboration.

Under our collaboration, we determined we had a performance obligation to perform R&D services. We allocated $40 million in total payments to the transaction price for our R&D services performance obligation. In the third quarter of 2019, we completed our R&D services performance obligation when we designated a development candidate and Biogen accepted the development candidate. Biogen’s decision to accept the development candidate was not within our control. We were recognizing revenue as we performed services based on our effort to satisfy our performance obligation relative to the total effort expected to satisfy our performance obligation. Because Biogen accepted the development candidate earlier than when we were previously estimating, we recognized $6.3 million of accelerated revenue in the third quarter of 2019.

When we commenced development for IONIS-MAPT_Rx we identified our development work as a separate performance obligation. We are recognizing our IONIS-MAPT_Rx development performance obligation based on the percentage of completion. From inception through December 2021, we have included $57 million in the transaction price for our IONIS-MAPT_Rx development performance obligation, including $19.5 million milestone payments we earned from Biogen in 2020 when we advanced IONIS-MAPT_Rx. We currently estimate we will satisfy our performance obligation in 2022.

In the fourth quarter of 2019, we identified another performance obligation upon Biogen’s license of IONIS-MAPT_Rx because the license we granted to Biogen is distinct from our other performance obligations. We recognized the $45 million license fee for IONIS-MAPT_Rx as revenue at that time because Biogen had full use of the license without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the license after we delivered it to Biogen.

In the fourth quarter of 2021, we earned a $10 million milestone payment when Biogen advanced ION582, which we recognized in full because we did not have any performance obligations related to this milestone payment.

During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with Biogen (in millions, except percentage amounts):

	Year Ended December 31,
	2021			2020			2019
SPINRAZA royalties (commercial revenue)	$	267.8		$	286.6		$	293.0
R&D revenue		161.0			122.0			180.6
Total revenue from our relationship with Biogen	$	428.8		$	408.6		$	473.6
Percentage of total revenue		53	%		56	%		42	%

Our consolidated balance sheet at December 31, 2021 and 2020 included deferred revenue of $407.5 million and $465.8 million, respectively, related to our relationship with Biogen.

Joint Development and Commercialization Arrangement

AstraZeneca

Eplontersen Collaboration

In December 2021, we entered into a joint development and commercialization agreement with AstraZeneca to develop and commercialize eplontersen for the treatment of ATTR. We are jointly developing and preparing to commercialize eplontersen with AstraZeneca in the U.S. We granted AstraZeneca exclusive rights to commercialize eplontersen outside the U.S., except certain countries in Latin America. Under the terms of the agreement, we received a $200 million upfront payment. We are eligible to receive up to $485 million in development and approval milestones, and up to $2.9 billion in sales-related milestone payments. The agreement also includes territory-specific development, commercial and medical affairs cost-sharing provisions. In addition, we are eligible to receive up to mid-20 percent royalties for sales in the U.S. and tiered royalties up to the high teens for sales outside the U.S.

We evaluated our eplontersen collaboration under ASC 808 and identified four material components: (i) the license we granted to AstraZeneca in 2021, (ii) the co-development activities that we and AstraZeneca will perform, (iii) the co-commercialization activities that we and AstraZeneca will perform and (iv) the co-medical affairs activities that we and AstraZeneca will perform.

We determined that we had a vendor-customer relationship within the scope of ASC 606 for the license we granted to AstraZeneca and as a result we had one performance obligation. For our sole performance obligation, we determined the transaction price was the $200 million upfront payment we received. We recognized the upfront payment in full in 2021 because we did not have any remaining performance obligations after we delivered the license to AstraZeneca.

We also concluded that the co-development activities, the co-commercialization activities and the co-medical affairs activities are within the scope of ASC 808 because we and AstraZeneca are active participants exposed to the risks and benefits of the activities under the collaboration. AstraZeneca will pay 55 percent of the costs associated with the ongoing global Phase 3 development program. As we will continue to lead the Phase 3 development program, we will recognize as revenue the 55 percent of cost-share funding AstraZeneca is responsible for in the same period we incur the related development expenses. As AstraZeneca is responsible for the majority of the commercial and medical affairs costs in the U.S. and all costs associated with bringing eplontersen to market outside the U.S., we will recognize cost-share funding we receive from AstraZeneca related to these activities as a reduction of our commercial and medical affairs expenses.

We will achieve the next payment of up to $50 million upon the first regulatory approval under this collaboration. Through December 2021, we have generated $200 million in payments under this collaboration.

Research and Development Partners

AstraZeneca

In addition to our collaboration for eplontersen, we have two other collaborations with AstraZeneca. One is focused on the treatment of cardiovascular, renal and metabolic diseases and the other is focused on the treatment of oncology diseases. We and AstraZeneca are currently developing six medicines under these collaborations, including medicines in development to treat people with ATTR amyloidosis, cardiovascular disease, a genetically associated form of kidney disease, NASH and cancer. From inception through December 2021, we have received more than $386 million from our AstraZeneca research and development collaborations.

Cardiovascular, Renal and Metabolic Diseases Collaboration

In July 2015, we and AstraZeneca formed a collaboration to discover and develop antisense therapies for treating cardiovascular, renal and metabolic diseases. Under our collaboration, AstraZeneca has licensed five medicines from us. AstraZeneca is responsible for global development, regulatory and commercialization activities and costs for each of the medicines it has licensed from us.

Under the terms of the agreement, we received a $65 million upfront payment. We are eligible to receive license fees and milestone payments of up to more than $5.5 billion as medicines under this collaboration advance, including up to $1.1 billion for the achievement of development milestones, up to $2.9 billion for regulatory milestones and up to $1.5 billion for commercial milestones. In addition, we are eligible to receive tiered royalties up to the low teens on net sales from any product that AstraZeneca successfully commercializes under this collaboration agreement. We will achieve the next payment of $10 million under this collaboration if AstraZeneca advances a medicine under this collaboration. From inception through December 2021, we have received over $282 million in an upfront fee, license fees, milestone payments, and other payments under this collaboration, including $30 million we earned in 2021 when AstraZeneca licensed a target for a metabolic disease and $10 million we earned in 2021 when AstraZeneca advanced a target for a metabolic disease.

At the commencement of this collaboration, we identified one performance obligation, which was to perform R&D services for AstraZeneca. We determined the transaction price to be the $65 million upfront payment we received and we allocated it to our single performance obligation. We recognized revenue for our R&D services performance obligation as we performed services based on our effort to satisfy this performance obligation relative to our total effort expected to satisfy our performance obligation. We completed our performance obligation in the fourth quarter of 2021. As we achieve milestone payments for our R&D services, we include these amounts in our transaction price for our R&D services performance obligation. From inception through December 2021, we have included $90 million in payments in the transaction price for our R&D services performance obligation.

Under this collaboration, we have also generated additional payments that we concluded were not part of our R&D services performance obligation. We recognized each of these payments in full in the respective quarter we generated the payment because the payments were distinct and we did not have any performance obligations for the respective payment. For example, in the fourth quarter of 2021, we earned a $30 million license fee when AstraZeneca licensed a target for a metabolic disease. We recognized the license fee as revenue at that time because AstraZeneca had full use of the license without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the license after we delivered it to AstraZeneca.

Oncology Collaboration

In December 2012, we entered into a collaboration agreement with AstraZeneca to discover and develop antisense medicines to treat cancer. We and AstraZeneca also established an oncology research program. In 2020, AstraZeneca licensed ION736, an investigational medicine in development targeting FOXP3 for the treatment of cancer. AstraZeneca is responsible for global development, regulatory and commercialization activities and costs for ION736.

Under the terms of this agreement, we received $31 million in upfront payments. We are eligible to receive milestone payments and license fees up to $160 million under this collaboration, including up to $42 million for the achievement of development milestones and up to $105 million for the achievement of regulatory milestones. In addition, we are eligible to receive tiered royalties up to the low teens on net sales from any product that AstraZeneca successfully commercializes under this collaboration agreement. From inception through December 2021, we have received over $141 million in upfront fees, milestone payments, and other payments under this oncology collaboration, including $13 million we earned when AstraZeneca licensed ION736 in 2020. We will achieve the next payment of $12 million if AstraZeneca advances ION736 in development.

We completed all of the performance obligations we identified under this collaboration in the first quarter of 2018.

Under this collaboration, we have also generated additional payments that we concluded were not part of other performance obligations discussed above. We recognized each of these payments in full in the respective quarter we generated the payment because the payments were distinct and we did not have any performance obligations for the respective payment. In 2020, we earned a $13 million license fee when AstraZeneca licensed ION736 because AstraZeneca had full use of the license without any continuing involvement from us.

During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with AstraZeneca (in millions, except percentage amounts):

	Year Ended December 31,
	2021			2020			2019
R&D revenue	$	254.6		$	88.0		$	28.1
Percentage of total revenue		31	%		12	%		3	%

We did not have any deferred revenue from our relationship with AstraZeneca at December 31, 2021. Our consolidated balance sheet at December 31, 2020 included deferred revenue of $10.0 million from our relationship with AstraZeneca.

Bayer

In May 2015, we entered into an exclusive license agreement with Bayer to develop and commercialize IONIS-FXI_Rx for the prevention of thrombosis. We were responsible for completing a Phase 2 study of IONIS-FXI_Rx in people with end-stage renal disease on hemodialysis. Under the terms of the agreement, we received a $100 million upfront payment in the second quarter of 2015. In February 2017, we amended our agreement with Bayer to advance IONIS-FXI_Rx and to initiate development of fesomersen, which Bayer licensed. In conjunction with the decision to advance these programs, we received a $75 million payment from Bayer. In October 2019, Bayer decided it would advance fesomersen following positive clinical results. Bayer is now responsible for all global development, regulatory and commercialization activities and costs for the FXI program.

We are eligible to receive up to $385 million in license fees, milestone payments and other payments, including up to $125 million for the achievement of development milestones and up to $110 million for the achievement of sales milestones. In addition, we are eligible to receive tiered royalties in the low to high 20 percent range on gross margins of both medicines combined. From inception through December 2021, we have received over $191 million from this collaboration. We will achieve the next payment of $20 million if Bayer initiates a Phase 3 study for the FXI program.

At the commencement of this collaboration, we identified three performance obligations, the license of IONIS-FXI_Rx, R&D services and delivery of API, all of which we completed in 2016.

In February 2017, when we amended our collaboration with Bayer, we identified two new performance obligations, one for the license of fesomersen and one for R&D services. We determined the transaction price to be the $75 million payment. We allocated $64.9 million to the license of fesomersen based on its estimated relative stand-alone selling price and recognized the associated revenue upon our delivery of the license in the first quarter of 2017. We allocated $10.1 million to our R&D services performance obligation based on an estimated relative stand-alone selling price. We recognized revenue for our R&D services performance obligation as we performed services based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. We completed our obligation in the third quarter of 2019.

In the fourth quarter of 2019, we earned a $10 million milestone payment when Bayer decided it would advance fesomersen. We recognized this milestone payment in full in the fourth quarter of 2019 because we did not have any performance obligations related to this milestone payment.

During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with Bayer (in millions, except percentage amounts):

	Year Ended December 31,
	2021			2020			2019
R&D revenue	$	1.1		$	3.2		$	14.3
Percentage of total revenue		0	%		0	%		1	%

Our consolidated balance sheet at December 31, 2021 included an insignificant amount of deferred revenue related to our relationship with Bayer. We did not have any deferred revenue from our relationship with Bayer at December 31, 2020.

GSK

In March 2010, we entered into an alliance with GSK using our antisense drug discovery platform to discover and develop new medicines against targets for serious and rare diseases, including infectious diseases and some conditions causing blindness. Under the terms of the agreement, we received upfront payments of $35 million. Our collaboration with GSK currently includes two medicines targeting hepatitis B virus, or HBV: bepirovirsen and IONIS-HBV-L_Rx. We designed these medicines to reduce the production of viral proteins associated with HBV infection. In the third quarter of 2019, following positive Phase 2 results, GSK licensed our HBV program. GSK is responsible for all global development, regulatory and commercialization activities and costs for the HBV program.

Under our agreement, if GSK successfully develops these medicines and achieves pre-agreed sales targets, we could receive license fees and milestone payments of more than $260 million, including up to $47.5 million for the achievement of development milestones, up to $120 million for the achievement of regulatory milestones and up to $70 million for the achievement of sales milestones. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales from any product that GSK successfully commercializes under this alliance. From inception through December 2021, we have received more than $190 million in payments under this alliance with GSK. We will achieve the next payment of $15 million if GSK initiates a Phase 3 study of a medicine under this program.

We completed our R&D services performance obligations under our collaboration in the first quarter of 2015. We identified a new performance obligation when we granted GSK the license of the HBV program and assigned related intellectual property rights in the third quarter of 2019 because the license was distinct from our other performance obligations. We recognized the $25 million license fee for the HBV program as revenue at that time because GSK had full use of the license without any continuing involvement from us. Additionally, we did not have any further performance obligations related to the license after we delivered it to GSK.

We do not have any remaining performance obligations under our collaboration with GSK; however, we can still earn additional payments and royalties as GSK advances the HBV program.

During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with GSK (in millions, except percentage amounts):

	Year Ended December 31,
	2021		2020			2019
R&D revenue	$	—	$	0.2		$	25.4
Percentage of total revenue		—		0	%		2	%

We did not have any deferred revenue from our relationship with GSK at December 31, 2021 and 2020.

Novartis

In January 2017, we initiated a collaboration with Novartis to develop and commercialize pelacarsen and olezarsen.We received a $75 million upfront payment in the first quarter of 2017. In the first quarter of 2019, Novartis licensed pelacarsen and we earned a $150 million license fee. Novartis is responsible for conducting and funding future development and regulatory activities for pelacarsen, including a global Phase 3 cardiovascular outcomes study that Novartis initiated in the fourth quarter 2019. In connection with Novartis’ license of pelacarsen, we and Novartis established a more definitive framework under which the companies would negotiate the co-commercialization of pelacarsen in selected markets. Included in this framework is an option by which Novartis could solely commercialize pelacarsen in exchange for Novartis paying us increased sales milestone payments based on sales of pelacarsen. When Novartis decided to not exercise its option for olezarsen, we retained rights to develop and commercialize olezarsen.

Under the collaboration, we are eligible to receive up to $675 million in milestone payments, including $25 million for the achievement of a development milestone, up to $290 million for the achievement of regulatory milestones and up to $360 million for the achievement of sales milestones. From inception through December 2021, we have received nearly $425 million in upfront payments, milestone payments, license fees and other payments from this collaboration. We are also eligible to receive tiered royalties in the mid-teens to low 20 percent range on net sales of pelacarsen. In August 2021, we earned a $25 million milestone payment from Novartis when Novartis achieved 50 percent enrollment in the Lp(a) HORIZON Phase 3 cardiovascular outcome study of pelacarsen. We recognized the milestone payment in full in the third quarter of 2021 because we did not have any remaining performance obligations related to the milestone payment. We will achieve the next payment of up to $75 million if Novartis advances regulatory activities for pelacarsen.

In conjunction with this collaboration, we entered into a SPA with Novartis. As part of the SPA, Novartis purchased 1.6 million shares of our common stock for $100 million in the first quarter of 2017.

At the commencement of this collaboration, we identified four separate performance obligations:

●

R&D services for pelacarsen;

●

R&D services for olezarsen;

●

API for pelacarsen; and

●

API for olezarsen.

We determined that the R&D services for each medicine and the API for each medicine were distinct performance obligations.

We determined our transaction price to be $108.4 million, comprised of the following:

●

$75 million from the upfront payment;

●

$28.4 million for the premium paid by Novartis for its purchase of our common stock at a premium in the first quarter of 2017; and

●

$5.0 million for the potential premium Novartis would have paid if they purchased our common stock in the future.

We allocated the transaction price based on the estimated stand-alone selling price of each performance obligation as follows:

●

$64.0 million for the R&D services for pelacarsen;

●

$40.1 million for the R&D services for olezarsen;

●

$1.5 million for the delivery of pelacarsen API; and

●

$2.8 million for the delivery of olezarsen API.

We completed our R&D services performance obligations for olezarsen and pelacarsenin 2019. As such, we recognized all revenue we allocated to the olezarsen and pelacarsenR&D services as of the end of 2019.

We recognized revenue related to the R&D services for pelacarsen and olezarsen performance obligations as we performed services based on our effort to satisfy our performance obligations relative to our total effort expected to satisfy our performance obligations.

During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with Novartis (in millions, except percentage amounts):

	Year Ended December 31,
	2021			2020			2019
R&D revenue	$	25.5		$	1.0		$	187.4
Percentage of total revenue		3	%		0	%		17	%

We did not have any deferred revenue from our relationship with Novartis at December 31, 2021 and 2020.

Roche

Huntington’s Disease

In April 2013, we formed an alliance with Hoffman-La Roche Inc. and F. Hoffmann-La Roche Ltd., collectively Roche, to develop treatments for HD based on our antisense technology. Under the agreement, we discovered and developed tominersen, an investigational medicine targeting HTT protein. We developed tominersen through completion of our Phase 1/2 clinical study in people with early stage HD. In the fourth quarter of 2017, upon completion of the Phase 1/2 study, Roche exercised its option to license tominersen. Roche is responsible for all global development, regulatory and commercialization activities and costs for tominersen.

Under the terms of the agreement, we received an upfront payment of $30 million in April 2013 and an additional $3 million payment in 2017. We are eligible to receive up to $365 million in a license fee and milestone payments including up to $70 million for the achievement of development milestones, up to $170 million for the achievement of regulatory milestones and up to $80 million for the achievement of sales milestones. In addition, we are eligible to receive up to $136.5 million in milestone payments for each additional medicine successfully developed. We are also eligible to receive tiered royalties up to the mid-teens on net sales of any product resulting from this alliance. From inception through December 2021, we have received $150 million in upfront fees, milestone payments and license fees under this collaboration. We will achieve the next payment of $15 million if Roche advances tominersen into registration.

In January 2022, Roche announced it is actively preparing to initiate a new Phase 2 study of tominersen in patients with HD. Post-hoc analyses from the GENERATION HD1 study suggested tominersen may benefit younger adult patients with lower disease burden. In March 2021, Roche decided to discontinue dosing in the Phase 3 GENERATION HD1 study of tominersen in patients with manifest HD based on the results of a pre-planned review of data from the Phase 3 study conducted by an unblinded iDMC. We do not have any remaining performance obligations related to tominersen under this collaboration with Roche; however, we can still earn additional payments and royalties as Roche advances tominersen.

IONIS-FB-L_Rx for Complement-Mediated Diseases

In October 2018, we entered into a collaboration agreement with Roche to develop IONIS-FB-L_Rx for the treatment of complement-mediated diseases. We are currently conducting Phase 2 studies in two disease indications for IONIS-FB-L_Rx, one for the treatment of patients with GA, the advanced stage of dry AMD, and a second for the treatment of patients with IgA nephropathy. Roche has the option to license IONIS-FB-L_Rx at the completion of these studies. Upon licensing, Roche will be responsible for global development, regulatory and commercialization activities and costs.

Under the terms of this agreement, we received a $75 million upfront payment in the fourth quarter of 2018. We are eligible to receive more than $680 million in development, regulatory and sales milestone payments and license fees. In addition, we are also eligible to receive tiered royalties from the high teens to 20 percent on net sales. From inception through December 2021, we have received $75 million in upfront fees, milestone payments and license fees under this collaboration. We will achieve the next payment of $20 million if we further advance the Phase 2 study in patients with dry AMD.

At the commencement of this collaboration, we identified one performance obligation, which was to perform R&D services for Roche. We determined the transaction price to be the $75 million upfront payment we received and allocated it to our single performance obligation. We are recognizing revenue for our R&D services performance obligation as we perform services based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. During the fourth quarter of 2020, we updated our estimate of the total effort we expected to expend to satisfy our performance obligation under this collaboration. In the fourth quarter of 2020, we recorded a cumulative catch up adjustment of $9.2 million to decrease revenue because we updated our total cost estimate to complete the Phase 2 study of IONIS-FB-L_Rxfor the treatment of patients with GA. We currently estimate we will satisfy our performance obligation in the fourth quarter of 2023.

During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with Roche (in millions, except percentage amounts):

	Year Ended December 31,
	2021			2020			2019
R&D revenue	$	17.2		$	5.9		$	57.0
Percentage of total revenue		2	%		1	%		5	%

Our consolidated balance sheet at December 31, 2021 and 2020 included deferred revenue of $31.6 million and $47.2 million related to our relationship with Roche, respectively.

Commercialization Partnerships

Swedish Orphan Biovitrum AB (Sobi)

We began commercializing TEGSEDI and WAYLIVRA in Europe in January 2021 and TEGSEDI in North America in April 2021 through distribution agreements with Sobi. Under our agreements, we are responsible for supplying finished goods inventory to Sobi and Sobi is responsible for selling each medicine to the end customer. In exchange, we earn a distribution fee on net sales from Sobi for each medicine.

PTC Therapeutics

In August 2018, we entered into an exclusive license agreement with PTC Therapeutics to commercialize TEGSEDI and WAYLIVRA in Latin America and certain Caribbean countries. Under the license agreement, we are eligible to receive royalties from PTC in the mid-20 percent range on net sales for each medicine. In December 2021, we started receiving royalties from PTC for TEGSEDI sales.

Technology Enhancement Collaboration

Bicycle License Agreement

In December 2020, we entered into a collaboration agreement with Bicycle and obtained an option to license its peptide technology to potentially increase the delivery capabilities of our LICA medicines. In July 2021, we paid $42 million when we exercised our option to license Bicycle’s technology, which included an equity investment in Bicycle. As part of our stock purchase, we entered into a lockup agreement with Bicycle that restricts our ability to trade our Bicycle shares for one year. In 2021, we recorded a $7.2 million equity investment for the shares we received in Bicycle. We recognized the remaining $34.8 million as R&D expense in 2021. From inception through December 31, 2021, we have paid Bicycle $46.6 million under this collaboration agreement.

Other Agreements

Alnylam Pharmaceuticals, Inc.

