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Collaborative Arrangements and Licensing Agreements [Abstract]

Stockholders' Equity

4. Stockholders’ Equity

Preferred Stock

We are authorized to issue up to 15,000,000 shares of “blank check” Preferred Stock. As of December 31, 2016, 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, 2016.

Common Stock

At December 31, 2016 and 2015, we had 300,000,000 shares of common stock authorized, of which 121,636,273 and 120,351,480 were issued and outstanding, respectively. As of December 31, 2016, total common shares reserved for future issuance were 14,703,837.

During the years ended December 31, 2016, 2015 and 2014, we issued 1,285,000, 1,908,000 and 1,972,000 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 $13.7 million, $24.9 million and $23.1 million in 2016, 2015 and 2014, respectively.

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 20,000,000 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 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. At December 31, 2016, a total of 2,732,089 options were outstanding, of which options to purchase 2,542,372 shares were exercisable, and 25,552 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, after receiving approval from our stockholders, we amended our 2011 Equity Incentive Plan to increase the total number of shares reserved for issuance. We increased the shares available under our 2011 Equity Incentive Plan from 5,500,000 to 11,000,000. The plan expires in June 2021. 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 options and restricted stock unit awards to our employees, directors and consultants. Under the 2011 Plan, stock options cannot vest in a period of less than two years and restricted stock unit awards cannot vest in a period of less than three 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, 2016, a total of 5,830,078 options were outstanding, of which 1,827,264 were exercisable, 737,113 restricted stock unit awards were outstanding, and 3,661,538 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 issue to our chief executive officer and chief operating officer will accelerate upon a change of control, as defined in the 2011 Plan.

Corporate Transactions and Change in Control under 2011 Plan

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 Plan:



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 (the 2002 Plan). In June 2015, after receiving approval from our stockholders, we amended our 2002 Non-Employee Directors Stock Option Plan to increase the total number of shares reserved for issuance. We increased the shares available under our 2002 Non-Employee Directors Stock Option Plan from 1,200,000 to 2,000,000. Options under this plan expire ten years from the date of grant. Options granted become exercisable in four equal annual installments beginning one year after the date of grant. At December 31, 2016, a total of 615,812 options were outstanding, of which 368,877 were exercisable, 41,151 restricted stock unit awards were outstanding, and 747,869 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, we reserved an additional 150,000 shares of common stock for the ESPP resulting in a total of 3,374,596 million shares authorized under the plan as of December 31, 2016. The ESPP permits full-time employees to purchase common stock through payroll deductions (which cannot exceed 10 percent of each employee’s compensation) at the lower of 85 percent of fair market value at the beginning of the purchase period or the end of each six-month 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 2016, employees purchased and we issued to employees 46,051 shares under the ESPP at a weighted average price of $30.47 per share. At December 31, 2016, there were 585,713 shares available for purchase under the ESPP.

Stock Option Activity

The following table summarizes the stock option activity for the year ended December 31, 2016 (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, 2015		8,041		$	33.21
Granted		2,428		$	54.79
Exercised		(994	)	$	12.63
Cancelled/forfeited/expired		(297	)	$	53.65
Outstanding at December 31, 2016		9,178		$	40.48		4.46		$	122,738
Exercisable at December 31, 2016		4,898		$	28.73		3.40		$	107,969

The weighted-average estimated fair values of options granted were $26.72, $27.44 and $17.54 for the years ended December 31, 2016, 2015 and 2014, respectively. The total intrinsic value of options exercised during the years ended December 31, 2016, 2015 and 2014 were $28.0 million, $84.7 million and $62.8 million, respectively, which we determined as of the date of exercise. The amount of cash received from the exercise of stock options was $12.6 million, $23.6 million and $22.4 million for the years ended December 31, 2016, 2015 and 2014, respectively. For the year ended December 31, 2016, the weighted-average fair value of options exercised was $40.83. As of December 31, 2016, total unrecognized compensation cost related to non-vested stock-based compensation plans was $48.1 million. We will adjust the total unrecognized compensation cost for future changes in estimated forfeitures. We expect to recognize this cost over a weighted average period of 1.1 years.

Restricted Stock Unit Activity

The following table summarizes the RSU activity for the year ended December 31, 2016 (in thousands, except per share data):

	Number of Shares			Weighted Average Grant Date Fair Value Per Share
Non-vested at December 31, 2015		751		$	47.47
Granted		346		$	41.79
Vested		(270	)	$	39.22
Cancelled/forfeited		(49	)	$	49.38
Non-vested at December 31, 2016		778		$	47.68

For the years ended December 31, 2016, 2015 and 2014, the weighted-average grant date fair value of RSUs granted was $41.79, $65.69 and $44.94 per RSU, respectively. As of December 31, 2016, total unrecognized compensation cost related to RSUs was $13.3 million. We will adjust the total unrecognized compensation cost for future changes in estimated forfeitures. We expect to recognize this cost over a weighted average period of 1.2 years.