Under the terms of our agreement with Alnylam, we co-exclusively (with ourselves) licensed to Alnylam our patent estate relating to antisense motifs and mechanisms and oligonucleotide chemistry for double-stranded RNAi therapeutics, with Alynylam having the exclusive right to grant platform sublicenses for double-stranded RNAi. In exchange for such rights, Alynylam gave us a technology access fee, participation in fees from Alnylam’s partnering programs, as well as future milestone and royalty payments from Alnylam. We retained exclusive rights to our patents for single-stranded antisense therapeutics and for a limited number of double-stranded RNAi therapeutic targets and all rights to single-stranded RNAi, or ssRNAi, therapeutics. In turn, Alnylam nonexclusively licensed to us its patent estate relating to antisense motifs and mechanisms and oligonucleotide chemistry to research, develop and commercialize single-stranded antisense therapeutics, ssRNAi therapeutics, and to research double-stranded RNAi compounds. We also received a license to develop and commercialize double-stranded RNAi therapeutics targeting a limited number of therapeutic targets on a nonexclusive basis. Additionally, in 2015, we and Alnylam entered into an alliance in which we cross-licensed intellectual property. Under this alliance, we and Alnylam each obtained exclusive license rights to four therapeutic programs. Alnylam granted us an exclusive, royalty-bearing license to its chemistry, RNA targeting mechanism and target-specific intellectual property for oligonucleotides against four targets, including FXI and Apo(a) and two other targets. In exchange, we granted Alnylam an exclusive, royalty-bearing license to our chemistry, RNA targeting mechanism and target-specific intellectual property for oligonucleotides against four other targets. Alnylam also granted us a royalty-bearing, non-exclusive license to new platform technology arising from May 2014 through April 2019 for single-stranded antisense therapeutics. In turn, we granted Alnylam a royalty-bearing, non-exclusive license to new platform technology arising from May 2014 through April 2019 for double-stranded RNAi therapeutics.

In the fourth quarter 2020, we completed an arbitration process with Alnylam. The arbitration panel awarded us $41.2 million for payments owed to us by Alnylam related to Alnylam’s agreement with Sanofi Genzyme. We recognized the $41.2 million payment from Alnylam as revenue in the fourth quarter of 2020 because we did not have any performance obligations for the respective payment.

During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with Alnylam (in millions, except percentage amounts):

	Year Ended December 31,
	2021		2020			2019
R&D revenue	$	—	$	47.9		$	24.1
Percentage of total revenue		—		7	%		2	%

We did not have any deferred revenue from our relationship with Alnylam at December 31, 2021 and 2020.

Akcea Merger

12 Months Ended

Dec. 31, 2021

Akcea Merger [Abstract]

Akcea Merger

7. Akcea Merger

Purchase Price and Direct Transaction Costs Accounting for the Akcea Merger

In October 2020, we reacquired the shares of Akcea’s common stock we did not own, increasing our ownership from 76 percent to 100 percent. Under the purchase agreement, we purchased 24.8 million shares at $18.15 per share, resulting in a total purchase price of $450.6 million.

To reflect our 100 percent ownership, we accounted for the increase in our ownership by eliminating the noncontrolling interest adjustment in stockholders’ equity in accordance with the Consolidation accounting guidance (ASC Topic 810). We recognized the difference between the purchase price and the adjustment to noncontrolling interest in stockholders’ equity as additional-paid-in capital. Refer to our Statement of Stockholders’ Equity for detailed amounts.

We accounted for the transaction costs related to the Akcea Merger as a direct charge to stockholders’ equity. We incurred $40.6 million of direct transaction costs from the Akcea Merger, primarily comprised of banking and legal fees.

Equity Award Payouts related to the Akcea Merger

In October 2020, as part of the Akcea Merger, Ionis cancelled all of Akcea’s equity awards. In exchange for the cancelled awards, if eligible under the terms of the Akcea Merger, we paid holder’s a cash payment. We paid $18.15 for each outstanding RSU. For each outstanding option with an exercise price less than $18.15, we paid $18.15 less the exercise price. As a result, we paid out $53.4 million in the fourth quarter of 2020 related to Akcea’s cancelled equity awards. We accounted for these payments as part of the transaction costs recorded to stockholders’ equity in the fourth quarter of 2020. Because we did not replace the Akcea awards, we recognized all unrecognized non-cash stock-based compensation ($59.3 million) under Akcea’s Plan in our statement of operations in the post-merger period in the fourth quarter of 2020.

Severance and Retention Costs related to the Akcea Merger

As a result of the Akcea Merger, we incurred severance and retention expenses of $27.0 million. During 2021 and 2020, we recorded $11.7 million and $15.3 million of severance and retention related costs in operating expenses, respectively. As of December 31, 2021, we have recognized all severance and retention costs related to the Akcea Merger.

The following table summarizes the severance and retention expenses related to the Akcea Merger that we recognized for the periods indicated (in millions):

	Year Ended December 31, 2021		Year Ended December 31, 2020
R&D expenses	$	5.1	$	3.9
SG&A expenses		6.6		11.4
Total	$	11.7	$	15.3

The following table summarizes the severance and retention reserve amounts related to the Akcea Merger that we included in accrued compensation for the period indicated (in millions):

	Year Ended December 31, 2021
Beginning balance as of January 1, 2021	$	14.7
Amount expensed during the year		13.5
Reserve adjustments during the year		(1.8	)
Net amount expensed during the year		11.7
Amounts paid during the year		(26.4	)
Ending balance as of December 31, 2021	$	—

The reserve adjustments during the period primarily related to forfeitures of severance and retention payments as a result of employee terminations before they earned the amounts.

Severance and Retention Costs related to our Restructured Operations

12 Months Ended

Dec. 31, 2021

Severance and Retention Costs related to our Restructured Operations [Abstract]

Severance and Retention Costs related to our Restructured Operations

8. Severance and Retention Costs related to our Restructured Operations

Restructured European Operations

In the fourth quarter of 2020, we entered into a distribution agreement with Sobi to commercialize TEGSEDI and WAYLIVRA in Europe. Under the distribution agreement, Sobi took over all material distribution operations at the end of January 2021. We remain the marketing authorization holder for TEGSEDI and WAYLIVRA in Europe. We will continue to maintain limited European operations including regulatory, manufacturing, and the management of relationships with key opinion leaders. We will also continue to lead the TEGSEDI and WAYLIVRA global commercial strategy.

As a result of this change, we incurred severance and retention expenses of $14.2 million. During 2021 and 2020, we recorded $1.7 million and $12.5 million of severance and retention related costs in operating expenses, respectively. As of December 31, 2021, we have recognized all severance and retention costs related to this agreement.

The following table summarizes the severance and retention expenses related to our restructured European operations that we recognized for the periods indicated (in millions):

	Year Ended December 31, 2021		Year Ended December 31, 2020
R&D expenses	$	0.6	$	4.2
SG&A expenses		1.1		8.3
Total	$	1.7	$	12.5

The following table summarizes the severance and retention reserve amounts related to our restructured European operations that we included in accrued compensation for the period indicated (in millions):

	Year Ended December 31, 2021
Beginning balance as of January 1, 2021	$	12.4
Amount expensed during the year		2.6
Reserve adjustments during the year		(0.9	)
Net amount expensed during the year		1.7
Amounts paid during the year		(14.1	)
Ending balance as of December 31, 2021	$	—

The reserve adjustments during the period primarily related to tax expense adjustments.

Restructured North American TEGSEDI Operations

In April 2021, we entered into a distribution agreement with Sobi for TEGSEDI in North America. Under the terms of the distribution agreement, we will retain the marketing authorizations for TEGSEDI in the U.S. and Canada. We will continue to supply commercial product to Sobi and manage regulatory and manufacturing processes, as well as relationships with key opinion leaders. We will also continue to lead the TEGSEDI global commercial strategy. Sobi will otherwise have responsibility for commercializing TEGSEDI in the U.S. and Canada.

In connection with restructuring our North American TEGSEDI operations, or Restructured North American TEGSEDI Operations, we enacted a plan to reorganize our Akcea workforce in North America to better align with the needs of our business and to focus on our wholly owned pipeline.

The following table summarizes the severance expenses related to our Restructured North American TEGSEDI Operations that we recognized for the period indicated (in millions):

	Year Ended December 31, 2021
R&D expenses	$	2.3
SG&A expenses		7.1
Total	$	9.4

We recognized all severance expenses related to our Restructured North American TEGSEDI Operations during the three months ended June 30, 2021.

The following table summarizes the severance reserve amounts related to our Restructured North American TEGSEDI Operations that we included in accrued compensation for the period indicated (in millions):

	Year Ended December 31, 2021
Beginning balance as of January 1, 2021	$	—
Net amount expensed during the year		9.4
Amounts paid during the year		(9.4	)
Ending balance as of December 31, 2021	$	—

Employment Benefits	12 Months Ended
Employment Benefits	Dec. 31, 2021
Employment Benefits [Abstract]
Employment Benefits	9. Employment Benefits We have employee 401(k) salary deferral plans covering all employees. Employees could make contributions by withholding a percentage of their salary up to the IRS annual limits of $20,500 and $27,000 in 2021 for employees under 50 years old and employees 50 years old or over, respectively. We made approximately $5.5 million, $5.7 million and $6.4 million in matching contributions for the years ended December 31, 2021, 2020 and 2019, respectively.

- Definition

The entire disclosure for retirement benefits.

+ References

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Reference 3: http://www.xbrl.org/2003/role/disclosureRef
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Reference 7: http://www.xbrl.org/2003/role/disclosureRef
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Reference 8: http://www.xbrl.org/2003/role/disclosureRef
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Reference 9: http://www.xbrl.org/2003/role/disclosureRef
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Reference 12: http://www.xbrl.org/2003/role/disclosureRef
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Reference 13: http://www.xbrl.org/2003/role/disclosureRef
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Reference 14: http://www.xbrl.org/2003/role/disclosureRef
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+ Details

Legal Proceedings	12 Months Ended
Legal Proceedings	Dec. 31, 2021
Legal Proceedings [Abstract]
Legal Proceedings	10. Legal Proceedings From time to time, we are involved in legal proceedings arising in the ordinary course of our business. Periodically, we evaluate the status of each legal matter and assess our potential financial exposure. If the potential loss from any legal proceeding is considered probable and the amount can be reasonably estimated, we accrue a liability for the estimated loss. Significant judgment is required to determine the probability of a loss and whether the amount of the loss is reasonably estimable. The outcome of any proceeding is not determinable in advance. As a result, the assessment of a potential liability and the amount of accruals recorded are based only on the information available to us at the time. As additional information becomes available, we reassess the potential liability related to the legal proceeding, and may revise our estimates. On August 5, 2021, four purported former stockholders of Akcea filed an action in the Delaware Court of Chancery captioned John Makris, et al. v. Ionis Pharmaceuticals, Inc., et al., C.A. No. 2021-0681, or the “Delaware Action.” The plaintiffs in the Delaware Action assert claims against (i) former members of Akcea’s board of directors; and (ii) Ionis, or collectively, the “Defendants.” The plaintiffs assert putatively direct claims on behalf of a purported class of former Akcea stockholders. The plaintiffs in the Delaware Action assert that the Defendants breached their fiduciary duties in connection with the October 2020 take-private transaction that we and Akcea entered into, in which Akcea became a wholly-owned subsidiary of Ionis. We believe that the claims asserted in the Delaware Action are without merit and filed a motion to dismiss the claims in November 2021. Briefing on the motion to dismiss is ongoing, and pursuant to an agreed-upon scheduling order that has been entered by the Court, argument on the motion to dismiss is expected later in the first quarter of 2022. On January 19, 2022, a purported stockholder of Ionis filed a stockholder derivative complaint in the Delaware Court of Chancery captioned Leo Shumacher, et al. v. Joseph Loscalzo, et al., C.A. No. 2022-0059, or the “Action.” The complaint names as defendants the current members of Ionis’ board of directors, collectively the Directors. The company is a nominal defendant. Plaintiff asserts a breach of fiduciary duty claim against the Directors for awarding and receiving allegedly excessive compensation. Plaintiff also asserts an unjust enrichment claim against the non-employee Directors as a result of the compensation they received. The complaint seeks, among other things, damages, restitution, attorneys’ fees and costs, and such other relief as deemed just and proper by the court. Defendants have not yet responded to the complaint in this Action.

Fourth Quarter Financial Data (Unaudited)

12 Months Ended

Dec. 31, 2021

Fourth Quarter Financial Data (Unaudited) [Abstract]

Fourth Quarter Financial Data (Unaudited)

11. Fourth Quarter Financial Data (Unaudited)

The following financial information reflects all normal recurring adjustments, which are, in the opinion of management, necessary for a fair statement of the results of the interim periods. Summarized fourth quarter data for 2021 and 2020 are as follows (in thousands, except per share data).

Three Months Ended December 31,	2021		2020
Revenue	$	440,006	$	290,281
Operating expenses	$	219,403	$	312,945
Income (loss) from operations	$	220,603	$	(22,664	)
Net income (loss)	$	224,613	$	(355,687	)
Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders	$	224,613	$	(354,532	)
Basic net income (loss) per share (1) (2)	$	1.59	$	(2.54	)
Diluted net income (loss) per share (1) (3)	$	1.41	$	(2.54	)

________________

(1)	We compute net income (loss) per share independently for each quarter during the year.

(2)

Our basic net loss per share calculation for the fourth quarter of 2020 considered our net loss for Ionis on a stand-alone basis plus our share of Akcea’s net loss for the period. To calculate the portion of Akcea’s net loss attributable to our ownership, we multiplied Akcea’s loss per share by the weighted average shares we owned in Akcea during the period. As a result of this calculation, our total net loss available to Ionis common stockholders for the calculation of net loss per share is different than net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders in the consolidated statements of operations.

Our basic net loss per share for the fourth quarter of 2020 was calculated as follows (in thousands, except per share amounts):

Three Months Ended December 31, 2020	Weighted Average Shares Owned in Akcea		Akcea’s Net Loss Per Share			Basic Net Loss Per Share Calculation
Akcea’s net loss in the pre-merger period attributable to our ownership		77,095	$	(0.05	)	$	(3,603	)
Akcea’s net loss in the post-merger period attributable to our ownership							(85,987	)
Akcea’s total net loss attributable to our ownership						$	(89,590	)
Ionis’ stand-alone net loss							(266,418	)
Net loss available to Ionis common stockholders						$	(356,008	)
Weighted average shares outstanding							139,956
Basic net loss per share						$	(2.54	)

(3)

We had net income available to Ionis common stockholders for the fourth quarter of 2021. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during the period as follows (in thousands except per share amounts):

Three Months Ended December 31, 2021	Income (Numerator)		Shares (Denominator)		Per-Share Amount
Net income available to Ionis common stockholders	$	224,612		141,205	$	1.59
Effect of dilutive securities:
Shares issuable upon exercise of stock options		—		46
Shares issuable upon restricted stock award issuance		—		1,065
Shares issuable related to our ESPP		—		34
Shares issuable related to our 0 percent convertible notes		777		10,936
Shares issuable related to our 0.125 percent convertible notes		716		6,590
Shares issuable related to our 1 percent convertible notes		105		464
Income available to Ionis common stockholders, plus assumed conversions	$	226,210		160,340	$	1.41

Organization and Significant Accounting Policies (Policies)

12 Months Ended

Dec. 31, 2021

Organization and Significant Accounting Policies [Abstract]

Basis of Presentation

Basic and Diluted Net Income (Loss) per Share

Basic net income (loss) per share

We calculated our basic net loss per share for the year ended December 31, 2020 as follows (in thousands, except per share amounts):

Year Ended December 31, 2020	Weighted Average Shares Owned in Akcea		Akcea’s Net Loss Per Share			Basic Net Loss Per Share Calculation
Akcea’s net loss in the pre-merger period attributable to our ownership		77,095	$	(1.45	)	$	(111,775	)
Akcea’s net loss in the post-merger period attributable to our ownership							(85,987	)
Akcea’s total net loss attributable to our ownership						$	(197,762	)
Ionis’ stand-alone net loss							(246,702	)
Net loss available to Ionis common stockholders						$	(444,464	)
Weighted average shares outstanding							139,612
Basic net loss per share						$	(3.18	)

We calculated our basic net income per share for the year ended December 31, 2019 as follows (in thousands, except per share amounts):

Year Ended December 31, 2019	Weighted Average Shares Owned in Akcea		Akcea’s Net Income Per Share		Basic Net Income Per Share Calculation
Common shares		70,100	$	0.49	$	34,073
Akcea’s net income attributable to our ownership					$	34,073
Ionis’ stand-alone net income						246,487
Net income available to Ionis common stockholders					$	280,560
Weighted average shares outstanding						139,998
Basic net income per share					$	2.00

Diluted net income (loss) per share

●

0.125 percent convertible senior notes, or 0.125% Notes;

●

Note hedges related to the 0.125% Notes;

●

1 percent convertible senior notes, or 1% Notes;

●

Dilutive stock options;

●

Unvested restricted stock units, or RSUs;

●

Unvested performance restricted stock units, or PRSUs; and

●

Employee Stock Purchase Plan, or ESPP.

For the year ended December 31, 2021, common stock underlying the following would also have had an anti-dilutive effect on net loss per share:

●

0 percent convertible senior notes, or 0% Notes; and

●

Note hedges related to the 0% Notes.

Year Ended December 31, 2019	Net Income Available to Ionis Common Stockholders (Numerator)		Shares (Denominator)		Per-Share Amount
Net income available to Ionis common stockholders	$	280,560		139,998	$	2.00
Effect of dilutive securities:
Shares issuable upon exercise of stock options		—		2,090
Shares issuable upon restricted stock award issuance		—		766
Shares issuable related to our ESPP		—		18
Shares issuable related to our 0.125 percent convertible notes		860		217
Shares issuable related to our 1 percent convertible notes		9,527		10,075
	$	290,947		153,164	$	1.90

Revenue Recognition

Our Revenue Sources

Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue

Commercial Revenue: TEGSEDI and WAYLIVRA revenue, net

Research and development revenue under collaborative agreements

Steps to Recognize Revenue

We use a five-step process to determine the amount of revenue we should recognize and when we should recognize it. The five step process is as follows:

Identify the contract

Accounting rules require us to first determine if we have a contract with our partner, including confirming that we have met each of the following criteria:

●

We and our partner approved the contract and we are both committed to perform our obligations;

●

We have identified our rights, our partner’s rights and the payment terms;

●

We have concluded that the contract has commercial substance, meaning that the risk, timing, or amount of our future cash flows is expected to change as a result of the contract; and

●

We believe collectability of the consideration is probable.

Identify the performance obligations

We next identify our performance obligations, which represent the distinct goods and services we are required to provide under the contract.

Determine the transaction price

Allocate the transaction price

●

Estimated future product sales;

●

Estimated royalties we may receive from future product sales;

●

Estimated contractual milestone payments we may receive;

●

Expenses we expect to incur;

●

Estimated income taxes; and

●

A discount rate.

●

The number of internal hours we estimate we will spend performing these services;

●

The estimated cost of work we will perform;

●

The estimated cost of work that we will contract with third parties to perform; and

●

The estimated cost of API we will use.

Recognize revenue

The following are examples of when we typically recognize revenue based on the types of payments we receive.

Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue

Commercial Revenue: TEGSEDI and WAYLIVRA revenue, net

Reserves for TEGSEDI and WAYLIVRA commercial revenue

The following were the components of variable consideration related to TEGSEDI and WAYLIVRA product sales prior to our agreements with Sobi:

Research and development revenue under collaboration agreements:

Upfront payments

Milestone payments

License fees

Sublicense fees

Amendments to Agreements

From time to time we amend our collaboration agreements. When this occurs, we are required to assess the following items to determine the accounting for the amendment:

If the additional goods and/or services are distinct from the other performance obligations in the original agreement; and

If the goods and/or services are at a stand-alone selling price.

Multiple agreements

●

Whether the agreements were negotiated together with a single objective;

●

Whether the amount of consideration in one contract depends on the price or performance of the other agreement; or

●

Whether the goods and/or services promised under the agreements are a single performance obligation.

Our evaluation involves significant judgment to determine whether a group of agreements might be so closely related that accounting guidance requires us to account for them as a combined arrangement.

Contracts Receivable

Unbilled SPINRAZA Royalties

Deferred Revenue

Cost of Sales

Research and Development Expenses

Patent Expenses

Based on our existing patents, we estimate amortization expense related to patents in each of the next five years to be the following:

Year Ending December 31,	Amortization (in millions)
2022	$	2.2
2023	$	2.1
2024	$	1.9
2025	$	1.8
2026	$	1.8

Estimated Liability for Clinical Development Costs

Noncontrolling Interest in Akcea Therapeutics, Inc.

Concentration of Credit Risk

Cash, Cash Equivalents and Investments

Inventory Valuation

Our inventory consisted of the following (in thousands):

	December 31,
	2021		2020
Raw materials:
Raw materials- clinical	$	14,507	$	9,206
Raw materials- commercial		4,139		7,502
Total raw materials		18,646		16,708
Work in process		5,770		2,252
Finished goods		390		3,005
Total inventory	$	24,806	$	21,965

Property, Plant and Equipment

We carry our property, plant and equipment at cost and depreciate it on the straight-line method over its estimated useful life, which consists of the following (in thousands):

	Estimated Useful	December 31,
	Lives (in years)	2021			2020
Computer software, laboratory, manufacturing and other equipment	3 to 10	$	72,802		$	68,990
Building, building improvements and building systems	15 to 40		144,046			137,879
Land improvements	20		10,077			8,391
Leasehold improvements	5 to 15		20,144			17,263
Furniture and fixtures	5 to 10		10,591			12,871
			257,660			245,394
Less accumulated depreciation			(102,653	)		(87,379	)
			155,007			158,015
Land			23,062			23,062
Total		$	178,069		$	181,077

We depreciate our leasehold improvements using the shorter of the estimated useful life or remaining lease term.

Fair Value of Financial Instruments

Leases

Long-Lived Assets

Use of Estimates

Stock-Based Compensation Expense

RSU’s:

PRSU’s:

See Note 4, Stockholders’ Equity, for additional information regarding our stock-based compensation plans.

Accumulated Other Comprehensive Loss

	Year Ended December 31,
	2021			2020			2019
Beginning balance accumulated other comprehensive loss	$	(21,071	)	$	(25,290	)	$	(32,016	)
Unrealized gains (losses) on securities, net of tax (1)		(11,486	)		3,729			6,633
Currency translation adjustment		(111	)		617			93
Adjustments to other comprehensive loss from purchase of noncontrolling interest of Akcea Therapeutics, Inc.		—			(127	)		—
Net other comprehensive loss for the period		(11,597	)		4,219			6,726
Ending balance accumulated other comprehensive loss	$	(32,668	)	$	(21,071	)	$	(25,290	)

________________

(1)	We did not have tax expense included in our other comprehensive loss for the years ended December 31, 2021 and 2020. For the year ended December 31, 2019, we had a tax benefit of $1.4 million included in other comprehensive loss.

Convertible Debt

Adoption of ASU 2020-06

The following table summarizes the adjustments we made to the consolidated balance sheet we originally reported at December 31, 2020 to adopt ASU 2020-06 (in thousands):

	December 31, 2020
	As Previously Reported			ASU 2020-06 Adjustment			As Revised
1 percent convertible senior notes	$	293,161		$	15,648		$	308,809
0.125 percent convertible senior notes	$	455,719		$	84,417		$	540,136
Additional paid-in-capital	$	2,113,646		$	(218,127	)	$	1,895,519
Accumulated deficit	$	(1,249,368	)	$	118,062		$	(1,131,306	)

	Year Ended December 31, 2020
	As Previously Reported			ASU 2020-06 Adjustment			As Revised
Interest expense	$	(44,990	)	$	35,480		$	(9,510	)
Loss before income tax expense	$	(170,032	)	$	35,480		$	(134,552	)
Income tax expense	$	(316,734	)	$	(28,457	)	$	(345,191	)
Net loss	$	(486,766	)	$	7,023		$	(479,743	)
Net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders	$	(451,286	)	$	7,023		$	(444,263	)
Basic and diluted net loss per share	$	(3.23	)	$	0.05		$	(3.18	)

	Year Ended December 31, 2019
	As Previously Reported			ASU 2020-06 Adjustment			As Revised
Interest expense	$	(48,768	)	$	36,328		$	(12,440	)
Loss on early retirement of debt		(21,865	)		(44,331	)		(66,196	)
Income before income tax benefit (expense)	$	346,769		$	(8,003	)	$	338,766
Income tax expense	$	(43,507	)	$	(8,000	)	$	(51,507	)
Net income	$	303,262		$	(16,003	)	$	287,259
Net income attributable to Ionis Pharmaceuticals, Inc. common stockholders	$	294,146		$	(16,003	)	$	278,143
Basic net income per share		2.12			(0.12	)		2.00
Diluted net income per share	$	2.08		$	(0.18	)	$	1.90

	December 31, 2020
	As Previously Reported			ASU 2020-06 Adjustment			As Revised
Additional paid-in-capital	$	2,113,646		$	(218,127	)	$	1,895,519
Accumulated deficit	$	(1,249,368	)	$	118,062		$	(1,131,306	)
Total stockholders’ equity	$	843,347		$	(100,065	)	$	743,282

	December 31, 2019
	As Previously Reported			ASU 2020-06 Adjustment			As Revised
Additional paid-in-capital	$	2,203,778		$	(218,128	)	$	1,985,650
Accumulated deficit	$	(707,534	)	$	111,039		$	(596,495	)
Total stockholders’ equity	$	1,684,547		$	(107,088	)	$	1,577,459

Call Spread

Segment Information

Fair Value Measurements

	At December 31, 2021		Quoted Prices in Active Markets (Level 1)		Significant Other Observable Inputs (Level 2)		Significant Unobservable Inputs (Level 3)
Cash equivalents (1)	$	541,199	$	541,199	$	—	$	—
Corporate debt securities (2)		764,059		—		764,059		—
Debt securities issued by U.S. government agencies (2)		120,868		—		120,868		—
Debt securities issued by the U.S. Treasury (2)		182,634		182,634		—		—
Debt securities issued by states of the U.S. and political subdivisions of the states (3)		174,464		—		174,464		—
Other municipal debt securities (2)		6,099		—		6,099		—
Investment in Bicycle Therapeutics plc (4)		14,330		—		—		14,330
Investment in ProQR Therapeutics N.V. (4)		3,875		3,875		—		—
Total	$	1,807,528	$	727,708	$	1,065,490	$	14,330

	At December 31, 2020		Quoted Prices in Active Markets (Level 1)		Significant Other Observable Inputs (Level 2)
Cash equivalents (1)	$	221,125	$	221,125	$	—
Corporate debt securities (5)		846,315		—		846,315
Debt securities issued by U.S. government agencies (2)		174,861		—		174,861
Debt securities issued by the U.S. Treasury (6)		358,497		358,497		—
Debt securities issued by states of the U.S. and political subdivisions of the states (2)		136,309		—		136,309
Other municipal debt securities (2)		6,225		—		6,225
Investment in ProQR Therapeutics N.V. (4)		2,031		2,031		—
Total	$	1,745,363	$	581,653	$	1,163,710

________________

(1)	Included in cash and cash equivalents on our consolidated balance sheet.

(2)	Included in short-term investments.

(3)	$2.3 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.

(4)	Included in other current assets on our consolidated balance sheet.

(5)	$10.0 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.

(6)	$17.5 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.

Convertible Notes

Income Taxes

We do not provide for a U.S. income tax liability and foreign withholding taxes on undistributed foreign earnings of our foreign subsidiaries.

Impact of Recently Issued Accounting Standards

Organization and Significant Accounting Policies (Tables)

12 Months Ended

Dec. 31, 2021

Organization and Significant Accounting Policies [Abstract]

Basic Net Income (Loss) per Share

We calculated our basic net loss per share for the year ended December 31, 2020 as follows (in thousands, except per share amounts):

Year Ended December 31, 2020	Weighted Average Shares Owned in Akcea		Akcea’s Net Loss Per Share			Basic Net Loss Per Share Calculation
Akcea’s net loss in the pre-merger period attributable to our ownership		77,095	$	(1.45	)	$	(111,775	)
Akcea’s net loss in the post-merger period attributable to our ownership							(85,987	)
Akcea’s total net loss attributable to our ownership						$	(197,762	)
Ionis’ stand-alone net loss							(246,702	)
Net loss available to Ionis common stockholders						$	(444,464	)
Weighted average shares outstanding							139,612
Basic net loss per share						$	(3.18	)

We calculated our basic net income per share for the year ended December 31, 2019 as follows (in thousands, except per share amounts):

Year Ended December 31, 2019	Weighted Average Shares Owned in Akcea		Akcea’s Net Income Per Share		Basic Net Income Per Share Calculation
Common shares		70,100	$	0.49	$	34,073
Akcea’s net income attributable to our ownership					$	34,073
Ionis’ stand-alone net income						246,487
Net income available to Ionis common stockholders					$	280,560
Weighted average shares outstanding						139,998
Basic net income per share					$	2.00

Basic and Diluted Net Income Per Share

Year Ended December 31, 2019	Net Income Available to Ionis Common Stockholders (Numerator)		Shares (Denominator)		Per-Share Amount
Net income available to Ionis common stockholders	$	280,560		139,998	$	2.00
Effect of dilutive securities:
Shares issuable upon exercise of stock options		—		2,090
Shares issuable upon restricted stock award issuance		—		766
Shares issuable related to our ESPP		—		18
Shares issuable related to our 0.125 percent convertible notes		860		217
Shares issuable related to our 1 percent convertible notes		9,527		10,075
	$	290,947		153,164	$	1.90

Amortization Expense for Patents

Based on our existing patents, we estimate amortization expense related to patents in each of the next five years to be the following:

Year Ending December 31,	Amortization (in millions)
2022	$	2.2
2023	$	2.1
2024	$	1.9
2025	$	1.8
2026	$	1.8

Accrued Liabilities

Our accrued liabilities consisted of the following (in thousands):

	December 31,
	2021		2020
Clinical expenses	$	65,730	$	39,477
In-licensing expenses		8,044		8,264
Commercial expenses		2,471		11,559
Other miscellaneous expenses		12,315		30,861
Total accrued liabilities	$	88,560	$	90,161

Inventory

Our inventory consisted of the following (in thousands):

	December 31,
	2021		2020
Raw materials:
Raw materials- clinical	$	14,507	$	9,206
Raw materials- commercial		4,139		7,502
Total raw materials		18,646		16,708
Work in process		5,770		2,252
Finished goods		390		3,005
Total inventory	$	24,806	$	21,965

Property, Plant and Equipment

We carry our property, plant and equipment at cost and depreciate it on the straight-line method over its estimated useful life, which consists of the following (in thousands):

	Estimated Useful	December 31,
	Lives (in years)	2021			2020
Computer software, laboratory, manufacturing and other equipment	3 to 10	$	72,802		$	68,990
Building, building improvements and building systems	15 to 40		144,046			137,879
Land improvements	20		10,077			8,391
Leasehold improvements	5 to 15		20,144			17,263
Furniture and fixtures	5 to 10		10,591			12,871
			257,660			245,394
Less accumulated depreciation			(102,653	)		(87,379	)
			155,007			158,015
Land			23,062			23,062
Total		$	178,069		$	181,077

Changes in Accumulated Other Comprehensive Loss

	Year Ended December 31,
	2021			2020			2019
Beginning balance accumulated other comprehensive loss	$	(21,071	)	$	(25,290	)	$	(32,016	)
Unrealized gains (losses) on securities, net of tax (1)		(11,486	)		3,729			6,633
Currency translation adjustment		(111	)		617			93
Adjustments to other comprehensive loss from purchase of noncontrolling interest of Akcea Therapeutics, Inc.		—			(127	)		—
Net other comprehensive loss for the period		(11,597	)		4,219			6,726
Ending balance accumulated other comprehensive loss	$	(32,668	)	$	(21,071	)	$	(25,290	)

________________

(1)	We did not have tax expense included in our other comprehensive loss for the years ended December 31, 2021 and 2020. For the year ended December 31, 2019, we had a tax benefit of $1.4 million included in other comprehensive loss.

Adoption of ASU 2020-06

The following table summarizes the adjustments we made to the consolidated balance sheet we originally reported at December 31, 2020 to adopt ASU 2020-06 (in thousands):

	December 31, 2020
	As Previously Reported			ASU 2020-06 Adjustment			As Revised
1 percent convertible senior notes	$	293,161		$	15,648		$	308,809
0.125 percent convertible senior notes	$	455,719		$	84,417		$	540,136
Additional paid-in-capital	$	2,113,646		$	(218,127	)	$	1,895,519
Accumulated deficit	$	(1,249,368	)	$	118,062		$	(1,131,306	)

	Year Ended December 31, 2020
	As Previously Reported			ASU 2020-06 Adjustment			As Revised
Interest expense	$	(44,990	)	$	35,480		$	(9,510	)
Loss before income tax expense	$	(170,032	)	$	35,480		$	(134,552	)
Income tax expense	$	(316,734	)	$	(28,457	)	$	(345,191	)
Net loss	$	(486,766	)	$	7,023		$	(479,743	)
Net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders	$	(451,286	)	$	7,023		$	(444,263	)
Basic and diluted net loss per share	$	(3.23	)	$	0.05		$	(3.18	)

	Year Ended December 31, 2019
	As Previously Reported			ASU 2020-06 Adjustment			As Revised
Interest expense	$	(48,768	)	$	36,328		$	(12,440	)
Loss on early retirement of debt		(21,865	)		(44,331	)		(66,196	)
Income before income tax benefit (expense)	$	346,769		$	(8,003	)	$	338,766
Income tax expense	$	(43,507	)	$	(8,000	)	$	(51,507	)
Net income	$	303,262		$	(16,003	)	$	287,259
Net income attributable to Ionis Pharmaceuticals, Inc. common stockholders	$	294,146		$	(16,003	)	$	278,143
Basic net income per share		2.12			(0.12	)		2.00
Diluted net income per share	$	2.08		$	(0.18	)	$	1.90

	December 31, 2020
	As Previously Reported			ASU 2020-06 Adjustment			As Revised
Additional paid-in-capital	$	2,113,646		$	(218,127	)	$	1,895,519
Accumulated deficit	$	(1,249,368	)	$	118,062		$	(1,131,306	)
Total stockholders’ equity	$	843,347		$	(100,065	)	$	743,282

	December 31, 2019
	As Previously Reported			ASU 2020-06 Adjustment			As Revised
Additional paid-in-capital	$	2,203,778		$	(218,128	)	$	1,985,650
Accumulated deficit	$	(707,534	)	$	111,039		$	(596,495	)
Total stockholders’ equity	$	1,684,547		$	(107,088	)	$	1,577,459

Assets Measured at Fair Value on a Recurring Basis

	At December 31, 2021		Quoted Prices in Active Markets (Level 1)		Significant Other Observable Inputs (Level 2)		Significant Unobservable Inputs (Level 3)
Cash equivalents (1)	$	541,199	$	541,199	$	—	$	—
Corporate debt securities (2)		764,059		—		764,059		—
Debt securities issued by U.S. government agencies (2)		120,868		—		120,868		—
Debt securities issued by the U.S. Treasury (2)		182,634		182,634		—		—
Debt securities issued by states of the U.S. and political subdivisions of the states (3)		174,464		—		174,464		—
Other municipal debt securities (2)		6,099		—		6,099		—
Investment in Bicycle Therapeutics plc (4)		14,330		—		—		14,330
Investment in ProQR Therapeutics N.V. (4)		3,875		3,875		—		—
Total	$	1,807,528	$	727,708	$	1,065,490	$	14,330

	At December 31, 2020		Quoted Prices in Active Markets (Level 1)		Significant Other Observable Inputs (Level 2)
Cash equivalents (1)	$	221,125	$	221,125	$	—
Corporate debt securities (5)		846,315		—		846,315
Debt securities issued by U.S. government agencies (2)		174,861		—		174,861
Debt securities issued by the U.S. Treasury (6)		358,497		358,497		—
Debt securities issued by states of the U.S. and political subdivisions of the states (2)		136,309		—		136,309
Other municipal debt securities (2)		6,225		—		6,225
Investment in ProQR Therapeutics N.V. (4)		2,031		2,031		—
Total	$	1,745,363	$	581,653	$	1,163,710

________________

(1)	Included in cash and cash equivalents on our consolidated balance sheet.

(2)	Included in short-term investments.

(3)	$2.3 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.

(4)	Included in other current assets on our consolidated balance sheet.

(5)	$10.0 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.

(6)	$17.5 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.

Investments (Tables)

12 Months Ended

Dec. 31, 2021

Investments [Abstract]

Contract Maturity of Available-for-Sale Securities

The following table summarizes the contract maturity of the available-for-sale securities we held as of December 31, 2021:

One year or less	51	%
After one year but within two years	34	%
After two years but within three and a half years	15	%
Total	100	%

Summary of Investments

The following is a summary of our investments (in thousands):

	Amortized		Gross Unrealized					Estimated
December 31, 2021	Cost		Gains		Losses			Fair Value
Available-for-sale securities:
Corporate debt securities (1)	$	383,870	$	728	$	(226	)	$	384,372
Debt securities issued by U.S. government agencies		48,493		19		(18	)		48,494
Debt securities issued by the U.S. Treasury (1)		45,424		—		(64	)		45,360
Debt securities issued by states of the U.S. and political subdivisions of the states		134,770		45		(37	)		134,778
Total securities with a maturity of one year or less		612,557		792		(345	)		613,004
Corporate debt securities		382,000		331		(2,644	)		379,687
Debt securities issued by U.S. government agencies		72,935		—		(561	)		72,374
Debt securities issued by the U.S. Treasury		137,635		139		(500	)		137,274
Debt securities issued by states of the U.S. and political subdivisions of the states		39,909		1		(224	)		39,686
Other municipal debt securities		6,136		—		(37	)		6,099
Total securities with a maturity of more than one year		638,615		471		(3,966	)		635,120
Total available-for-sale securities	$	1,251,172	$	1,263	$	(4,311	)	$	1,248,124
Equity securities:
Total equity securities included in other current assets (2)	$	11,897	$	7,145	$	(837	)	$	18,205
Total equity securities included in deposits and other assets (3)		15,615		16,707		—			32,322
Total equity securities	$	27,512	$	23,852	$	(837	)	$	50,527
Total available-for-sale and equity securities	$	1,278,684	$	25,115	$	(5,148	)	$	1,298,651

	Amortized		Gross Unrealized					Estimated
December 31, 2020	Cost		Gains		Losses			Fair Value
Available-for-sale securities:
Corporate debt securities (1)	$	514,182	$	2,194	$	(41	)	$	516,335
Debt securities issued by U.S. government agencies		94,234		354		(2	)		94,586
Debt securities issued by the U.S. Treasury (1)		307,576		233		(9	)		307,800
Debt securities issued by states of the U.S. and political subdivisions of the states		104,271		196		(12	)		104,455
Other municipal debt securities		5,191		—		(7	)		5,184
Total securities with a maturity of one year or less		1,025,454		2,977		(71	)		1,028,360
Corporate debt securities		325,079		4,941		(40	)		329,980
Debt securities issued by U.S. government agencies		80,099		185		(9	)		80,275
Debt securities issued by the U.S. Treasury		50,318		383		(4	)		50,697
Debt securities issued by states of the U.S. and political subdivisions of the states		31,779		91		(16	)		31,854
Other municipal debt securities		1,041		—		—			1,041
Total securities with a maturity of more than one year		488,316		5,600		(69	)		493,847
Total available-for-sale securities	$	1,513,770	$	8,577	$	(140	)	$	1,522,207
Equity securities:
Total equity securities included in other current assets (2)	$	4,712	$	—	$	(2,681	)	$	2,031
Total equity securities included in deposits and other assets (3)		15,062		15,938		—			31,000
Total equity securities	$	19,774	$	15,938	$	(2,681	)	$	33,031
Total available-for-sale and equity securities	$	1,533,544	$	24,515	$	(2,821	)	$	1,555,238

________________

(1)	Includes investments classified as cash equivalents on our consolidated balance sheet.

(2)	Our equity securities included in other current assets consisted of our investments in publicly traded companies. We recognize publicly traded equity securities at fair value.

(3)

Temporarily Impaired Investments

	Number of Investments		Estimated Fair Value		Unrealized Losses
Corporate debt securities		272	$	552,966	$	(2,870	)
Debt securities issued by U.S. government agencies		15		114,338		(579	)
Debt securities issued by the U.S. Treasury		13		134,987		(564	)
Debt securities issued by states of the U.S. and political subdivisions of the states		425		126,401		(261	)
Other municipal debt securities		2		6,099		(37	)
Total temporarily impaired securities		727	$	934,791	$	(4,311	)

Long-Term Obligations and Commitments (Tables)

12 Months Ended

Dec. 31, 2021

Long-Term Obligations and Commitments [Abstract]

Long-Term Obligations

The carrying value of our long-term obligations was as follows (in thousands):

	December 31,
	2021			2020
				(as revised*)
0.125 percent convertible senior notes	$	542,314		$	540,136
1 percent convertible senior notes (1)		—			308,809
0 percent convertible senior notes		619,119			—
Long-term mortgage debt		59,713			59,984
Leases and other obligations		29,904			30,710
Total	$	1,251,050		$	939,639
Less: current portion (1)		(3,526	)		(316,110	)
Total Long-Term Obligations	$	1,247,524		$	623,529

________________

(1)	We classified the carrying value of our 1% Notes as a current liability on our consolidated balance sheet at December 31, 2020 because it matured in November 2021.

Convertible Notes [Abstract]

Maturity Schedules for Annual Debt and Other Obligations

Annual debt and other obligation maturities, including fixed and determinable interest, at December 31, 2021 are as follows (in thousands):

2022	$	3,498
2023		4,180
2024		4,180
2025		1,184,820
2026		3,494
Thereafter		57,439
Subtotal	$	1,257,611
Less: current portion		(3,526	)
Less: fixed and determinable interest		(15,498	)
Less: debt issuance costs		(20,302	)
Plus: lease liabilities		22,058
Plus: other liabilities		7,181
Total long-term debt	$	1,247,524

Amounts Related to Operating Leases

Amounts related to our operating leases were as follows (dollar amounts in millions):

	At December 31, 2021
Right-of-use operating lease assets (1)	$	18.0
Operating lease liabilities (2)	$	22.1
Weighted average remaining lease term	6.6 years
Weighted average discount rate		6.0	%

________________

(1)	Included in deposits and other assets on our consolidated balance sheet.

(2)	Current portion of $2.6 million was included in current portion of long-term obligations on our consolidated balance sheet, with the difference included in long-term obligations.

Future Payments for Operating Lease Liabilities

As of December 31, 2021, the future payments for our operating lease liabilities are as follows (in thousands):

	Operating Leases
Year ending December 31,	$
2022		4,075
2023		4,314
2024		4,223
2025		4,062
2026		3,778
Thereafter		7,035
Total minimum lease payments		27,487
Less:
Imputed interest		(5,429	)
Total operating lease liabilities	$	22,058

0% Notes [Member]

Convertible Notes [Abstract]

Convertible Senior Notes

At December 31, 2021, we had the following 0% Notes outstanding (amounts in millions except interest rate and price per share data):

	0% Notes
Outstanding principal balance	$	632.5
Unamortized debt issuance costs	$	13.4
Maturity date	April 2026
Interest rate	0 percent
Effective interest rate	0.5 percent
Conversion price per share	$	57.84
Effective conversion price per share with call spread	$	76.39
Total shares of common stock subject to conversion		10.9

0.125% Notes [Member]

Convertible Notes [Abstract]

Convertible Senior Notes

At December 31, 2021, we had the following 0.125% Notes outstanding with interest payable semi-annually (amounts in millions except interest rate and price per share data):

	0.125% Notes
Outstanding principal balance	$	548.8
Unamortized debt issuance costs	$	6.5
Maturity date	December 2024
Interest rate	0.125 percent
Effective interest rate	0.5 percent
Conversion price per share	$	83.28
Effective conversion price per share with call spread	$	123.38
Total shares of common stock subject to conversion		6.6

- Definition

Tabular disclosure of long-debt instruments or arrangements, including identification, terms, features, collateral requirements and other information necessary to a fair presentation. These are debt arrangements that originally required repayment more than twelve months after issuance or greater than the normal operating cycle of the entity, if longer.

+ References

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+ Details

Stockholders' Equity (Tables)

12 Months Ended

Dec. 31, 2021

Stockholders' Equity [Abstract]

Stock Option Activity

The following table summarizes the stock option activity under our stock plans for the year ended December 31, 2021 (in thousands, except per share and contractual life data):

	Number of Shares			Weighted Average Exercise Price Per Share		Average Remaining Contractual Term (Years)		Aggregate Intrinsic Value
Outstanding at December 31, 2020		12,439		$	54.11
Granted		3,382		$	53.07
Exercised		(219	)	$	38.69
Cancelled/forfeited/expired		(1,513	)	$	54.65
Outstanding at December 31, 2021		14,089		$	54.04		3.89	$	1,131
Exercisable at December 31, 2021		9,175		$	53.65		2.94	$	1,067

RSU Activity

The following table summarizes the RSU activity for the year ended December 31, 2021 (in thousands, except per share data):

	Number of Shares			Weighted Average Grant Date Fair Value Per Share
Non-vested at December 31, 2020		2,374		$	58.81
Granted		1,548		$	57.69
Vested		(834	)	$	57.47
Cancelled/forfeited		(411	)	$	59.24
Non-vested at December 31, 2021		2,677		$	58.51

Stock-Based Compensation Expense

The following table summarizes stock-based compensation expense for the years ended December 31, 2021, 2020 and 2019 (in thousands):

	Year Ended December 31,
	2021		2020		2019
Cost of sales	$	456	$	1,991	$	438
Research, development and patent		87,522		115,584		95,348
Selling, general and administrative		32,700		112,542		50,788
Total	$	120,678	$	230,117	$	146,574

Weighted-Average Assumptions for Stock Options

Ionis Employee Stock Options:

	Year Ended December 31,
	2021			2020			2019
Risk-free interest rate		0.6	%		1.5	%		2.3	%
Dividend yield		0.0	%		0.0	%		0.0	%
Volatility		54.0	%		58.6	%		60.3	%
Expected life	4.9 years			4.7 years			4.8 years

Ionis Board of Director Stock Options:

	Year Ended December 31,
	2021			2020			2019
Risk-free interest rate		1.2	%		0.5	%		1.9	%
Dividend yield		0.0	%		0.0	%		0.0	%
Volatility		55.9	%		57.6	%		60.7	%
Expected life	7.3 years			6.7 years			6.6 years

Weighted-Average Assumptions for ESPP

Ionis ESPP:

	Year Ended December 31,
	2021			2020			2019
Risk-free interest rate		0.1	%		0.8	%		2.4	%
Dividend yield		0.0	%		0.0	%		0.0	%
Volatility		42.4	%		47.9	%		45.6	%
Expected life	6 months			6 months			6 months

Income Taxes (Tables)

12 Months Ended

Dec. 31, 2021

Income Taxes [Abstract]

Income (Loss) Before Income Taxes

Income (loss) before income taxes is comprised of (in thousands):

	Year Ended December 31,
	2021			2020			2019
				(as revised*)			(as revised*)

United States	$	(29,966	)	$	(137,222	)	$	336,277
Foreign		818			2,670			2,489
Income (loss) before income taxes	$	(29,148	)	$	(134,552	)	$	338,766

Income Tax Expense (Benefit)

Our income tax expense (benefit) was as follows (in thousands):

	Year Ended December 31,
	2021			2020			2019
				(as revised*)			(as revised*)

Current:
Federal	$	(200	)	$	(837	)	$	35,861
State		(690	)		3,782			14,329
Foreign		339			518			413
Total current income tax expense (benefit)		(551	)		3,463			50,603

Deferred:
Federal		—			341,728			904
State		—			—			—
Total deferred income tax benefit		—			341,728			904
Total income tax expense (benefit)	$	(551	)	$	345,191		$	51,507

Reconciliation of Statutory to Effective Tax Rate

	Year Ended December 31,
	2021					2020					2019
						(as revised*)					(as revised*)

Pre-tax income (loss)	$	(29,148	)			$	(134,552	)			$	338,766

Statutory rate		(6,121	)	21.0	%		(28,256	)	21.0	%		71,141		21.0	%
State income tax net of federal benefit		4,278		(14.7	)%		(37,705	)	28.0	%		49,000		14.5	%
Foreign		143		(0.5	)%		49		0.0	%		340		0.1	%
Net change in valuation allowance		2,885		(9.9	)%		460,898		(342.5	)%		(37,314	)	(11.0	)%
Loss on debt transactions		262		(0.9	)%		—		—			9,911		2.9	%
Impact from outside basis differences		—		—			—		—			(16,344	)	(4.8	)%
Tax credits		(23,198	)	79.6	%		(18,774	)	14.0	%		(22,296	)	(6.6	)%
Deferred tax true-up		(24	)	0.1	%		(206	)	0.2	%		646		0.2	%
Tax rate change		12,838		(44.0	)%		(32,951	)	24.5	%		1,248		0.4	%
Non-deductible compensation		5,085		(17.4	)%		7,931		(5.9	)%		3,361		1.0	%
Other non-deductible items		84		(0.3	)%		193		(0.1	)%		329		0.1	%
Stock-based compensation		4,720		(16.2	)%		17,435		(13.0	)%		(4,837	)	(1.4	)%
Foreign-derived intangible income benefit		—		—			—		—			(2,071	)	(0.6	)%
Impacts from Akcea Merger		—		—			(22,032	)	16.4	%		—		—
Other		(1,503	)	5.1	%		(1,391	)	0.9	%		(1,607	)	(0.6	)%
Effective rate	$	(551	)	1.9	%	$	345,191		(256.5	)%	$	51,507		15.2	%

Deferred Tax Assets and Liabilities

Significant components of our deferred tax assets and liabilities as of December 31, 2021 and 2020 are as follows (in thousands):

	Year Ended December 31,
	2021			2020
				(as revised*)

Deferred Tax Assets:
Net operating loss carryovers	$	85,600		$	83,681
Tax credits		269,538			245,746
Deferred revenue		104,330			124,452
Stock-based compensation		86,611			80,055
Intangible and capital assets		92,542			98,443
Convertible debt		45,681			22,395
Interest expense limitation		6,996			—
Other		15,048			13,402
Total deferred tax assets	$	706,346		$	668,174

Deferred Tax Liabilities:
Fixed assets		(3,303	)		(3,611	)
Other		(5,270	)		(5,808	)
Net deferred tax asset	$	697,773		$	658,755
Valuation allowance		(697,773	)		(658,755	)
Total net deferred tax assets and liabilities	$	—		$	—

*	We revised our 2020 and 2019 amounts to reflect the simplified convertible instruments accounting guidance, which we adopted retrospectively. Refer to Note 1, Organization and Significant Accounting Policies, for further information.

Gross Unrecognized Tax Benefits

The following table summarizes our gross unrecognized tax benefits (in thousands):

	Year Ended December 31,
	2021			2020			2019
Beginning balance of unrecognized tax benefits	$	54,163		$	69,784		$	68,301
Decrease for prior period tax positions		(695	)		(24,154	)		(867	)
Increase for prior period tax positions		263			7,023			736
Increase for current period tax positions		1,354			1,510			1,614
Ending balance of unrecognized tax benefits	$	55,085		$	54,163		$	69,784

Collaborative Arrangements and Licensing Agreements (Tables)

12 Months Ended

Dec. 31, 2021

Biogen [Member]

Collaborative Arrangements and Licensing Agreements [Abstract]

Revenue from Collaborative Relationship

During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with Biogen (in millions, except percentage amounts):

	Year Ended December 31,
	2021			2020			2019
SPINRAZA royalties (commercial revenue)	$	267.8		$	286.6		$	293.0
R&D revenue		161.0			122.0			180.6
Total revenue from our relationship with Biogen	$	428.8		$	408.6		$	473.6
Percentage of total revenue		53	%		56	%		42	%

AstraZeneca [Member]

Collaborative Arrangements and Licensing Agreements [Abstract]

Revenue from Collaborative Relationship

During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with AstraZeneca (in millions, except percentage amounts):

	Year Ended December 31,
	2021			2020			2019
R&D revenue	$	254.6		$	88.0		$	28.1
Percentage of total revenue		31	%		12	%		3	%

Bayer [Member]

Collaborative Arrangements and Licensing Agreements [Abstract]

Revenue from Collaborative Relationship

During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with Bayer (in millions, except percentage amounts):

	Year Ended December 31,
	2021			2020			2019
R&D revenue	$	1.1		$	3.2		$	14.3
Percentage of total revenue		0	%		0	%		1	%

GSK [Member]

Collaborative Arrangements and Licensing Agreements [Abstract]

Revenue from Collaborative Relationship

During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with GSK (in millions, except percentage amounts):

	Year Ended December 31,
	2021		2020			2019
R&D revenue	$	—	$	0.2		$	25.4
Percentage of total revenue		—		0	%		2	%

Novartis [Member]

Collaborative Arrangements and Licensing Agreements [Abstract]

Revenue from Collaborative Relationship

During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with Novartis (in millions, except percentage amounts):

	Year Ended December 31,
	2021			2020			2019
R&D revenue	$	25.5		$	1.0		$	187.4
Percentage of total revenue		3	%		0	%		17	%

Roche [Member]

Collaborative Arrangements and Licensing Agreements [Abstract]

Revenue from Collaborative Relationship

During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with Roche (in millions, except percentage amounts):

	Year Ended December 31,
	2021			2020			2019
R&D revenue	$	17.2		$	5.9		$	57.0
Percentage of total revenue		2	%		1	%		5	%

Alnylam [Member]

Collaborative Arrangements and Licensing Agreements [Abstract]

Revenue from Collaborative Relationship

During the years ended December 31, 2021, 2020 and 2019, we earned the following revenue from our relationship with Alnylam (in millions, except percentage amounts):

	Year Ended December 31,
	2021		2020			2019
R&D revenue	$	—	$	47.9		$	24.1
Percentage of total revenue		—		7	%		2	%

Akcea Merger (Tables)

12 Months Ended

Dec. 31, 2021

Akcea Merger [Abstract]

Akcea Merger

The following table summarizes the severance and retention expenses related to the Akcea Merger that we recognized for the periods indicated (in millions):

	Year Ended December 31, 2021		Year Ended December 31, 2020
R&D expenses	$	5.1	$	3.9
SG&A expenses		6.6		11.4
Total	$	11.7	$	15.3

The following table summarizes the severance and retention reserve amounts related to the Akcea Merger that we included in accrued compensation for the period indicated (in millions):

	Year Ended December 31, 2021
Beginning balance as of January 1, 2021	$	14.7
Amount expensed during the year		13.5
Reserve adjustments during the year		(1.8	)
Net amount expensed during the year		11.7
Amounts paid during the year		(26.4	)
Ending balance as of December 31, 2021	$	—

Severance and Retention Costs related to our Restructured Operations (Tables)

12 Months Ended

Dec. 31, 2021

Restructured European Operations [Member]

Severance and Retention Costs [Abstract]

Severance and Retention Costs

The following table summarizes the severance and retention expenses related to our restructured European operations that we recognized for the periods indicated (in millions):

	Year Ended December 31, 2021		Year Ended December 31, 2020
R&D expenses	$	0.6	$	4.2
SG&A expenses		1.1		8.3
Total	$	1.7	$	12.5

	Year Ended December 31, 2021
Beginning balance as of January 1, 2021	$	12.4
Amount expensed during the year		2.6
Reserve adjustments during the year		(0.9	)
Net amount expensed during the year		1.7
Amounts paid during the year		(14.1	)
Ending balance as of December 31, 2021	$	—

Restructured North American TEGSEDI Operations [Member]

Severance and Retention Costs [Abstract]

Severance and Retention Costs

The following table summarizes the severance expenses related to our Restructured North American TEGSEDI Operations that we recognized for the period indicated (in millions):

	Year Ended December 31, 2021
R&D expenses	$	2.3
SG&A expenses		7.1
Total	$	9.4

	Year Ended December 31, 2021
Beginning balance as of January 1, 2021	$	—
Net amount expensed during the year		9.4
Amounts paid during the year		(9.4	)
Ending balance as of December 31, 2021	$	—

Fourth Quarter Financial Data (Unaudited) (Tables)

12 Months Ended

Dec. 31, 2021

Fourth Quarter Financial Data (Unaudited) [Abstract]

Fourth Quarter Financial Data (Unaudited)

Three Months Ended December 31,	2021		2020
Revenue	$	440,006	$	290,281
Operating expenses	$	219,403	$	312,945
Income (loss) from operations	$	220,603	$	(22,664	)
Net income (loss)	$	224,613	$	(355,687	)
Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders	$	224,613	$	(354,532	)
Basic net income (loss) per share (1) (2)	$	1.59	$	(2.54	)
Diluted net income (loss) per share (1) (3)	$	1.41	$	(2.54	)

________________

(1)	We compute net income (loss) per share independently for each quarter during the year.

(2)

Our basic net loss per share for the fourth quarter of 2020 was calculated as follows (in thousands, except per share amounts):

Three Months Ended December 31, 2020	Weighted Average Shares Owned in Akcea		Akcea’s Net Loss Per Share			Basic Net Loss Per Share Calculation
Akcea’s net loss in the pre-merger period attributable to our ownership		77,095	$	(0.05	)	$	(3,603	)
Akcea’s net loss in the post-merger period attributable to our ownership							(85,987	)
Akcea’s total net loss attributable to our ownership						$	(89,590	)
Ionis’ stand-alone net loss							(266,418	)
Net loss available to Ionis common stockholders						$	(356,008	)
Weighted average shares outstanding							139,956
Basic net loss per share						$	(2.54	)

(3)

Three Months Ended December 31, 2021	Income (Numerator)		Shares (Denominator)		Per-Share Amount
Net income available to Ionis common stockholders	$	224,612		141,205	$	1.59
Effect of dilutive securities:
Shares issuable upon exercise of stock options		—		46
Shares issuable upon restricted stock award issuance		—		1,065
Shares issuable related to our ESPP		—		34
Shares issuable related to our 0 percent convertible notes		777		10,936
Shares issuable related to our 0.125 percent convertible notes		716		6,590
Shares issuable related to our 1 percent convertible notes		105		464
Income available to Ionis common stockholders, plus assumed conversions	$	226,210		160,340	$	1.41

Organization and Significant Accounting Policies, Basis of Presentation (Details) - Akcea [Member]	Dec. 31, 2021	Oct. 31, 2020	Sep. 30, 2020	Jun. 30, 2017
Basis of Presentation [Abstract]
Percentage ownership	100.00%	100.00%	76.00%
Maximum [Member]
Basis of Presentation [Abstract]
Percentage ownership		77.00%		100.00%

Organization and Significant Accounting Policies, Basic Net Income (Loss) per Share (Details) - USD ($)
$ / shares in Units, shares in Thousands, $ in Thousands

1 Months Ended

2 Months Ended

3 Months Ended

10 Months Ended

12 Months Ended

Oct. 31, 2020

Dec. 31, 2020

Dec. 31, 2021

Dec. 31, 2020

Oct. 31, 2020

Dec. 31, 2021

Dec. 31, 2020

Dec. 31, 2019

Sep. 30, 2020

Basic Net Income (Loss) per Share [Abstract]

Basic net income (loss) per share (in dollars per share)

$ 1.59

^[1],[2]

$ (2.54)

^[1],[2]

$ (0.20)

$ (3.18)

$ 2.00

Net loss

$ 224,613

$ (354,532)

$ (28,597)

$ (444,263)

$ 278,143

Income (loss) available to Ionis common stockholders

$ 224,612

$ (356,008)

$ (444,464)

$ 280,560

Weighted average shares outstanding (in shares)

141,205

139,956

141,021

139,612

139,998

Ionis [Member]

Basic Net Income (Loss) per Share [Abstract]

Net loss

$ (266,418)

$ (246,702)

$ 246,487

Akcea [Member]

Basic Net Income (Loss) per Share [Abstract]

Percentage ownership

100.00%

76.00%

Basic Net Income (Loss) per Share [Abstract]

Weighted average shares owned in Akcea (in shares)

77,095

Basic net income (loss) per share (in dollars per share)

$ (0.05)

Net loss

$ (3,603)

$ (85,987)

$ (89,590)

Akcea [Member]

Basic Net Income (Loss) per Share [Abstract]

Weighted average shares owned in Akcea (in shares)

77,095

70,100

Basic net income (loss) per share (in dollars per share)

$ (1.45)

$ 0.49

Net loss

$ (85,987)

$ (111,775)

$ (197,762)

$ 34,073

[1]

We compute net income (loss) per share independently for each quarter during the year.

[2]

As discussed in Note 1, Organization and Significant Accounting Policies, we compute basic net income (loss) per share by dividing the total net income (loss) attributable to our common stockholders by our weighted-average number of common shares outstanding during the period. Our basic net income per share for the fourth quarter of 2021 was $1.59.Our basic net loss per share calculation for the fourth quarter of 2020 considered our net loss for Ionis on a stand-alone basis plus our share of Akcea’s net loss for the period. To calculate the portion of Akcea’s net loss attributable to our ownership, we multiplied Akcea’s loss per share by the weighted average shares we owned in Akcea during the period. As a result of this calculation, our total net loss available to Ionis common stockholders for the calculation of net loss per share is different than net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders in the consolidated statements of operations.

Organization and Significant Accounting Policies, Diluted Net Income (Loss) per Share (Details) - USD ($)
$ / shares in Units, shares in Thousands, $ in Thousands

3 Months Ended

12 Months Ended

Dec. 31, 2021

Dec. 31, 2020

Dec. 31, 2021

Dec. 31, 2020

Dec. 31, 2019

Nov. 30, 2021

Apr. 30, 2021

Dec. 31, 2016

Nov. 30, 2014

Net Income (Numerator) [Abstract]

Net income available to Ionis common stockholders

$ 224,612

$ (356,008)

$ (444,464)

$ 280,560

Net income available to Ionis common shareholders

$ 226,210

$ 290,947

Shares (Denominator) [Abstract]

Weighted average shares outstanding (in shares)

141,205

139,956

141,021

139,612

139,998

Effect of Diluted Securities [Abstract]

Shares issuable related to our ESPP (in shares)

Shares used in computing diluted net income per share (in shares)

160,340

141,021

139,612

153,164

Per-Share Amount [Abstract]

Basic net income per share (in dollars per share)

$ 1.59

^[1],[2]

$ (2.54)

^[1],[2]

$ (0.20)

$ (3.18)

$ 2.00

Diluted net income (loss) per share (in dollars per share)

$ 1.41

^[1],[3]

$ (2.54)

^[1]

$ (0.20)

$ (3.18)

$ 1.90

0.125% Notes [Member]

Diluted Net Income per Share [Abstract]

Interest rate on convertible senior notes

0.125%

Net Income (Numerator) [Abstract]

Shares issuable related to our convertible notes

$ 716

$ 860

Effect of Diluted Securities [Abstract]

Shares issuable related to our convertible notes (in shares)

6,590

217

1% Notes [Member]

Diluted Net Income per Share [Abstract]

Interest rate on convertible senior notes

1.00%

Net Income (Numerator) [Abstract]

Shares issuable related to our convertible notes

$ 105

$ 9,527

Effect of Diluted Securities [Abstract]

Shares issuable related to our convertible notes (in shares)

464

10,075

0% Notes [Member]

Diluted Net Income per Share [Abstract]

Interest rate on convertible senior notes

0.00%

Net Income (Numerator) [Abstract]

Shares issuable related to our convertible notes

$ 777

Effect of Diluted Securities [Abstract]

Shares issuable related to our convertible notes (in shares)

10,936

Stock Options [Member]

Effect of Diluted Securities [Abstract]

Shares issuable related to stock-based compensation (in shares)

2,090

Restricted Stock Awards [Member]

Effect of Diluted Securities [Abstract]

Shares issuable related to stock-based compensation (in shares)

1,065

766

[1]	We compute net income (loss) per share independently for each quarter during the year.
[2]	As discussed in Note 1, Organization and Significant Accounting Policies, we compute basic net income (loss) per share by dividing the total net income (loss) attributable to our common stockholders by our weighted-average number of common shares outstanding during the period. Our basic net income per share for the fourth quarter of 2021 was $1.59.Our basic net loss per share calculation for the fourth quarter of 2020 considered our net loss for Ionis on a stand-alone basis plus our share of Akcea’s net loss for the period. To calculate the portion of Akcea’s net loss attributable to our ownership, we multiplied Akcea’s loss per share by the weighted average shares we owned in Akcea during the period. As a result of this calculation, our total net loss available to Ionis common stockholders for the calculation of net loss per share is different than net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders in the consolidated statements of operations.
[3]	We had net income available to Ionis common stockholders for the fourth quarter of 2021. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during the period

Organization and Significant Accounting Policies, Revenue Recognition (Details) $ in Thousands	1 Months Ended				3 Months Ended								12 Months Ended
	Dec. 31, 2021 USD ($) PerformanceObligation	Feb. 28, 2017 USD ($) PerformanceObligation	Jul. 31, 2015 USD ($) PerformanceObligation	May 31, 2015 USD ($) PerformanceObligation	Dec. 31, 2021 USD ($) Target PerformanceObligation	Sep. 30, 2021 USD ($)	Dec. 31, 2020 USD ($)	Dec. 31, 2019 USD ($)	Dec. 31, 2018 USD ($)	Jun. 30, 2018 USD ($) Agreement	Dec. 31, 2017 USD ($) PerformanceObligation	Jun. 30, 2015 USD ($)	Dec. 31, 2021 USD ($) PerformanceObligation	Dec. 31, 2020 USD ($)	Dec. 31, 2019 USD ($)	Oct. 31, 2018 USD ($) PerformanceObligation	Apr. 30, 2018 USD ($) PerformanceObligation
Revenue Recognition [Abstract]
Revenue													$ 810,456	$ 729,264	$ 1,122,599
Biogen [Member]
Revenue Recognition [Abstract]
Number of agreements \| Agreement										2
TEGSEDI and WAYLIVRA [Member]
Revenue Recognition [Abstract]
Revenue													$ 55,500	$ 69,999	$ 42,253
PTC Therapeutics [Member] \| TEGSEDI and WAYLIVRA [Member]
Revenue Recognition [Abstract]
Revenue						$ 4,000
AstraZeneca [Member]
Revenue Recognition [Abstract]
Revenue	$ 200,000
Upfront payment received	$ 200,000
Number of separate performance obligations \| PerformanceObligation	1				1								1
Transaction price	$ 200,000				$ 200,000								$ 200,000
AstraZeneca [Member] \| Eplontersen [Member]
Revenue Recognition [Abstract]
Revenue					200,000
AstraZeneca [Member]
Revenue Recognition [Abstract]
Revenue					10,000								$ 10,000
Upfront payment received			$ 65,000
Number of separate performance obligations \| PerformanceObligation			1
Transaction price			$ 65,000
Roche IONIS-FB-L for Complement-Mediated Diseases [Member]
Revenue Recognition [Abstract]
Revenue							$ (9,200)
Upfront payment received									$ 75,000
Number of separate performance obligations \| PerformanceObligation																1
Transaction price																$ 75,000
Biogen 2018 Strategic Neurology [Member]
Revenue Recognition [Abstract]
Revenue					15,000
Upfront payment received										$ 375,000
Milestone payment received and added to transaction price					$ 7,500
Number of new targets advanced \| Target					2
Number of separate performance obligations \| PerformanceObligation																	1
Transaction price																	$ 552,000
Biogen Treatment of SMA [Member]
Revenue Recognition [Abstract]
Revenue								$ 8,300
Upfront payment received											$ 25,000
Number of separate performance obligations \| PerformanceObligation											1
Transaction price											$ 25,000
Biogen Treatment of SMA [Member] \| ION306 [Member]
Revenue Recognition [Abstract]
Revenue	$ 60,000				$ 60,000
Alnylam [Member]
Revenue Recognition [Abstract]
Revenue							$ 41,200
Bayer [Member]
Revenue Recognition [Abstract]
Upfront payment received				$ 100,000								$ 100,000
Number of separate performance obligations \| PerformanceObligation				3
Bayer [Member]
Revenue Recognition [Abstract]
Upfront payment received		$ 75,000
Number of separate performance obligations \| PerformanceObligation		3
Transaction price		$ 75,000

Organization and Significant Accounting Policies, Contracts Receivable (Details) - Partner	12 Months Ended
	Dec. 31, 2021	Dec. 31, 2020
Contracts Receivable [Abstract]
Period of time after billing when payment is received	3 months
Significant Partners [Abstract]
Number of significant customers	2	2
Contracts Receivables [Member] \| Credit Concentration [Member] \| Two Significant Customers [Member]
Significant Partners [Abstract]
Concentration percentage	93.80%	99.50%

Organization and Significant Accounting Policies, Deferred Revenue (Details) - USD ($) $ in Millions	12 Months Ended
	Dec. 31, 2021	Dec. 31, 2020
Deferred Revenue [Abstract]
Revenue recognized from amounts in beginning deferred revenue balance	$ 98.1	$ 100.4

Organization and Significant Accounting Policies, Research, Development and Patent Expenses (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2021	Dec. 31, 2020	Dec. 31, 2019
Research, Development and Patent Expenses [Abstract]
Research and development expenses	$ 638,200	$ 531,000	$ 461,500
Estimated Amortization Expense [Abstract]
Non-cash charges related to write-down	2,707	1,948	2,226
Patents [Member]
Research, Development and Patent Expenses [Abstract]
Research and development expenses	$ 5,300	4,100	4,200
Estimated useful life	10 years 2 months 12 days
Cost	$ 38,400	37,000
Accumulated amortization	9,400	9,100
Estimated Amortization Expense [Abstract]
2022	2,200
2023	2,100
2024	1,900
2025	1,800
2026	1,800
Non-cash charges related to write-down	$ 2,700	$ 1,900	$ 2,200

Organization and Significant Accounting Policies, Accrued Liabilities (Details) - USD ($) $ in Thousands	Dec. 31, 2021	Dec. 31, 2020
Accrued Liabilities [Abstract]
Clincial expenses	$ 65,730	$ 39,477
In-licensing expenses	8,044	8,264
Commercial expenses	2,471	11,559
Other miscellaneous expenses	12,315	30,861
Total accrued liabilities	$ 88,560	$ 90,161

Organization and Significant Accounting Policies, Noncontrolling Interest in Akcea Therapeutics, Inc. (Details) - Akcea [Member]	Dec. 31, 2021	Oct. 31, 2020	Sep. 30, 2020	Jun. 30, 2017
Noncontrolling Interest in Akcea Therapeutics, Inc. [Abstract]
Percentage ownership	100.00%	100.00%	76.00%
Minimum [Member]
Noncontrolling Interest in Akcea Therapeutics, Inc. [Abstract]
Percentage ownership		68.00%
Maximum [Member]
Noncontrolling Interest in Akcea Therapeutics, Inc. [Abstract]
Percentage ownership		77.00%		100.00%

Organization and Significant Accounting Policies, Cash, Cash Equivalents and Investments (Details) $ in Thousands	12 Months Ended
	Dec. 31, 2021 USD ($) Company	Dec. 31, 2020 USD ($) Investment	Dec. 31, 2019 USD ($)
Cash, Cash Equivalents and Investments [Abstract]
Number of publicly held companies in which there is an equity ownership interest of less than 20% \| Company	3
Number of privately held companies in which there is an equity ownership interest of less than 20% \| Company	7
Number of investments in privately held companies that were revalued \| Investment		3
Gain on investment	$ 10,103	$ 16,540	$ 192
Dynacure [Member]
Cash, Cash Equivalents and Investments [Abstract]
Gain on investment		6,300
Suzhou-Ribo [Member]
Cash, Cash Equivalents and Investments [Abstract]
Gain on investment		3,000
Aro Biotherapeutics [Member]
Cash, Cash Equivalents and Investments [Abstract]
Gain on investment		$ 5,500

Organization and Significant Accounting Policies, Inventory Valuation (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2021	Dec. 31, 2020
Inventory Valuation [Abstract]
Inventory write-off
Raw materials	18,646	16,708
Work in process	5,770	2,252
Finished goods	390	3,005
Total inventory	24,806	21,965
Clinical [Member]
Inventory Valuation [Abstract]
Raw materials	14,507	9,206
Commercial [Member]
Inventory Valuation [Abstract]
Raw materials	$ 4,139	$ 7,502

Organization and Significant Accounting Policies, Property, Plant and Equipment (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2021	Dec. 31, 2020
Property, Plant and Equipment [Abstract]
Less accumulated depreciation	$ (102,653)	$ (87,379)
Property, plant and equipment, net	178,069	181,077
Property, Plant and Equipment, Excluding Land [Member]
Property, Plant and Equipment [Abstract]
Property, plant and equipment	257,660	245,394
Property, plant and equipment, net	155,007	158,015
Computer Software, Laboratory, Manufacturing and Other Equipment [Member]
Property, Plant and Equipment [Abstract]
Property, plant and equipment	$ 72,802	68,990
Computer Software, Laboratory, Manufacturing and Other Equipment [Member] \| Minimum [Member]
Property, Plant and Equipment [Abstract]
Estimated useful lives	3 years
Computer Software, Laboratory, Manufacturing and Other Equipment [Member] \| Maximum [Member]
Property, Plant and Equipment [Abstract]
Estimated useful lives	10 years
Building, Building Improvements and Building Systems [Member]
Property, Plant and Equipment [Abstract]
Property, plant and equipment	$ 144,046	137,879
Building, Building Improvements and Building Systems [Member] \| Minimum [Member]
Property, Plant and Equipment [Abstract]
Estimated useful lives	15 years
Building, Building Improvements and Building Systems [Member] \| Maximum [Member]
Property, Plant and Equipment [Abstract]
Estimated useful lives	40 years
Land Improvements [Member]
Property, Plant and Equipment [Abstract]
Property, plant and equipment	$ 10,077	8,391
Estimated useful lives	20 years
Leasehold Improvements [Member]
Property, Plant and Equipment [Abstract]
Property, plant and equipment	$ 20,144	17,263
Leasehold Improvements [Member] \| Minimum [Member]
Property, Plant and Equipment [Abstract]
Estimated useful lives	5 years
Leasehold Improvements [Member] \| Maximum [Member]
Property, Plant and Equipment [Abstract]
Estimated useful lives	15 years
Furniture and Fixtures [Member]
Property, Plant and Equipment [Abstract]
Property, plant and equipment	$ 10,591	12,871
Furniture and Fixtures [Member] \| Minimum [Member]
Property, Plant and Equipment [Abstract]
Estimated useful lives	5 years
Furniture and Fixtures [Member] \| Maximum [Member]
Property, Plant and Equipment [Abstract]
Estimated useful lives	10 years
Land [Member]
Property, Plant and Equipment [Abstract]
Property, plant and equipment	$ 23,062	$ 23,062

Organization and Significant Accounting Policies, Long-Lived Assets (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2021	Dec. 31, 2020	Dec. 31, 2019
Long-Lived Assets [Abstract]
Charges related to write-down of patents	$ 2,707	$ 1,948	$ 2,226

Organization and Significant Accounting Policies, Stock-Based Compensation Expense (Details)	12 Months Ended
	Dec. 31, 2021 Period $ / shares shares	Dec. 31, 2020 $ / shares
RSUs [Member] \| Employees [Member]
Stock-Based Compensation Expense [Abstract]
Vesting period	4 years
RSUs [Member] \| Board of Directors [Member] \| Granted Prior to June 2020 [Member]
Stock-Based Compensation Expense [Abstract]
Vesting period	4 years
RSUs [Member] \| Board of Directors [Member] \| Granted After June 2020 [Member]
Stock-Based Compensation Expense [Abstract]
Vesting period	1 year
PRSUs [Member] \| Chief Executive Officer, Dr. Brett Monia [Member]
Stock-Based Compensation Expense [Abstract]
Number of performance periods \| Period	3
Vesting period	3 years
Number of units guaranteed to vest \| shares	0
Weighted-average grant date fair value (in dollars per share) \| $ / shares	$ 77.17	$ 93.09
PRSUs [Member] \| Chief Executive Officer, Dr. Brett Monia [Member] \| Minimum [Member]
Stock-Based Compensation Expense [Abstract]
Percentage of units guaranteed to vest	0.00%
PRSUs [Member] \| Chief Executive Officer, Dr. Brett Monia [Member] \| Maximum [Member]
Stock-Based Compensation Expense [Abstract]
Percentage of units guaranteed to vest	150.00%
PRSUs [Member] \| Chief Executive Officer, Dr. Brett Monia [Member] \| One-Year Period [Member]
Stock-Based Compensation Expense [Abstract]
Vesting percentage	33.30%
Vesting period	1 year
PRSUs [Member] \| Chief Executive Officer, Dr. Brett Monia [Member] \| Two-Year Period [Member]
Stock-Based Compensation Expense [Abstract]
Vesting percentage	33.30%
Vesting period	2 years
PRSUs [Member] \| Chief Executive Officer, Dr. Brett Monia [Member] \| Three-Year Period [Member]
Stock-Based Compensation Expense [Abstract]
Vesting percentage	33.30%
Vesting period	3 years

Organization and Significant Accounting Policies, Accumulated Other Comprehensive Loss (Details) - USD ($)
$ in Thousands

12 Months Ended

Dec. 31, 2021

Dec. 31, 2020

Dec. 31, 2019

Accumulated Other Comprehensive Loss [Roll Forward]

Balance

$ 743,282

$ 1,577,459

$ 1,100,623

Adjustments to other comprehensive loss from purchase of noncontrolling interest of Akcea Therapeutics, Inc.

(127)

Net other comprehensive loss for the period

(11,597)

4,219

6,726

Balance

771,737

743,282

1,577,459

Income tax expense (benefit) included in other comprehensive loss

(1,400)

Accumulated Other Comprehensive Loss [Member]

Accumulated Other Comprehensive Loss [Roll Forward]

Balance

(21,071)

(25,290)

(32,016)

Balance

(32,668)

(21,071)

(25,290)

Unrealized Gains (Losses) on Securities [Member]

Accumulated Other Comprehensive Loss [Roll Forward]

Other comprehensive loss before reclassifications, net of tax

^[1]

(11,486)

3,729

6,633

Currency Translation Adjustment [Member]

Accumulated Other Comprehensive Loss [Roll Forward]

Other comprehensive loss before reclassifications, net of tax

$ (111)

$ 617

$ 93

[1]	We did not have tax expense included in our other comprehensive loss for the years ended December 31, 2021 and 2020. For the year ended December 31, 2019, we had a tax benefit of $1.4 million included in other comprehensive loss.

- Definition

Amount after tax and reclassification adjustments of other comprehensive income (loss).

+ References

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+ Details

- Definition

Amount of tax expense (benefit) allocated to other comprehensive income (loss).

+ References

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+ Details

- Definition

Amount of stockholders' equity (deficit), net of receivables from officers, directors, owners, and affiliates of the entity, attributable to both the parent and noncontrolling interests. Amount excludes temporary equity. Alternate caption for the concept is permanent equity.

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+ Details

Organization and Significant Accounting Policies, Convertible Debt (Details)
$ / shares in Units, $ in Thousands

1 Months Ended

3 Months Ended

12 Months Ended

Apr. 30, 2021

USD ($)

Dec. 31, 2019

USD ($)

Dec. 31, 2021

USD ($)

$ / shares

Dec. 31, 2020

USD ($)

Note

$ / shares

Dec. 31, 2021

USD ($)

$ / shares

Dec. 31, 2020

USD ($)

Note

$ / shares

Dec. 31, 2019

USD ($)

$ / shares

Nov. 30, 2021

Dec. 31, 2018

USD ($)

Dec. 31, 2016

USD ($)

Nov. 30, 2014

USD ($)

Convertible Debt [Abstract]

Number of outstanding convertible notes | Note

Consolidated Balance Sheet [Abstract]

1 percent convertible senior notes, net

$ 0

$ 308,809

$ 0

$ 308,809

Additional paid-in capital

1,964,167

1,895,519

1,964,167

1,895,519

Accumulated deficit

(1,159,903)

(1,131,306)

(1,159,903)

(1,131,306)

Consolidated Statement of Operations [Abstract]

Interest expense

(9,349)

(9,510)

$ (12,440)

Loss on early retirement of debt

(8,627)

(66,196)

Income (loss) before income tax benefit (expense)

(29,148)

(134,552)

338,766

Income tax expense

551

(345,191)

(51,507)

Net income (loss)

224,613

(355,687)

(28,597)

(479,743)

287,259

Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders

$ 224,613

$ (354,532)

$ (28,597)

$ (444,263)

$ 278,143

Basic net loss per share (in dollars per share) | $ / shares

$ 1.59

^[1],[2]

$ (2.54)

^[1],[2]

$ (0.20)

$ (3.18)

$ 2.00

Diluted net loss per share (in dollars per share) | $ / shares

$ 1.41

^[1],[3]

$ (2.54)

^[1]

$ (0.20)

$ (3.18)

$ 1.90

Consolidated Statements of Stockholders' Equity [Abstract]

Balance

$ 1,577,459

$ 771,737

$ 743,282

$ 771,737

$ 743,282

$ 1,577,459

$ 1,100,623

Additional Paid In Capital [Member]

Consolidated Statement of Operations [Abstract]

Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders

Consolidated Statements of Stockholders' Equity [Abstract]

Balance

1,985,650

1,964,167

1,895,519

1,964,167

1,895,519

1,985,650

1,833,668

Accumulated Deficit [Member]

Consolidated Statement of Operations [Abstract]

Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders

(28,597)

(444,263)

278,143

Consolidated Statements of Stockholders' Equity [Abstract]

Balance

(596,495)

(1,159,903)

(1,131,306)

(1,159,903)

(1,131,306)

(596,495)

(840,251)

Total Ionis Stockholders' Equity [Member]

Consolidated Statement of Operations [Abstract]

Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders

(28,597)

(444,263)

278,143

Consolidated Statements of Stockholders' Equity [Abstract]

Balance

$ 1,364,005

$ 771,737

$ 743,282

$ 771,737

$ 743,282

$ 1,364,005

$ 961,539

0.125 Percent Convertible Senior Notes [Member]

Convertible Debt [Abstract]

Interest rate on convertible senior notes

0.125%

Consolidated Balance Sheet [Abstract]

Convertible senior notes

$ 542,314

$ 540,136

$ 542,314

$ 540,136

Consolidated Statement of Operations [Abstract]

Effective interest rate

0.50%

1 Percent Convertible Senior Notes [Member]

Convertible Debt [Abstract]

Interest rate on convertible senior notes

1.00%

Face amount of offering

$ 185,500

$ 500,000

Consolidated Statement of Operations [Abstract]

Loss on early retirement of debt

$ 8,600

$ (66,200)

Effective interest rate

1.40%

0 Percent Convertible Senior Notes [Member]

Convertible Debt [Abstract]

Interest rate on convertible senior notes

0.00%

Face amount of offering

$ 632,500

Consolidated Balance Sheet [Abstract]

Convertible senior notes

$ 619,119

$ 0

$ 619,119

$ 0

Consolidated Statement of Operations [Abstract]

Effective interest rate

0.50%

As Previously Reported [Member]

Consolidated Balance Sheet [Abstract]

1 percent convertible senior notes, net

293,161

Additional paid-in capital

2,113,646

Accumulated deficit

(1,249,368)

Consolidated Statement of Operations [Abstract]

Interest expense

(44,990)

$ (48,768)

Loss on early retirement of debt

(21,865)

Income (loss) before income tax benefit (expense)

(170,032)

346,769

Income tax expense

(316,734)

(43,507)

Net income (loss)

(486,766)

303,262

Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders

$ (451,286)

$ 294,146

Basic net loss per share (in dollars per share) | $ / shares

$ (3.23)

$ 2.12

Diluted net loss per share (in dollars per share) | $ / shares

$ (3.23)

$ 2.08

Consolidated Statements of Stockholders' Equity [Abstract]

Balance

$ 1,684,547

843,347

$ 843,347

$ 1,684,547

As Previously Reported [Member] | Additional Paid In Capital [Member]

Consolidated Statements of Stockholders' Equity [Abstract]

Balance

2,203,778

2,113,646

2,203,778

As Previously Reported [Member] | Accumulated Deficit [Member]

Consolidated Statements of Stockholders' Equity [Abstract]

Balance

(707,534)

(1,249,368)

(707,534)

As Previously Reported [Member] | 0.125 Percent Convertible Senior Notes [Member]

Consolidated Balance Sheet [Abstract]

Convertible senior notes

455,719

Adjustment [Member] | ASU 2020-06 [Member]

Consolidated Balance Sheet [Abstract]

1 percent convertible senior notes, net

15,648

Additional paid-in capital

(218,127)

Accumulated deficit

118,062

Net deferred tax assets

Consolidated Statement of Operations [Abstract]

Interest expense

35,480

36,328

Loss on early retirement of debt

(44,331)

Income (loss) before income tax benefit (expense)

35,480

(8,003)

Income tax expense

(28,457)

(8,000)

Net income (loss)

7,023

(16,003)

Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders

$ 7,023

$ (16,003)

Basic net loss per share (in dollars per share) | $ / shares

$ 0.05

$ (0.12)

Diluted net loss per share (in dollars per share) | $ / shares

$ 0.05

$ (0.18)

Consolidated Statements of Stockholders' Equity [Abstract]

Balance

(107,088)

(100,065)

$ (100,065)

$ (107,088)

Adjustment [Member] | ASU 2020-06 [Member] | Additional Paid In Capital [Member]

Consolidated Statements of Stockholders' Equity [Abstract]

Balance

(218,128)

(218,127)

(218,128)

Adjustment [Member] | ASU 2020-06 [Member] | Accumulated Deficit [Member]

Consolidated Statements of Stockholders' Equity [Abstract]

Balance

$ 111,039

118,062

$ 111,039

Adjustment [Member] | ASU 2020-06 [Member] | 0.125 Percent Convertible Senior Notes [Member]

Consolidated Balance Sheet [Abstract]

Convertible senior notes

$ 84,417

[1]	We compute net income (loss) per share independently for each quarter during the year.
[2]	As discussed in Note 1, Organization and Significant Accounting Policies, we compute basic net income (loss) per share by dividing the total net income (loss) attributable to our common stockholders by our weighted-average number of common shares outstanding during the period. Our basic net income per share for the fourth quarter of 2021 was $1.59.Our basic net loss per share calculation for the fourth quarter of 2020 considered our net loss for Ionis on a stand-alone basis plus our share of Akcea’s net loss for the period. To calculate the portion of Akcea’s net loss attributable to our ownership, we multiplied Akcea’s loss per share by the weighted average shares we owned in Akcea during the period. As a result of this calculation, our total net loss available to Ionis common stockholders for the calculation of net loss per share is different than net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders in the consolidated statements of operations.
[3]	We had net income available to Ionis common stockholders for the fourth quarter of 2021. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during the period

Organization and Significant Accounting Policies, Call Spread (Details)	Dec. 31, 2021	Apr. 30, 2021	Dec. 31, 2020	Dec. 31, 2019
0 Percent Convertible Senior Notes [Member]
Call Spread [Abstract]
Interest rate on convertible senior notes	0.00%	0.00%		0.00%
0.125 Percent Convertible Senior Notes [Member]
Call Spread [Abstract]
Interest rate on convertible senior notes	0.125%		0.125%	0.125%

Organization and Significant Accounting Policies, Segment Information (Details) - Segment	12 Months Ended
	Dec. 31, 2021	Dec. 31, 2020
Segment Information [Abstract]
Number of operating segments	1	2

Organization and Significant Accounting Policies, Fair Value Measurements (Details) - USD ($)
$ in Thousands

Dec. 31, 2021

Apr. 30, 2021

Dec. 31, 2020

Dec. 31, 2019

0.125% Notes [Member]

Fair Value Measurements [Abstract]

Interest rate on convertible senior notes

0.125%

0% Notes [Member]

Fair Value Measurements [Abstract]

Interest rate on convertible senior notes

0.00%

Recurring Basis [Member]

Fair Value Measurements [Abstract]

Cash equivalents

^[1]

$ 541,199

$ 221,125

Total

1,807,528

1,745,363

Recurring Basis [Member] | Bicycle Therapeutics plc [Member]

Fair Value Measurements [Abstract]

Investment

^[2]

14,330

Recurring Basis [Member] | ProQR Therapeutics N.V. [Member]

Fair Value Measurements [Abstract]

Investment

^[2]

3,875

2,031

Recurring Basis [Member] | Corporate Debt Securities [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

764,059

^[3]

846,315

^[4]

Recurring Basis [Member] | Corporate Debt Securities [Member] | Cash and Cash Equivalents [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

2,300

10,000

Recurring Basis [Member] | Debt Securities Issued by U.S. Government Agencies [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

^[3]

120,868

174,861

Recurring Basis [Member] | Debt Securities Issued by U.S. Government Agencies [Member] | Cash and Cash Equivalents [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

17,500

Recurring Basis [Member] | Debt Securities Issued by the U.S. Treasury [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

182,634

^[3]

358,497

^[5]

Recurring Basis [Member] | Debt Securities Issued by States of the U.S. and Political Subdivisions of the States [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

174,464

^[6]

136,309

^[3]

Recurring Basis [Member] | Other Municipal Debt Securities [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

^[3]

6,099

6,225

Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member]

Fair Value Measurements [Abstract]

Cash equivalents

541,199

221,125

Total

727,708

581,653

Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member] | Bicycle Therapeutics plc [Member]

Fair Value Measurements [Abstract]

Investment

Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member] | ProQR Therapeutics N.V. [Member]

Fair Value Measurements [Abstract]

Investment

3,875

2,031

Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member] | Corporate Debt Securities [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member] | Debt Securities Issued by U.S. Government Agencies [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member] | Debt Securities Issued by the U.S. Treasury [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

182,634

358,497

Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member] | Debt Securities Issued by States of the U.S. and Political Subdivisions of the States [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

Recurring Basis [Member] | Quoted Prices in Active Markets (Level 1) [Member] | Other Municipal Debt Securities [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member]

Fair Value Measurements [Abstract]

Cash equivalents

Total

1,065,490

1,163,710

Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | 0.125% Notes [Member]

Fair Value Measurements [Abstract]

Fair value of convertible notes

495,400

Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | 0% Notes [Member]

Fair Value Measurements [Abstract]

Fair value of convertible notes

559,200

Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | Bicycle Therapeutics plc [Member]

Fair Value Measurements [Abstract]

Investment

Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | ProQR Therapeutics N.V. [Member]

Fair Value Measurements [Abstract]

Investment

Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | Corporate Debt Securities [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

764,059

846,315

Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | Debt Securities Issued by U.S. Government Agencies [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

120,868

174,861

Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | Debt Securities Issued by the U.S. Treasury [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | Debt Securities Issued by States of the U.S. and Political Subdivisions of the States [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

174,464

136,309

Recurring Basis [Member] | Significant Other Observable Inputs (Level 2) [Member] | Other Municipal Debt Securities [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

6,099

6,225

Recurring Basis [Member] | Significant Unobservable Inputs (Level 3) [Member]

Fair Value Measurements [Abstract]

Cash equivalents

Total

14,330

$ 0

Recurring Basis [Member] | Significant Unobservable Inputs (Level 3) [Member] | Bicycle Therapeutics plc [Member]

Fair Value Measurements [Abstract]

Investment

14,330

Recurring Basis [Member] | Significant Unobservable Inputs (Level 3) [Member] | ProQR Therapeutics N.V. [Member]

Fair Value Measurements [Abstract]

Investment

Recurring Basis [Member] | Significant Unobservable Inputs (Level 3) [Member] | Corporate Debt Securities [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

Recurring Basis [Member] | Significant Unobservable Inputs (Level 3) [Member] | Debt Securities Issued by U.S. Government Agencies [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

Recurring Basis [Member] | Significant Unobservable Inputs (Level 3) [Member] | Debt Securities Issued by the U.S. Treasury [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

Recurring Basis [Member] | Significant Unobservable Inputs (Level 3) [Member] | Debt Securities Issued by States of the U.S. and Political Subdivisions of the States [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

Recurring Basis [Member] | Significant Unobservable Inputs (Level 3) [Member] | Other Municipal Debt Securities [Member]

Fair Value Measurements [Abstract]

Available-for-sale securities

$ 0

[1]	Included in cash and cash equivalents on our consolidated balance sheet.
[2]	Included in other current assets on our consolidated balance sheet.
[3]	Included in short-term investments.
[4]	$10.0 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.
[5]	$17.5 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.
[6]	$2.3 million included in cash and cash equivalents on our consolidated balance sheet, with the difference included in short-term investments on our consolidated balance sheet.

Investments, Contract Maturity of Available-for-Sale Securities (Details)	12 Months Ended
	Dec. 31, 2021 Company
Contract Maturity of Available-for-Sale Securities [Abstract]
One year or less	51.00%
After one year but within two years	34.00%
After two years but within three and a half years	15.00%
Total	100.00%
Percentage of available-for-sale securities with a maturity of less than two years	85.00%
Maximum contract maturity period, range 1	1 year
Maximum contract maturity period, range 2	2 years
Maximum contract maturity period, range 3	3 years 6 months
Ownership Interests in Private and Public Companies [Abstract]
Number of privately held companies in which there is an equity ownership interest of less than 20%	7
Number of publicly held companies in which there is an equity ownership interest of less than 20%	3

Investments, Summary of Investments (Details) - USD ($)
$ in Thousands

12 Months Ended

Dec. 31, 2021

Dec. 31, 2020

Summary of Investments [Abstract]

Amortized cost

$ 1,278,684

$ 1,533,544

Gross unrealized gains

25,115

24,515

Gross unrealized losses

(5,148)

(2,821)

Estimated fair value

1,298,651

1,555,238

Available-for-sale Securities [Member]

Summary of Investments [Abstract]

Amortized cost

1,251,172

1,513,770

Gross unrealized gains

1,263

8,577

Gross unrealized losses

(4,311)

(140)

Estimated fair value

1,248,124

1,522,207

Available-for-sale Securities [Member] | Securities with Maturity of One Year or Less [Member]

Summary of Investments [Abstract]

Amortized cost

612,557

1,025,454

Gross unrealized gains

792

2,977

Gross unrealized losses

(345)

(71)

Estimated fair value

613,004

1,028,360

Available-for-sale Securities [Member] | Securities with Maturity of More than One Year [Member]

Summary of Investments [Abstract]

Amortized cost

638,615

488,316

Gross unrealized gains

471

5,600

Gross unrealized losses

(3,966)

(69)

Estimated fair value

635,120

493,847

Corporate Debt Securities [Member] | Securities with Maturity of One Year or Less [Member]

Summary of Investments [Abstract]

Amortized cost

^[1]

383,870

514,182

Gross unrealized gains

728

2,194

Gross unrealized losses

(226)

(41)

Estimated fair value

384,372

516,335

Corporate Debt Securities [Member] | Securities with Maturity of More than One Year [Member]

Summary of Investments [Abstract]

Amortized cost

382,000

325,079

Gross unrealized gains

331

4,941

Gross unrealized losses

(2,644)

(40)

Estimated fair value

379,687

329,980

Debt Securities Issued by U.S. Government Agencies [Member] | Securities with Maturity of One Year or Less [Member]

Summary of Investments [Abstract]

Amortized cost

48,493

94,234

Gross unrealized gains

354

Gross unrealized losses

(18)

(2)

Estimated fair value

48,494

94,586

Debt Securities Issued by U.S. Government Agencies [Member] | Securities with Maturity of More than One Year [Member]

Summary of Investments [Abstract]

Amortized cost

72,935

80,099

Gross unrealized gains

185

Gross unrealized losses

(561)

(9)

Estimated fair value

72,374

80,275

Debt Securities Issued by the U.S. Treasury [Member] | Securities with Maturity of One Year or Less [Member]

Summary of Investments [Abstract]

Amortized cost

^[1]

45,424

307,576

Gross unrealized gains

233

Gross unrealized losses

(64)

(9)

Estimated fair value

45,360

307,800

Debt Securities Issued by the U.S. Treasury [Member] | Securities with Maturity of More than One Year [Member]

Summary of Investments [Abstract]

Amortized cost

137,635

50,318

Gross unrealized gains

139

383

Gross unrealized losses

(500)

(4)

Estimated fair value

137,274

50,697

Debt Securities Issued by States of the U.S. and Political Subdivisions of the States [Member] | Securities with Maturity of One Year or Less [Member]

Summary of Investments [Abstract]

Amortized cost

134,770

104,271

Gross unrealized gains

196

Gross unrealized losses

(37)

(12)

Estimated fair value

134,778

104,455

Debt Securities Issued by States of the U.S. and Political Subdivisions of the States [Member] | Securities with Maturity of More than One Year [Member]

Summary of Investments [Abstract]

Amortized cost

39,909

31,779

Gross unrealized gains

Gross unrealized losses

(224)

(16)

Estimated fair value

39,686

31,854

Other Municipal Debt Securities [Member] | Securities with Maturity of One Year or Less [Member]

Summary of Investments [Abstract]

Amortized cost

5,191

Gross unrealized gains

Gross unrealized losses

(7)

Estimated fair value

5,184

Other Municipal Debt Securities [Member] | Securities with Maturity of More than One Year [Member]

Summary of Investments [Abstract]

Amortized cost

6,136

1,041

Gross unrealized gains

Gross unrealized losses

(37)

Estimated fair value

6,099

1,041

Equity Securities [Member]

Summary of Investments [Abstract]

Amortized cost

27,512

19,774

Gross unrealized gains

23,852

15,938

Gross unrealized losses

(837)

(2,681)

Estimated fair value

50,527

33,031

Equity Securities in Publicly Traded Company [Member]

Summary of Investments [Abstract]

Amortized cost

^[2]

11,897

4,712

Gross unrealized gains

7,145

Gross unrealized losses

(837)

(2,681)

Estimated fair value

18,205

2,031

Equity Securities in Private Companies [Member]

Summary of Investments [Abstract]

Amortized cost

^[3]

15,615

15,062

Gross unrealized gains

16,707

15,938

Gross unrealized losses

Estimated fair value

$ 32,322

$ 31,000

[1]	Includes investments classified as cash equivalents on our consolidated balance sheet.
[2]	Our equity securities included in other current assets consisted of our investments in publicly traded companies. We recognize publicly traded equity securities at fair value.
[3]	Our equity securities included in deposits and other assets consisted of our investments in privately held companies. We recognize our private company equity securities at cost minus impairments, plus or minus changes resulting from observable price changes in orderly transactions for the identical or similar investment of the same issuer on our consolidated balance sheet.

Investments, Investments Temporarily Impaired (Details) $ in Thousands	Dec. 31, 2021 USD ($) Investment
Temporarily Impaired Investments [Abstract]
Number of investments \| Investment	727
Estimated fair value, less than 12 months of temporary impairment	$ 934,791
Unrealized losses, less than 12 months of temporary impairment	$ (4,311)
Corporate Debt Securities [Member]
Temporarily Impaired Investments [Abstract]
Number of investments \| Investment	272
Estimated fair value, less than 12 months of temporary impairment	$ 552,966
Unrealized losses, less than 12 months of temporary impairment	$ (2,870)
Debt Securities Issued by U.S. Government Agencies [Member]
Temporarily Impaired Investments [Abstract]
Number of investments \| Investment	15
Estimated fair value, less than 12 months of temporary impairment	$ 114,338
Unrealized losses, less than 12 months of temporary impairment	$ (579)
Debt Securities Issued by the U.S. Treasury [Member]
Temporarily Impaired Investments [Abstract]
Number of investments \| Investment	13
Estimated fair value, less than 12 months of temporary impairment	$ 134,987
Unrealized losses, less than 12 months of temporary impairment	$ (564)
Debt Securities Issued by States of the U.S. and Political Subdivisions of the States [Member]
Temporarily Impaired Investments [Abstract]
Number of investments \| Investment	425
Estimated fair value, less than 12 months of temporary impairment	$ 126,401
Unrealized losses, less than 12 months of temporary impairment	$ (261)
Other Municipal Debt Securities [Member]
Temporarily Impaired Investments [Abstract]
Number of investments \| Investment	2
Estimated fair value, less than 12 months of temporary impairment	$ 6,099
Unrealized losses, less than 12 months of temporary impairment	$ (37)

Long-Term Obligations and Commitments, Long-Term Obligations (Details) - USD ($)
$ in Thousands

Dec. 31, 2021

Nov. 30, 2021

Apr. 30, 2021

Dec. 31, 2020

Dec. 31, 2019

Dec. 31, 2016

Nov. 30, 2014

Long-Term Obligations [Abstract]

Long-term mortgage debt

$ 59,713

$ 59,984

Leases and other obligations

29,904

30,710

Total

1,251,050

939,639

Less: current portion

(3,526)

(316,110)

^[1]

Total Long-Term Obligations

1,247,524

623,529

0.125 Percent Convertible Senior Notes [Member]

Long-Term Obligations [Abstract]

Convertible senior notes

$ 542,314

$ 540,136

Interest rate on convertible senior notes

0.125%

1 Percent Convertible Senior Notes [Member]

Long-Term Obligations [Abstract]

Convertible senior notes

$ 0

$ 308,809

^[1]

Interest rate on convertible senior notes

1.00%

0 Percent Convertible Senior Notes [Member]

Long-Term Obligations [Abstract]

Convertible senior notes

$ 619,119

$ 0

Interest rate on convertible senior notes

0.00%

[1]	We classified the carrying value of our 1% Notes as a current liability on our consolidated balance sheet at December 31, 2020 because it matured in November 2021.

Long-Term Obligations and Commitments, Convertible Debt and Call Spread (Details) - USD ($) $ / shares in Units, $ in Thousands, shares in Millions	1 Months Ended			12 Months Ended
	Nov. 30, 2021	Apr. 30, 2021	Dec. 31, 2019	Dec. 31, 2021	Dec. 31, 2020	Dec. 31, 2019	Dec. 31, 2016	Nov. 30, 2014
Convertible Debt [Abstract]
Repurchase of convertible notes				$ 61,967	$ 0	$ 0
Unamortized debt issuance costs				20,302
Cost of call spread		$ 46,900	$ 52,600
Purchase of note hedges		136,700	108,700	136,620	0	108,684
Proceeds from issuance of warrants		89,800	$ 56,100	89,752	0	56,110
Loss on early retirement of debt				(8,627)	0	(66,196)
Amortization of debt discount and debt issuance costs				4,900	$ 3,200	$ 2,900
0% Notes [Member]
Convertible Debt [Abstract]
Face amount of offering		$ 632,500
Outstanding principal balance				632,500
Unamortized debt issuance costs				$ 13,400
Maturity date				Apr. 30, 2026
Interest rate		0.00%	0.00%	0.00%		0.00%
Effective interest rate				0.50%
Conversion price per share (in dollars per share)				$ 57.84
Effective conversion price per share with call spread (in dollars per share)				$ 76.39
Total shares of common stock subject to conversion (in shares)				10.9
Percentage of principal amount used as purchase price upon occurrence of fundamental change				100.00%
0.125% Notes [Member]
Convertible Debt [Abstract]
Outstanding principal balance				$ 548,800
Unamortized debt issuance costs				$ 6,500
Maturity date				Dec. 31, 2024
Interest rate			0.125%	0.125%	0.125%	0.125%
Effective interest rate				0.50%
Conversion price per share (in dollars per share)				$ 83.28
Effective conversion price per share with call spread (in dollars per share)				$ 123.38
Total shares of common stock subject to conversion (in shares)				6.6
Percentage of principal amount used as purchase price upon occurrence of fundamental change				100.00%
0.125% Convertible Senior Notes Issued in Exchange for 1 Percent Notes [Member]
Convertible Debt [Abstract]
Face amount of offering			$ 439,300			$ 439,300
0.125% Convertible Senior Notes Issued under Subscription Agreements [Member]
Convertible Debt [Abstract]
Face amount of offering			109,500			109,500
1% Notes [Member]
Convertible Debt [Abstract]
Face amount of offering							$ 185,500	$ 500,000
Principal amount repurchased		$ 247,900	375,600	$ 247,900		375,600
Repurchase of convertible notes	$ 62,000	$ 257,000
Outstanding principal balance			$ 309,900			$ 309,900
Interest rate	1.00%	1.00%	1.00%	1.00%	1.00%	1.00%	1.00%	1.00%
Effective interest rate				1.40%
Loss on early retirement of debt		$ 8,600	$ (66,200)
Percentage of principal amount used as purchase price upon occurrence of fundamental change				100.00%
2.75% Convertible Senior Notes [Member]
Convertible Debt [Abstract]
Interest rate							2.75%

Long-Term Obligations and Commitments, Research and Development and Manufacturing Facilities (Details) $ in Millions	1 Months Ended	12 Months Ended
	Jul. 31, 2017 USD ($) Facility	Dec. 31, 2021
Research and Development and Manufacturing Facilities [Abstract]
Number of purchased facilities financed with mortgage debt \| Facility	2
Long-term Mortgage Debt [Member]
Research and Development and Manufacturing Facilities [Abstract]
Face amount	$ 60.4
Primary R&D Facility [Member]
Research and Development and Manufacturing Facilities [Abstract]
Payment to acquire building	$ 79.4
Interest rate	3.88%
Period to make interest only payments on mortgage loan		5 years
Manufacturing Facility [Member]
Research and Development and Manufacturing Facilities [Abstract]
Payment to acquire building	$ 14.0
Interest rate	4.20%
Period to make interest only payments on mortgage loan		5 years

Long-Term Obligations and Commitments, Maturity Schedules for Annual Debt and Other Obligations (Details) - USD ($)
$ in Thousands

Dec. 31, 2021

Dec. 31, 2020

Annual Debt and Other Obligation Maturities [Abstract]

$ 3,498

4,180

4,180

1,184,820

3,494

57,439

1,257,611

Less: current portion

(3,526)

$ (316,110)

^[1]

Less: fixed and determinable interest

(15,498)

Less: debt issuance costs

(20,302)

Plus: lease liabilities

^[2]

22,058

Plus: other other liabilities

7,181

Total long-term debt

$ 1,247,524

$ 623,529

[1]	We classified the carrying value of our 1% Notes as a current liability on our consolidated balance sheet at December 31, 2020 because it matured in November 2021.
[2]	Current portion of $2.6 million was included in current portion of long-term obligations on our consolidated balance sheet, with the difference included in long-term obligations.

Long-Term Obligations and Commitments, Operating Leases (Details)
$ in Thousands

1 Months Ended

12 Months Ended

Jan. 31, 2022

USD ($)

Dec. 31, 2021

USD ($)

Option

Dec. 31, 2020

USD ($)

Dec. 31, 2019

USD ($)

Operating Leases [Abstract]

Lease payments to be made over initial term of lease

$ 27,487

Right-of-use operating lease assets

^[1]

$ 18,000

Operating Lease, Right-of-Use Asset, Statement of Financial Position [Extensible List]

Other Assets, Noncurrent

Operating lease liabilities

^[2]

$ 22,058

Weighted average remaining lease term

6 years 7 months 6 days

Weighted average discount rate

6.00%

Current portion of operating lease liabilities

$ 2,600

Operating Lease, Liability, Current, Statement of Financial Position [Extensible List]

Long-term Obligations, Excluding Convertible Debt, Current

Operating Lease, Liability, Noncurrent, Statement of Financial Position [Extensible List]

Long-term Obligations Excluding Convertible Debt, Noncurrent

Operating lease cash payments

$ 3,300

$ 3,800

$ 3,900

Carlsbad Facility [Member]

Operating Leases [Abstract]

Number of options to extend lease | Option

Term of lease extension

5 years

Carlsbad Office Spaces [Member]

Operating Leases [Abstract]

Number of options to extend lease | Option

Term of lease extension

5 years

Boston Office Space [Member]

Operating Leases [Abstract]

Term of lease extension

5 years

Initial term of operating lease

123 months

Period of free rent under lease

3 months

Tenant improvement allowance

$ 3,800

Subleased Office Space in Boston [Member] | Subsequent Event [Member]

Operating Leases [Abstract]

Term of sublease

83 months

Period of free rent under sublease

7 months

Lease payments to be received under sublease

$ 9,600

Another Office Space in Boston [Member]

Operating Leases [Abstract]

Number of options to extend lease | Option

Term of lease extension

5 years

Initial term of operating lease

91 months

Period of free rent under lease

7 months

Lease payments to be made over initial term of lease

$ 6,800

[1]	Included in deposits and other assets on our consolidated balance sheet.
[2]	Current portion of $2.6 million was included in current portion of long-term obligations on our consolidated balance sheet, with the difference included in long-term obligations.

Long-Term Obligations and Commitments, Future Payments for Operating Lease Liabilities (Details) - USD ($)
$ in Thousands

12 Months Ended

Dec. 31, 2021

Dec. 31, 2020

Dec. 31, 2019

Annual Future Payments for Operating Lease Liabilities [Abstract]

$ 4,075

4,314

4,223

4,062

3,778

7,035

Total minimum lease payments

27,487

Less: Imputed interest

(5,429)

Total operating lease liabilities

^[1]

22,058

Rent expense

$ 3,400

$ 3,700

$ 3,600

[1]	Current portion of $2.6 million was included in current portion of long-term obligations on our consolidated balance sheet, with the difference included in long-term obligations.

Stockholders' Equity, Preferred and Common Stock (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2021	Dec. 31, 2020	Dec. 31, 2019
Common Stock [Abstract]
Common stock, shares authorized to issue (in shares)	300,000,000	300,000,000
Common stock, shares issued (in shares)	141,210,015	140,365,594
Common stock, shares outstanding (in shares)	141,210,015	140,365,594
Net proceeds from stock option exercises, vesting of restricted stock units, and ESPP purchases	$ 11,565	$ 52,036	$ 119,657
Preferred Stock [Member]
Preferred Stock [Abstract]
Preferred stock, shares authorized (in shares)	15,000,000
Preferred stock, shares outstanding (in shares)	0
Series C Junior Participating Preferred Stock [Member]
Preferred Stock [Abstract]
Preferred stock, shares issued (in shares)	0
Preferred stock, shares outstanding (in shares)	0
Common Stock [Member]
Common Stock [Abstract]
Common stock, shares authorized to issue (in shares)	300,000,000	300,000,000
Common stock, shares issued (in shares)	141,200,000	140,400,000
Common stock, shares outstanding (in shares)	141,200,000	140,400,000
Common shares reserved for future issuance (in shares)	46,200,000
Number of shares issued for stock option exercises, vesting of restricted stock units, and ESPP purchases (in shares)	1,100,000	1,700,000	3,100,000
Net proceeds from stock option exercises, vesting of restricted stock units, and ESPP purchases	$ 11,600	$ 52,000	$ 119,700

Stockholders' Equity, Share Repurchase Program (Details) - USD ($) $ in Thousands	3 Months Ended	12 Months Ended
	Mar. 31, 2020	Dec. 31, 2021	Dec. 31, 2020	Dec. 31, 2019	Sep. 30, 2019
Share Repurchase Program [Abstract]
Authorized amount of share repurchase program					$ 125,000
Shares repurchased (in shares)	1,500,000			535,000
Shares repurchased	$ 90,500	$ 0	$ 90,548	$ 34,392

Stockholders' Equity, Stock Plans (Details)	1 Months Ended	12 Months Ended
Stockholders' Equity, Stock Plans (Details)	Jun. 30, 2009 shares	Dec. 31, 2021 Officer $ / shares shares	Jun. 30, 2021 shares	Dec. 31, 2020 shares	Jun. 30, 2020 shares	Jun. 30, 2019 shares	May 31, 2017 shares	Jun. 30, 2015 shares	May 31, 2015 shares
Stock Options [Member]
Stock Plans [Abstract]
Number of options outstanding (in shares)		14,089,000		12,439,000
Number of options exercisable (in shares)		9,175,000
1989 Stock Option Plan [Member]
Stock Plans [Abstract]
Number of shares authorized for issuance under the Plan (in shares)		20,000,000.0
Number of options outstanding (in shares)		28,000
Number of options exercisable (in shares)		28,000
Number of shares available for grant (in shares)		49,000
1989 Stock Option Plan [Member] \| Stock Options [Member]
Stock Plans [Abstract]
Vesting period		4 years
Award term		7 years
1989 Stock Option Plan [Member] \| Stock Options [Member] \| One Year from Date of Grant [Member]
Stock Plans [Abstract]
Vesting percentage		25.00%
Period before options are exercisable		1 year
2011 Equity Incentive Plan [Member]
Stock Plans [Abstract]
Number of shares authorized for issuance under the Plan (in shares)			29,700,000			23,000,000.0	16,000,000.0	11,000,000.0	5,500,000
Reduction in fungible share reserve for each share issued pursuant to full value award (n shares)			(1.7)
Increase in fungible share reserve for each share returning from a full value award (in shares)			1.7
Number of options outstanding (in shares)		12,800,000
Number of options exercisable (in shares)		8,300,000
Number of shares available for grant (in shares)		8,500,000
Number of executive officers terminated before change in control when vesting will accelerate for executive officers \| Officer		1
Period before change in control when vesting will accelerate for executive officers		3 months
Period after change in control when vesting will accelerate for executive officers		12 months
2011 Equity Incentive Plan [Member] \| Stock Options [Member]
Stock Plans [Abstract]
Vesting period		4 years
Award term		7 years
2011 Equity Incentive Plan [Member] \| Stock Options [Member] \| Issued after December 31, 2021 [Member]
Stock Plans [Abstract]
Vesting period		10 years
2011 Equity Incentive Plan [Member] \| Stock Options [Member] \| One Year from Date of Grant [Member]
Stock Plans [Abstract]
Vesting percentage		25.00%
Period before options are exercisable		1 year
2011 Equity Incentive Plan [Member] \| Restricted Stock Units [Member]
Stock Plans [Abstract]
Vesting period		4 years
Number of awards outstanding (in shares)		2,500,000
2020 Equity Incentive Plan [Member]
Stock Plans [Abstract]
Number of shares authorized for issuance under the Plan (in shares)			1,600,000	2,600,000
Number of options outstanding (in shares)		200,000
Number of options exercisable (in shares)		0
Number of shares available for grant (in shares)		1,300,000
2020 Equity Incentive Plan [Member] \| Stock Options [Member]
Stock Plans [Abstract]
Vesting period		4 years
Award term		7 years
2020 Equity Incentive Plan [Member] \| Stock Options [Member] \| Issued after December 31, 2021 [Member]
Stock Plans [Abstract]
Vesting period		10 years
2020 Equity Incentive Plan [Member] \| Stock Options [Member] \| One Year from Date of Grant [Member]
Stock Plans [Abstract]
Vesting percentage		25.00%
Period before options are exercisable		1 year
2020 Equity Incentive Plan [Member] \| Restricted Stock Units [Member]
Stock Plans [Abstract]
Vesting period		4 years
Number of awards outstanding (in shares)		100,000
2002 Non-Employee Directors' Stock Option Plan [Member]
Stock Plans [Abstract]
Number of shares authorized for issuance under the Plan (in shares)					2,800,000			2,000,000.0	1,200,000
Number of options outstanding (in shares)		1,000,000.0
Number of options exercisable (in shares)		800,000
Number of shares available for grant (in shares)		700,000
2002 Non-Employee Directors' Stock Option Plan [Member] \| Stock Options [Member]
Stock Plans [Abstract]
Award term		10 years
2002 Non-Employee Directors' Stock Option Plan [Member] \| Restricted Stock Units [Member]
Stock Plans [Abstract]
Number of awards outstanding (in shares)		100,000
Employee Stock Purchase Plan [Member]
Stock Plans [Abstract]
Number of shares authorized for issuance under the Plan (in shares)		3,200,000
Number of additional shares reserved for issuance (in shares)	150,000	150,000
Maximum percentage of employee compensation used to purchase shares		10.00%
Percentage of fair market value used to determine purchase price of stock		85.00%
Holding period for purchased stock		6 months
Shares purchased and issued under ESPP (in shares)		70,000.00
Weighted average purchase price (in dollars per share) \| $ / shares		$ 39.26
Shares available for purchase under ESPP (in shares)		600,000

Stockholders' Equity, Stock Option Activity (Details) - Stock Options [Member] - USD ($) $ / shares in Units, shares in Thousands, $ in Thousands	12 Months Ended
	Dec. 31, 2021	Dec. 31, 2020	Dec. 31, 2019
Number of Shares [Abstract]
Outstanding at beginning of period (in shares)	12,439
Granted (in shares)	3,382
Exercised (in shares)	(219)
Cancelled/forfeited/expired (in shares)	(1,513)
Outstanding at end of period (in shares)	14,089	12,439
Exercisable at end of period (in shares)	9,175
Weighted Average Exercise Price Per Share [Abstract]
Outstanding at beginning of period (in dollars per share)	$ 54.11
Granted (in dollars per share)	53.07
Exercised (in dollars per share)	38.69
Cancelled/forfeited/expired (in dollars per share)	54.65
Outstanding at end of period (in dollars per share)	54.04	$ 54.11
Exercisable at end of period (in dollars per share)	$ 53.65
Average Remaining Contractual Term, Aggregate Intrinsic Value and Other [Abstract]
Average remaining contractual term, outstanding at end of period	3 years 10 months 20 days
Average remaining contractual term, exercisable at end of period	2 years 11 months 8 days
Aggregate intrinsic value, outstanding at end of period	$ 1,131
Aggregate intrinsic value, exercisable at end of period	$ 1,067
Weighted average fair value of options granted (in dollars per share)	$ 24.35	$ 29.43	$ 28.76
Intrinsic value of options exercised	$ 2,500	$ 15,500	$ 83,800
Cash received from exercise of stock options	$ 8,500	$ 43,700	$ 105,900
Weighted-average fair value of options exercised (in dollars per share)	$ 50.13
Unrecognized Compensation Expense [Abstract]
Unrecognized compensation cost related to non-vested stock options	$ 49,600
Weighted average period for recognition	1 year 1 month 6 days

Stockholders' Equity, Restricted Stock Unit Activity (Details) - Restricted Stock Units [Member] - USD ($) $ / shares in Units, shares in Thousands, $ in Millions	12 Months Ended
	Dec. 31, 2021	Dec. 31, 2020	Dec. 31, 2019
Number of Shares [Abstract]
Non-vested at beginning of period (in shares)	2,374
Granted (in shares)	1,548
Vested (in shares)	(834)
Cancelled/forfeited (in shares)	(411)
Non-vested at end of period (in shares)	2,677	2,374
Weighted Average Grant Date Fair Value per Share [Abstract]
Non-vested at beginning of period (in dollars per share)	$ 58.81
Granted (in dollars per share)	57.69	$ 60.86	$ 60.23
Vested (in dollars per share)	57.47
Cancelled/forfeited (in dollars per share)	59.24
Non-vested at end of period (in dollars per share)	$ 58.51	$ 58.81
Unrecognized Compensation Expense [Abstract]
Unrecognized compensation cost related to non-vested units	$ 57.0
Weighted average period for recognition	1 year 2 months 12 days

Stockholders' Equity, Stock-based Compensation Expense (Details) $ in Thousands	3 Months Ended	12 Months Ended
	Sep. 30, 2019 USD ($) Officer	Dec. 31, 2021 USD ($)	Dec. 31, 2020 USD ($)	Dec. 31, 2019 USD ($)	Oct. 31, 2020 USD ($)
Stock-Based Compensation [Abstract]
Stock-based compensation expense		$ 120,678	$ 230,117	$ 146,574
Cost of Sales [Member]
Stock-Based Compensation [Abstract]
Stock-based compensation expense		456	1,991	438
Research, Development and Patent [Member]
Stock-Based Compensation [Abstract]
Stock-based compensation expense		87,522	115,584	95,348
Selling, General and Administrative [Member]
Stock-Based Compensation [Abstract]
Stock-based compensation expense		$ 32,700	$ 112,542	$ 50,788
Akcea [Member]
Stock-Based Compensation [Abstract]
Stock-based compensation expense	$ (19,100)
Unrecognized compensation cost related to non-vested units					$ 59,300
Number of executive officers terminating employment \| Officer	3

Stockholders' Equity, Stock-based Valuation Information (Details)	12 Months Ended
	Dec. 31, 2021	Dec. 31, 2020	Dec. 31, 2019
Employee Stock Options [Member]
Weighted-Average Assumptions [Abstract]
Risk-free interest rate	0.60%	1.50%	2.30%
Dividend yield	0.00%	0.00%	0.00%
Volatility	54.00%	58.60%	60.30%
Expected life	4 years 10 months 24 days	4 years 8 months 12 days	4 years 9 months 18 days
Board of Director Stock Options [Member]
Weighted-Average Assumptions [Abstract]
Risk-free interest rate	1.20%	0.50%	1.90%
Dividend yield	0.00%	0.00%	0.00%
Volatility	55.90%	57.60%	60.70%
Expected life	7 years 3 months 18 days	6 years 8 months 12 days	6 years 7 months 6 days
ESPP [Member]
Weighted-Average Assumptions [Abstract]
Risk-free interest rate	0.10%	0.80%	2.40%
Dividend yield	0.00%	0.00%	0.00%
Volatility	42.40%	47.90%	45.60%
Expected life	6 months	6 months	6 months

Income Taxes, Income (Loss) Before Income Taxes (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2021	Dec. 31, 2020	Dec. 31, 2019
Income Taxes [Abstract]
United States	$ (29,966)	$ (137,222)	$ 336,277
Foreign	818	2,670	2,489
Income (loss) before income tax benefit (expense)	$ (29,148)	$ (134,552)	$ 338,766

- Definition

Amount of income (loss) from continuing operations, including income (loss) from equity method investments, before deduction of income tax expense (benefit), and income (loss) attributable to noncontrolling interest.

+ References

Reference 1: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 280
-SubTopic 10
-Section 50
-Paragraph 32
-Subparagraph (c)
-URI http://asc.fasb.org/extlink&oid=123359005&loc=d3e8933-108599

Reference 2: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 280
-SubTopic 10
-Section 50
-Paragraph 30
-Subparagraph (b)
-URI http://asc.fasb.org/extlink&oid=123359005&loc=d3e8906-108599

Reference 3: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 280
-SubTopic 10
-Section 50
-Paragraph 32
-Subparagraph (f)
-URI http://asc.fasb.org/extlink&oid=123359005&loc=d3e8933-108599

Reference 4: http://fasb.org/us-gaap/role/ref/legacyRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 940
-SubTopic 20
-Section 25
-Paragraph 1
-URI http://asc.fasb.org/extlink&oid=123384075&loc=d3e41242-110953

Reference 5: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 280
-SubTopic 10
-Section 50
-Paragraph 22
-URI http://asc.fasb.org/extlink&oid=123359005&loc=d3e8736-108599

Reference 6: http://fasb.org/us-gaap/role/ref/legacyRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 220
-SubTopic 10
-Section S99
-Paragraph 2
-Subparagraph (SX 210.5-03(10))
-URI http://asc.fasb.org/extlink&oid=123367319&loc=SL114868664-224227

Reference 7: http://fasb.org/us-gaap/role/ref/legacyRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 944
-SubTopic 220
-Section S99
-Paragraph 1
-Subparagraph (SX 210.7-04(8))
-URI http://asc.fasb.org/extlink&oid=120400993&loc=SL114874131-224263

Reference 8: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 942
-SubTopic 235
-Section S99
-Paragraph 1
-Subparagraph (SX 210.9-05(b)(2))
-URI http://asc.fasb.org/extlink&oid=120399901&loc=d3e537907-122884

Reference 9: http://www.xbrl.org/2003/role/exampleRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 280
-SubTopic 10
-Section 50
-Paragraph 31
-URI http://asc.fasb.org/extlink&oid=123359005&loc=d3e8924-108599

Reference 10: http://fasb.org/us-gaap/role/ref/legacyRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 942
-SubTopic 220
-Section S99
-Paragraph 1
-Subparagraph (SX 210.9-04(15))
-URI http://asc.fasb.org/extlink&oid=120399700&loc=SL114874048-224260

+ Details

Income Taxes, Income Tax Expense (Benefit) (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2021	Dec. 31, 2020	Dec. 31, 2019
Current [Abstract]
Federal	$ (200)	$ (837)	$ 35,861
State	(690)	3,782	14,329
Foreign	339	518	413
Total current income tax expense (benefit)	(551)	3,463	50,603
Deferred [Abstract]
Federal	0	341,728	904
State	0	0	0
Total deferred income tax benefit	0	341,728	904
Total income tax expense (benefit)	$ (551)	$ 345,191	$ 51,507

Income Taxes, Reconciliation of Statutory to Effective Tax Rate (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2021	Dec. 31, 2020	Dec. 31, 2019
Reconciliation Between Effective and Statutory Tax Rate [Abstract]
Pre-tax income (loss)	$ (29,148)	$ (134,552)	$ 338,766
Statutory rate	(6,121)	(28,256)	71,141
State income tax net of federal benefit	4,278	(37,705)	49,000
Foreign	143	49	340
Net change in valuation allowance	2,885	460,898	(37,314)
Loss on debt transactions	262	0	9,911
Impact from outside basis differences	0	0	(16,344)
Tax credits	(23,198)	(18,774)	(22,296)
Deferred tax true-up	(24)	(206)	646
Tax rate change	12,838	(32,951)	1,248
Non-deductible compensation	5,085	7,931	3,361
Other non-deductible items	84	193	329
Stock-based compensation	4,720	17,435	(4,837)
Foreign-derived intangible income benefit	0	0	(2,071)
Impacts from Akcea Merger	0	(22,032)	0
Other	(1,503)	(1,391)	(1,607)
Total income tax expense (benefit)	$ (551)	$ 345,191	$ 51,507
Reconciliation Between Effective and Statutory Tax Rate Percentage [Abstract]
Statutory rate	21.00%	21.00%	21.00%
State income tax net of federal benefit	(14.70%)	28.00%	14.50%
Foreign	(0.50%)	0.00%	0.10%
Net change in valuation allowance	(9.90%)	(342.50%)	(11.00%)
Loss on debt transactions	(0.90%)	0.00%	2.90%
Impact from outside basis differences	0.00%	0.00%	(4.80%)
Tax credits	79.60%	14.00%	(6.60%)
Deferred tax true-up	0.10%	0.20%	0.20%
Tax rate change	(44.00%)	24.50%	0.40%
Non-deductible compensation	(17.40%)	(5.90%)	1.00%
Other nondeductible items	(0.30%)	(0.10%)	0.10%
Stock-based compensation	(16.20%)	(13.00%)	(1.40%)
Foreign-derived intangible income benefit	0.00%	0.00%	(0.60%)
Impacts from Akcea Merger	0.00%	16.40%	0.00%
Other	5.10%	0.90%	(0.60%)
Effective rate	1.90%	(256.50%)	15.20%

Income Taxes, Deferred Tax Assets and Liabilities (Details) - USD ($) $ in Thousands	3 Months Ended	12 Months Ended
	Dec. 31, 2020	Dec. 31, 2021
Deferred Tax Assets [Abstract]
Net operating loss carryovers	$ 83,681	$ 85,600
Tax credits	245,746	269,538
Deferred revenue	124,452	104,330
Stock-based compensation	80,055	86,611
Intangible and capital assets	98,443	92,542
Convertible debt	22,395	45,681
Interest expense limitation	0	6,996
Other	13,402	15,048
Total deferred tax assets	668,174	706,346
Deferred Tax Liabilities [Abstract]
Fixed assets	(3,611)	(3,303)
Other	(5,808)	(5,270)
Net deferred tax asset	658,755	697,773
Valuation allowance	(658,755)	(697,773)
Total net deferred tax assets and liabilities	0	0
Increase in valuation allowance	$ 341,000	$ 39,000

Income Taxes, Tax Credit Carryforwards (Details) $ in Millions	Dec. 31, 2021 USD ($)
Federal [Member]
Operating Loss Carryforwards [Abstract]
Net operating loss carryforwards	$ 271.5
Federal [Member] \| Research and Development [Member]
Tax Credit Carryforwards [Abstract]
Tax credit carryforwards	225.5
California [Member]
Operating Loss Carryforwards [Abstract]
Net operating loss carryforwards	333.8
California [Member] \| Research and Development [Member]
Tax Credit Carryforwards [Abstract]
Tax credit carryforwards	$ 99.7

Income Taxes, Gross Unrecognized Tax Benefits (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2021	Dec. 31, 2020	Dec. 31, 2019
Gross Unrecognized Tax Benefits [Roll Forward]
Beginning balance of unrecognized tax benefits	$ 54,163	$ 69,784	$ 68,301
Decrease for prior period tax positions	(695)	(24,154)	(867)
Increase for prior period tax positions	263	7,023	736
Increase for current period tax positions	1,354	1,510	1,614
Ending balance of unrecognized tax benefits	55,085	54,163	69,784
Unrecognized tax benefits that could impact effective tax rate, if recognized	6,200	6,400	400
Interest and penalties on gross unrecognized tax benefits	$ 500	$ 300	$ 0

Collaborative Arrangements and Licensing Agreements, Biogen (Details) $ in Thousands	1 Months Ended			3 Months Ended						12 Months Ended
	Dec. 31, 2021 USD ($) Medicine Program	Sep. 30, 2013 USD ($) PerformanceObligation	Dec. 31, 2012 USD ($) Program	Dec. 31, 2021 USD ($) Medicine Program	Jun. 30, 2021 USD ($)	Dec. 31, 2019 USD ($)	Sep. 30, 2019 USD ($)	Jun. 30, 2018 USD ($)	Dec. 31, 2017 USD ($) PerformanceObligation	Dec. 31, 2021 USD ($) Medicine Program	Dec. 31, 2020 USD ($)	Dec. 31, 2019 USD ($)	Apr. 30, 2018 USD ($) PerformanceObligation
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue										$ 810,456	$ 729,264	$ 1,122,599
SPINRAZA Royalties [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue										267,776	286,583	292,992
R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue										$ 468,061	364,565	770,149
Biogen [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of medicines currently being developed \| Medicine	9			9						9
Revenue										$ 428,800	408,600	$ 473,600
Deferred revenue	$ 407,500			$ 407,500						$ 407,500	$ 465,800
Biogen [Member] \| Revenue [Member] \| Strategic Partner [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Concentration percentage										53.00%	56.00%	42.00%
Biogen [Member] \| Minimum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received	3,100,000			3,100,000						$ 3,100,000
Biogen [Member] \| SPINRAZA Royalties [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue										267,800	$ 286,600	$ 293,000
Biogen [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue										161,000	122,000	$ 180,600
SPINRAZA [Member] \| Minimum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative revenue earned	1,600,000			1,600,000						$ 1,600,000
Royalty percentage received on net sales of medicine										11.00%
SPINRAZA [Member] \| Maximum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Royalty percentage received on net sales of medicine										15.00%
SPINRAZA [Member] \| SPINRAZA Royalties [Member] \| Maximum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative revenue earned	1,200,000			1,200,000						$ 1,200,000
SPINRAZA [Member] \| R&D Revenue [Member] \| Minimum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative revenue earned	435,000			435,000						$ 435,000
New Antisense Medicines for the Treatment of SMA [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Royalty percentage received on net sales of medicine										20.00%
Upfront payment received									$ 25,000
Maximum amount of payments receivable for license fees, milestone payments and other payments	1,200,000			1,200,000						$ 1,200,000
Next prospective payment	45,000			45,000						45,000
Number of separate performance obligations \| PerformanceObligation									1
Transaction price									$ 25,000
Revenue						$ 8,300
New Antisense Medicines for the Treatment of SMA [Member] \| ION306 [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Maximum amount of payments receivable for development, commercialization and sales milestones	555,000			555,000						555,000
Maximum amount of payments receivable for development milestones	45,000			45,000						45,000
Maximum amount of payments receivable for regulatory milestones	110,000			110,000						110,000
Maximum amount of payments receivable for sales milestones	400,000			400,000						$ 400,000
Revenue	60,000			60,000
2018 Strategic Neurology [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Royalty percentage received on net sales of medicine										20.00%
Upfront payment received								$ 375,000
Next prospective payment	7,500			7,500						$ 7,500
Number of separate performance obligations \| PerformanceObligation													1
Transaction price													$ 552,000
Term of collaboration agreement										10 years
Upfront payment received, including purchase of stock								1,000,000
Proceeds from issuance of common stock								$ 625,000
Percentage cash premium paid on shares purchased								25.00%
Maximum amount of payments receivable per medicine for milestone payments	$ 270,000			$ 270,000						$ 270,000
Number of programs being advanced \| Program	9			9						9
Premium paid on shares purchased								$ 177,000
Cumulative payments included in transaction price for performance obligation	$ 616,000			$ 616,000						$ 616,000
Milestone payments achieved and included in transaction price for performance obligation										23,000	11,000
Revenue				15,000
2018 Strategic Neurology [Member] \| Maximum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received	1,100,000			1,100,000						1,100,000
2013 Strategic Neurology [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Upfront payment received		$ 100,000
Next prospective payment	$ 70,000			$ 70,000						$ 70,000
Number of separate performance obligations \| PerformanceObligation		1
Transaction price		$ 100,000
Number of medicines currently being advanced \| Medicine	6			6						6
Revenue							$ (16,500)
2013 Strategic Neurology [Member] \| Minimum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received	$ 280,000			$ 280,000						$ 280,000
2013 Strategic Neurology [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments included in transaction price for performance obligation											145,000
2013 Strategic Neurology [Member] \| Medicines for Parkinson's Disease [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of medicines currently being advanced \| Medicine	1			1						1
2013 Strategic Neurology [Member] \| Medicines for ALS [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of medicines currently being advanced \| Medicine	3			3						3
2013 Strategic Neurology [Member] \| Medicines for Multiple System Atrophy [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of medicines currently being advanced \| Medicine	1			1						1
2013 Strategic Neurology [Member] \| Medicines for Undisclosed Targets [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of medicines currently being advanced \| Medicine	1			1						1
2013 Strategic Neurology [Member] \| Antisense Molecule [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Maximum amount of payments receivable per program for license fee and milestone payments	$ 260,000			$ 260,000						$ 260,000
Maximum amount of payments receivable per program for development milestones	60,000			60,000						60,000
Maximum amount of payments receivable per program for regulatory milestones	130,000			130,000						130,000
2013 Strategic Neurology [Member] \| ION541 [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue					$ 10,000
2012 Neurology [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received	155,000			155,000						155,000
Upfront payment received			$ 30,000
Next prospective payment	25,000			25,000						25,000
Maximum amount of payments receivable per program for license fee and milestone payments	210,000			210,000						210,000
Maximum amount of payments receivable per program for development milestones	10,000			10,000						10,000
Maximum amount of payments receivable per program for regulatory milestones	130,000			130,000						130,000
Number of programs under which medicines are to be developed and commercialized \| Program			3
Revenue							$ 6,300
2012 Neurology [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments included in transaction price for performance obligation	40,000			40,000						40,000
2012 Neurology [Member] \| IONIS-MAPT [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments included in transaction price for performance obligation	$ 57,000			57,000						$ 57,000
Milestone payments achieved and included in transaction price for performance obligation											$ 19,500
Term of extension study										1 year
Revenue						$ 45,000
2012 Neurology [Member] \| ION582 [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue				$ 10,000

Collaborative Arrangements and Licensing Agreements, AstraZeneca (Details) $ in Thousands	1 Months Ended			3 Months Ended		12 Months Ended
	Dec. 31, 2021 USD ($) PerformanceObligation Agreement Medicine Component	Jul. 31, 2015 USD ($) PerformanceObligation	Dec. 31, 2012 USD ($)	Dec. 31, 2021 USD ($) PerformanceObligation Agreement Medicine Component	Jun. 30, 2020 USD ($)	Dec. 31, 2021 USD ($) PerformanceObligation Agreement Medicine Component	Dec. 31, 2020 USD ($)	Dec. 31, 2019 USD ($)
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue						$ 810,456	$ 729,264	$ 1,122,599
R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue						468,061	364,565	$ 770,149
AstraZeneca [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Deferred revenue	$ 0			$ 0		$ 0	$ 10,000
AstraZeneca [Member] \| Revenue [Member] \| Strategic Partner [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Concentration percentage						31.00%	12.00%	3.00%
AstraZeneca [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue						$ 254,600	$ 88,000	$ 28,100
Eplontersen Collaboration [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Upfront payment received	200,000
Maximum amount of payments receivable for development and regulatory milestones	485,000			485,000		485,000
Maximum amount of payments receivable for sales-related milestones	$ 2,900,000			$ 2,900,000		$ 2,900,000
Royalty percentage received on sales of medicine in U.S.						20.00%
Number of material components \| Component	4			4		4
Percentage of costs associated with ongoing global Phase 3 development program paid by AstraZeneca						55.00%
Number of separate performance obligations \| PerformanceObligation	1			1		1
Transaction price	$ 200,000			$ 200,000		$ 200,000
Next prospective payment	50,000			50,000		50,000
Revenue	200,000
Research and Development Collaborations [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received	$ 386,000			$ 386,000		$ 386,000
Number of collaboration agreements \| Agreement	2			2		2
Number of medicines currently being developed \| Medicine	6			6		6
Cardiovascular, Renal and Metabolic Diseases Collaboration [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of licensed medicines \| Medicine	5			5		5
Upfront payment received		$ 65,000
Number of collaboration agreements \| Agreement	1			1		1
Minimum amount of payments receivable for license fees and milestones	$ 5,500,000			$ 5,500,000		$ 5,500,000
Maximum amount of payments receivable for development milestones	1,100,000			1,100,000		1,100,000
Maximum amount of payments receivable for regulatory milestones	2,900,000			2,900,000		2,900,000
Maximum amount of payments receivable for commercialization milestones	1,500,000			1,500,000		1,500,000
Number of separate performance obligations \| PerformanceObligation		1
Transaction price		$ 65,000
Next prospective payment	10,000			10,000		10,000
Revenue				10,000		10,000
Cardiovascular, Renal and Metabolic Diseases Collaboration [Member] \| Minimum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received	282,000			282,000		282,000
Cardiovascular, Renal and Metabolic Diseases Collaboration [Member] \| Target for Metabolic Disease [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue						30,000
Cardiovascular, Renal and Metabolic Diseases Collaboration [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments included in transaction price for performance obligation	$ 90,000			$ 90,000		$ 90,000
Oncology Collaboration [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Upfront payment received			$ 31,000
Number of collaboration agreements \| Agreement	1			1		1
Maximum amount of payments receivable for license fees and milestones	$ 160,000			$ 160,000		$ 160,000
Maximum amount of payments receivable for development milestones	42,000			42,000		42,000
Maximum amount of payments receivable for regulatory milestones	105,000			105,000		105,000
Next prospective payment	12,000			12,000		12,000
Oncology Collaboration [Member] \| Minimum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received	$ 141,000			$ 141,000		$ 141,000
Oncology Collaboration [Member] \| ION736 [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue					$ 13,000		$ 13,000

Collaborative Arrangements and Licensing Agreements, Bayer (Details) $ in Thousands	1 Months Ended		3 Months Ended		12 Months Ended
	Feb. 28, 2017 USD ($) PerformanceObligation	May 31, 2015 USD ($) PerformanceObligation	Dec. 31, 2019 USD ($)	Jun. 30, 2015 USD ($)	Dec. 31, 2021 USD ($)	Dec. 31, 2020 USD ($)	Dec. 31, 2019 USD ($)
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue					$ 810,456	$ 729,264	$ 1,122,599
R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue					468,061	364,565	$ 770,149
Bayer [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue			$ 10,000
Deferred revenue						$ 0
Bayer [Member] \| Revenue [Member] \| Strategic Partner [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Concentration percentage					0.00%	0.00%	1.00%
Bayer [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue					$ 1,100	$ 3,200	$ 14,300
Bayer [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Upfront payment received		$ 100,000		$ 100,000
Maximum amount of payments receivable for license fees and milestones					385,000
Maximum amount of payments receivable for development milestones					125,000
Maximum amount of payments receivable for sales milestones					$ 110,000
Royalty percentage received on gross margins of both medicines combined					20.00%
Next prospective payment					$ 20,000
Number of separate performance obligations \| PerformanceObligation		3
Bayer [Member] \| Minimum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received					$ 191,000
Bayer [Member] \| R&D Services for Fesomersen [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Transaction price	$ 10,100
Bayer [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Upfront payment received	75,000
Payment received for advancing programs	$ 75,000
Number of separate performance obligations \| PerformanceObligation	3
Number of new performance obligations \| PerformanceObligation	2
Transaction price	$ 75,000
Bayer [Member] \| Fesomersen [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of new performance obligations \| PerformanceObligation	1
Transaction price	$ 64,900
Bayer [Member] \| R&D Services for Fesomersen [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of new performance obligations \| PerformanceObligation	1

Collaborative Arrangements and Licensing Agreements, GSK (Details) $ in Thousands	1 Months Ended	3 Months Ended	12 Months Ended
	Mar. 31, 2010 USD ($)	Sep. 30, 2019 USD ($)	Dec. 31, 2021 USD ($) Medicine	Dec. 31, 2020 USD ($)	Dec. 31, 2019 USD ($)
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue			$ 810,456	$ 729,264	$ 1,122,599
R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue			$ 468,061	364,565	$ 770,149
GSK [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Upfront payment received	$ 35,000
Number of medicines currently being developed \| Medicine			2
Minimum amount of payments receivable for license fees and milestones			$ 260,000
Maximum amount of payments receivable for development milestones			47,500
Maximum amount of payments receivable for regulatory milestones			120,000
Maximum amount of payments receivable for sales milestones			70,000
Next prospective payment			15,000
Revenue		$ 25,000
Deferred revenue			$ 0	$ 0
GSK [Member] \| Revenue [Member] \| Strategic Partner [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Concentration percentage			0.00%	0.00%	2.00%
GSK [Member] \| Minimum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received			$ 190,000
GSK [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue			$ 0	$ 200	$ 25,400

Collaborative Arrangements and Licensing Agreements, Novartis (Details) $ in Thousands, shares in Millions	3 Months Ended			12 Months Ended
	Sep. 30, 2021 USD ($)	Mar. 31, 2019 USD ($)	Mar. 31, 2017 USD ($) PerformanceObligation shares	Dec. 31, 2021 USD ($)	Dec. 31, 2020 USD ($)	Dec. 31, 2019 USD ($)	Aug. 31, 2021
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue				$ 810,456	$ 729,264	$ 1,122,599
Licensing and Other Royalties [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue				19,119	8,117	17,205
R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue				468,061	364,565	$ 770,149
Novartis [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Upfront payment received			$ 75,000
Maximum amount of payments receivable for milestones				675,000
Maximum amount of payments receivable for development milestones				25,000
Maximum amount of payments receivable for regulatory milestones				290,000
Maximum amount of payments receivable for sales milestones				360,000
Cumulative payments received				425,000
Next prospective payment				75,000
Shares issued (in shares) \| shares			1.6
Proceeds from sale of common stock			$ 100,000
Number of separate performance obligations \| PerformanceObligation			4
Transaction price			$ 108,400
Premium received on shares issued			28,400
Potential premium received if common stock is purchased in the future			5,000
Deferred revenue				$ 0	$ 0
Novartis [Member] \| Revenue [Member] \| Strategic Partner [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Concentration percentage				3.00%	0.00%	17.00%
Novartis [Member] \| Licensing and Other Royalties [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue		$ 150,000
Novartis [Member] \| R&D Services for Pelacarsen [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Transaction price			64,000
Novartis [Member] \| R&D Services for Olezarsen [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Transaction price			40,100
Novartis [Member] \| Pelacarsen API [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Royalty percentage received on sales of medicine				20.00%
Percentage enrollment in Lp(a) HORIZON Phase 3 cardiovascular outcome study							50.00%
Transaction price			1,500
Revenue	$ 25,000
Novartis [Member] \| Olezarsen API [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Transaction price			$ 2,800
Novartis [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue				$ 25,500	$ 1,000	$ 187,400

Collaborative Arrangements and Licensing Agreements, Roche (Details) $ in Thousands	1 Months Ended	3 Months Ended		12 Months Ended
	Apr. 30, 2013 USD ($) PerformanceObligation	Dec. 31, 2020 USD ($)	Dec. 31, 2018 USD ($)	Dec. 31, 2021 USD ($) Indication	Dec. 31, 2020 USD ($)	Dec. 31, 2019 USD ($)	Dec. 31, 2017 USD ($)	Oct. 31, 2018 USD ($) PerformanceObligation
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue				$ 810,456	$ 729,264	$ 1,122,599
R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue				468,061	364,565	$ 770,149
Roche [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Deferred revenue		$ 47,200		$ 31,600	$ 47,200
Roche [Member] \| Revenue [Member] \| Strategic Partner [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Concentration percentage				2.00%	1.00%	5.00%
Roche [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue				$ 17,200	$ 5,900	$ 57,000
Huntington's Disease [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Upfront payment received	$ 30,000
Milestone payment received							$ 3,000
Maximum amount of payments receivable for license fees and milestones				365,000
Maximum amount of payments receivable for development milestones				70,000
Maximum amount of payments receivable for regulatory milestones				170,000
Maximum amount of payments receivable for sales milestones				80,000
Maximum amount of payment receivable for each additional medicine developed				136,500
Cumulative payments received				150,000
Next prospective payment				15,000
Number of separate performance obligations \| PerformanceObligation	1
Transaction price	$ 30,000
Revenue						$ 35,000
IONIS-FB-L for Complement-Mediated Diseases [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Upfront payment received			$ 75,000
Minimum amount of payments receivable for license fees and milestones				680,000
Cumulative payments received				75,000
Next prospective payment				$ 20,000
Number of separate performance obligations \| PerformanceObligation								1
Transaction price								$ 75,000
Number of disease indications \| Indication				2
Royalty percentage received on net sales of medicine				20.00%
Revenue		$ (9,200)
IONIS-FB-L for Complement-Mediated Diseases [Member] \| GA [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of disease indications \| Indication				1
IONIS-FB-L for Complement-Mediated Diseases [Member] \| IgA Nephropathy [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of disease indications \| Indication				1

Collaborative Arrangements and Licensing Agreements, PTC Therapeutics (Details)	12 Months Ended
	Dec. 31, 2021
PTC Therapeutics [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Royalty percentage received on net sales of each medicine from PTC	20.00%

Collaborative Arrangements and Licensing Agreements, Bicycle License Agreement (Details) - USD ($) $ in Millions	1 Months Ended	12 Months Ended
	Jul. 31, 2021	Dec. 31, 2021	Dec. 31, 2020	Dec. 31, 2019
Collaborative Arrangement and Licensing Agreement [Abstract]
R&D expense		$ 638.2	$ 531.0	$ 461.5
Bicycle License Agreement [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Payment of license fee	$ 42.0
Trading restriction period under lock up agreement		1 year
Equity investment		$ 7.2
R&D expense		34.8
Cumulative payments made		$ 46.6

Collaborative Arrangements and Licensing Agreements, Alnylam Pharmaceuticals, Inc. (Details) - USD ($) $ in Thousands	3 Months Ended	12 Months Ended
	Dec. 31, 2020	Dec. 31, 2021	Dec. 31, 2020	Dec. 31, 2019
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue		$ 810,456	$ 729,264	$ 1,122,599
R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue		468,061	364,565	$ 770,149
Alnylam [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Award from arbitration panel	$ 41,200
Revenue	41,200
Deferred revenue	$ 0	$ 0	$ 0
Alnylam [Member] \| Revenue [Member] \| Strategic Partner [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Concentration percentage		0.00%	7.00%	2.00%
Alnylam [Member] \| R&D Revenue [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue		$ 0	$ 47,900	$ 24,100

- Definition

Amount, excluding tax collected from customer, of revenue from satisfaction of performance obligation by transferring promised good or service to customer. Tax collected from customer is tax assessed by governmental authority that is both imposed on and concurrent with specific revenue-producing transaction, including, but not limited to, sales, use, value added and excise.

+ References

Reference 1: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 280
-SubTopic 10
-Section 50
-Paragraph 30
-Subparagraph (a)
-URI http://asc.fasb.org/extlink&oid=123359005&loc=d3e8906-108599

Reference 2: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 280
-SubTopic 10
-Section 50
-Paragraph 40
-URI http://asc.fasb.org/extlink&oid=123359005&loc=d3e9031-108599

Reference 3: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 280
-SubTopic 10
-Section 50
-Paragraph 41
-Subparagraph (a)
-URI http://asc.fasb.org/extlink&oid=123359005&loc=d3e9038-108599

Reference 4: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 280
-SubTopic 10
-Section 50
-Paragraph 32
-Subparagraph (b)
-URI http://asc.fasb.org/extlink&oid=123359005&loc=d3e8933-108599

Reference 5: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 280
-SubTopic 10
-Section 50
-Paragraph 32
-Subparagraph (a)
-URI http://asc.fasb.org/extlink&oid=123359005&loc=d3e8933-108599

Reference 6: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 606
-SubTopic 10
-Section 50
-Paragraph 4
-Subparagraph (a)
-URI http://asc.fasb.org/extlink&oid=123351226&loc=SL49130543-203045

Reference 7: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 280
-SubTopic 10
-Section 50
-Paragraph 22
-Subparagraph (b)
-URI http://asc.fasb.org/extlink&oid=123359005&loc=d3e8736-108599

Reference 8: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 280
-SubTopic 10
-Section 50
-Paragraph 22
-Subparagraph (a)
-URI http://asc.fasb.org/extlink&oid=123359005&loc=d3e8736-108599

Reference 9: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 280
-SubTopic 10
-Section 50
-Paragraph 42
-URI http://asc.fasb.org/extlink&oid=123359005&loc=d3e9054-108599

Reference 10: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 606
-SubTopic 10
-Section 50
-Paragraph 5
-URI http://asc.fasb.org/extlink&oid=123351226&loc=SL49130545-203045

Reference 11: http://www.xbrl.org/2003/role/disclosureRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 924
-SubTopic 10
-Section S99
-Paragraph 1
-Subparagraph (SAB Topic 11.L)
-URI http://asc.fasb.org/extlink&oid=6472922&loc=d3e499488-122856

+ Details

Akcea Merger (Details) - USD ($) $ / shares in Units, shares in Millions, $ in Millions	1 Months Ended	3 Months Ended	12 Months Ended		24 Months Ended
	Oct. 31, 2020	Dec. 31, 2020	Dec. 31, 2021	Dec. 31, 2020	Dec. 31, 2021	Sep. 30, 2020
Akcea Merger [Member]
Severance and Retention Costs [Abstract]
Beginning balance			$ 14.7
Amount expensed during the year			13.5
Reserve adjustments during the year			(1.8)
Net amount expensed during the year			11.7	$ 15.3	$ 27.0
Amounts paid during the year			(26.4)
Ending balance		$ 14.7		14.7
Akcea Merger [Member] \| Accrued Compensation [Member]
Severance and Retention Costs [Abstract]
Ending balance			0.0		$ 0.0
Akcea Merger [Member] \| R&D Expenses [Member]
Severance and Retention Costs [Abstract]
Net amount expensed during the year			5.1	3.9
Akcea Merger [Member] \| SG&A Expenses [Member]
Severance and Retention Costs [Abstract]
Net amount expensed during the year			$ 6.6	11.4
Akcea [Member]
Akcea Merger [Abstract]
Percentage ownership	100.00%		100.00%		100.00%	76.00%
Shares purchased (in shares)	24.8
Purchase price per share (in dollars per share)	$ 18.15
Purchase price	$ 450.6
Direct transaction costs		$ 40.6		$ 40.6
Cash purchase price of equity awards (in dollars per share)		$ 18.15
Payments for cancelled equity awards		$ 53.4
Unrecognized compensation cost related to non-vested units	$ 59.3

Severance and Retention Costs related to our Restructured Operations, Restructured European Operations (Details) - Restructured European Operations [Member] - USD ($) $ in Millions	12 Months Ended		24 Months Ended
	Dec. 31, 2021	Dec. 31, 2020	Dec. 31, 2021
Severance and Retention Costs related to our Restructured European Operations [Abstract]
Beginning balance	$ 12.4
Amount expensed during the year	2.6
Reserve adjustments during the year	(0.9)
Net amount expensed during the year	1.7	$ 12.5	$ 14.2
Amounts paid during the year	(14.1)
Ending balance	0.0	12.4	$ 0.0
R&D Expenses [Member]
Severance and Retention Costs related to our Restructured European Operations [Abstract]
Net amount expensed during the year	0.6	4.2
SG&A Expenses [Member]
Severance and Retention Costs related to our Restructured European Operations [Abstract]
Net amount expensed during the year	$ 1.1	$ 8.3

Severance and Retention Costs related to our Restructured Operations, Restructured North American TEGSEDI Operations (Details) - Restructured North American TEGSEDI Operations [Member] $ in Millions	12 Months Ended
	Dec. 31, 2021 USD ($)
Severance and Retention Costs [Abstract]
Beginning balance	$ 0.0
Net amount expensed during the year	9.4
Amounts paid during the year	(9.4)
Ending balance	0.0
R&D Expenses [Member]
Severance and Retention Costs [Abstract]
Net amount expensed during the year	2.3
SG&A Expenses [Member]
Severance and Retention Costs [Abstract]
Net amount expensed during the year	$ 7.1

Employment Benefits (Details) - USD ($)	12 Months Ended
Employment Benefits (Details) - USD ($)	Dec. 31, 2021	Dec. 31, 2020	Dec. 31, 2019
Employee Benefits [Abstract]
Matching contributions	$ 5,500,000	$ 5,700,000	$ 6,400,000
Minimum [Member]
Employee Benefits [Abstract]
Employee contribution limit per calendar year	20,500
Maximum [Member]
Employee Benefits [Abstract]
Employee contribution limit per calendar year	$ 27,000

Legal Proceedings (Details)	Aug. 05, 2021 Plaintiff
John Makris, et al. v. Ionis Pharmaceuticals, Inc., et al. [Member]
Legal Procedings [Abstract]
Number of plaintiffs	4

Fourth Quarter Financial Data (Unaudited) (Details) - USD ($)
$ / shares in Units, shares in Thousands, $ in Thousands

1 Months Ended

2 Months Ended

3 Months Ended

12 Months Ended

Oct. 31, 2020

Dec. 31, 2020

Dec. 31, 2021

Dec. 31, 2020

Dec. 31, 2021

Dec. 31, 2020

Dec. 31, 2019

Nov. 30, 2021

Apr. 30, 2021

Dec. 31, 2016

Nov. 30, 2014

Fourth Quarter Financial Data (Unaudited) [Abstract]

Revenue

$ 440,006

$ 290,281

Operating expenses

219,403

312,945

$ 840,642

$ 901,346

$ 756,716

Income (loss) from operations

220,603

(22,664)

(30,186)

(172,082)

365,883

Net income (loss)

224,613

(355,687)

(28,597)

(479,743)

287,259

Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders

$ 224,613

$ (354,532)

$ (28,597)

$ (444,263)

$ 278,143

Basic net income (loss) per share (in dollars per share)

$ 1.59

^[1],[2]

$ (2.54)

^[1],[2]

$ (0.20)

$ (3.18)

$ 2.00

Diluted net income (loss) per share (in dollars per share)

$ 1.41

^[1],[3]

$ (2.54)

^[1]

$ (0.20)

$ (3.18)

$ 1.90

Income (Numerator) [Abstract]

Income (loss) available to Ionis common stockholders

$ 224,612

$ (356,008)

$ (444,464)

$ 280,560

Net income available to Ionis common shareholders

$ 226,210

$ 290,947

Shares (Denominator) [Abstract]

Shares used in computing basic net income (loss) per share (in shares)

141,205

139,956

141,021

139,612

139,998

Effect of Diluted Securities [Abstract]

Shares issuable related to our ESPP (in shares)

Shares used in computing diluted net income per share (in shares)

160,340

141,021

139,612

153,164

0 Percent Convertible Senior Notes [Member]

Fourth Quarter Financial Data (Unaudited) [Abstract]

Interest rate on convertible senior notes

0.00%

Income (Numerator) [Abstract]

Shares issuable related to our convertible notes

$ 777

Effect of Diluted Securities [Abstract]

Shares issuable related to our convertible notes (in shares)

10,936

0.125 Percent Convertible Senior Notes [Member]

Fourth Quarter Financial Data (Unaudited) [Abstract]

Interest rate on convertible senior notes

0.125%

Income (Numerator) [Abstract]

Shares issuable related to our convertible notes

$ 716

$ 860

Effect of Diluted Securities [Abstract]

Shares issuable related to our convertible notes (in shares)

6,590

217

1 Percent Convertible Senior Notes [Member]

Fourth Quarter Financial Data (Unaudited) [Abstract]

Interest rate on convertible senior notes

1.00%

Income (Numerator) [Abstract]

Shares issuable related to our convertible notes

$ 105

$ 9,527

Effect of Diluted Securities [Abstract]

Shares issuable related to our convertible notes (in shares)

464

10,075

Stock Options [Member]

Effect of Diluted Securities [Abstract]

Shares issuable related to stock-based compensation (in shares)

2,090

Restricted Stock Awards [Member]

Effect of Diluted Securities [Abstract]

Shares issuable related to stock-based compensation (in shares)

1,065

766

Ionis [Member]

Fourth Quarter Financial Data (Unaudited) [Abstract]

Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders

$ (266,418)

$ (246,702)

$ 246,487

Akcea [Member]

Fourth Quarter Financial Data (Unaudited) [Abstract]

Net income (loss) attributable to Ionis Pharmaceuticals, Inc. common stockholders

$ (3,603)

$ (85,987)

$ (89,590)

Basic net income (loss) per share (in dollars per share)

$ (0.05)

Weighted average shares owned in Akcea (in shares)

77,095

[1]	We compute net income (loss) per share independently for each quarter during the year.
[2]	As discussed in Note 1, Organization and Significant Accounting Policies, we compute basic net income (loss) per share by dividing the total net income (loss) attributable to our common stockholders by our weighted-average number of common shares outstanding during the period. Our basic net income per share for the fourth quarter of 2021 was $1.59.Our basic net loss per share calculation for the fourth quarter of 2020 considered our net loss for Ionis on a stand-alone basis plus our share of Akcea’s net loss for the period. To calculate the portion of Akcea’s net loss attributable to our ownership, we multiplied Akcea’s loss per share by the weighted average shares we owned in Akcea during the period. As a result of this calculation, our total net loss available to Ionis common stockholders for the calculation of net loss per share is different than net loss attributable to Ionis Pharmaceuticals, Inc. common stockholders in the consolidated statements of operations.
[3]	We had net income available to Ionis common stockholders for the fourth quarter of 2021. As a result, we computed diluted net income per share using the weighted-average number of common shares and dilutive common equivalent shares outstanding during the period