Stock-based Compensation Expense and Valuation Information

The following table summarizes stock-based compensation expense for the years ended December 31, 2016, 2015 and 2014 (in thousands), which was allocated as follows and includes $10.1 million and $6.5 million of stock-based compensation expense for Akcea employees in 2016 and 2015, respectively:

	Year Ended December 31,
	2016			2015			2014
Research, development and patents		$	55,099		$	43,638		$	25,843
General and administrative			17,009			15,676			5,540
Total		$	72,108		$	59,314		$	31,383

Determining Fair Value

Valuation. We measure stock-based compensation expense for equity-classified awards, principally related to stock options, RSUs, 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.

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 options granted based on actual and projected exercise patterns. We recognize compensation expense for stock options granted, RSUs, 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), an entity recognizes 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, 2016, 2015 and 2014, we used the following weighted-average assumptions in our Black-Scholes calculations:

Employee Stock Options:

	December 31,
	2016	2015	2014
Risk-free interest rate	1.5 %	1.5 %	1.7 %
Dividend yield	0.0 %	0.0 %	0.0 %
Volatility	58.7 %	53.8 %	50.1 %
Expected life	4.5 years	4.5 years	4.7 years

Board of Director Stock Options:

	December 31,
	2016	2015	2014
Risk-free interest rate	1.3 %	2.1 %	2.2 %
Dividend yield	0.0 %	0.0 %	0.0 %
Volatility	53.1 %	52.2 %	54.2 %
Expected life	6.5 years	6.9 years	6.9 years

ESPP:

	December 31,
	2016	2015	2014
Risk-free interest rate	0.4 %	0.1 %	0.1 %
Dividend yield	0.0 %	0.0 %	0.0 %
Volatility	86.4 %	51.7 %	60.1 %
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. Our historical forfeiture estimates have not been materially different from our actual forfeitures.

- 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.

+ References

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+ Details

Income Taxes

12 Months Ended

Dec. 31, 2016

Income Taxes [Abstract]

Income Taxes

5. Income Taxes

The provisions for income taxes on income from continuing operations were as follows (in thousands):

	Year Ended December 31,
	2016		2015			2014
Current:
Federal	$	1,067	$	379		$	263
State		1,867		(7	)		(4,295	)
Total current		2,934		372			(4,032	)

Deferred:
Federal		—		—			(8,948	)
State		—		—			(2,427	)
Total deferred		—		—			(11,375	)
Income tax expense (benefit)	$	2,934	$	372		$	(15,407	)

In periods in which we have a year-to-date pre-tax loss from continuing operations and pre-tax income in other categories of earnings, such as other comprehensive income, intraperiod tax allocation rules require us to allocate the tax provision to the other categories of earnings. We then record a related tax benefit in continuing operations. During 2016 and 2015, we recorded unrealized losses on our investments in available-for-sale securities in other comprehensive income, therefore we did not have to allocate our tax provision to our other categories of earnings. However, during 2014, we recorded unrealized gains on our investments in available-for-sale securities and had to allocate our tax provision between continuing operations and other comprehensive income. As a result, for the year ended December 31, 2014, we recorded a $12.8 million tax benefit, in continuing operations and a $12.8 million tax expense, in other comprehensive income.

The reconciliation between our effective tax rate on loss from continuing operations and the statutory U.S. tax rate is as follows (in thousands):

	Year Ended December 31,
	2016					2015					2014
Pre-tax loss	$	(83,622	)			$	(87,906	)			$	(54,391	)

Statutory rate		(29,268	)	35.0	%		(30,767	)	35.0	%		(19,035	)	35.0	%
State income tax net of federal benefit		(276	)	0.3	%		1		0.0	%		(3,125	)	5.7	%
Net change in valuation allowance		55,927		(66.9	)%		69,499		(79.1	)%		29,547		(54.3	)%
Loss on debt extinguishment		—		0.0	%		—		0.0	%		2,406		(4.4	)%
Tax credits		(26,954	)	32.2	%		(41,284	)	47.0	%		(23,628	)	43.4	%
California franchise tax refund		—		0.0	%		—		0.0	%		(2,795	)	5.1	%
Deferred tax true-up		2,591		(3.1	)%		1,496		(1.7	)%		977		(1.8	)%
Other		914		(1.1	)%		1,427		(1.6	)%		246		(0.5	)%
Effective rate	$	2,934		(3.5	)%	$	372		(0.4	)%	$	(15,407	)	28.2	%

Significant components of our deferred tax assets and liabilities as of December 31, 2016 and 2015 are as follows (in thousands):

	Year Ended December 31,
	2016			2015
Deferred Tax Assets:
Net operating loss carryovers	$	194,372		$	218,493
R&D credits		193,845			153,601
Deferred revenue		54,203			45,110
Stock-based compensation		48,209			31,093
Other		26,228			19,655
Total deferred tax assets	$	516,857		$	467,952

Deferred Tax Liabilities:
Convertible debt	$	(62,669	)	$	(55,928	)
Unrealized gain in other comprehensive income		-			(5,288	)
Intangible and capital assets		(2,030	)		(2,643	)
Net deferred tax asset	$	452,158		$	404,093
Valuation allowance		(452,158	)		(404,093	)

Net deferreds	$	—		$	—

We have net deferred tax assets relating primarily to net operating loss carryforwards, or NOL’s, and research and development tax credit carryforwards. Subject to certain limitations, we may use these deferred tax assets to offset taxable income in future periods. Since we have a history of losses and the likelihood of future profitability is not assured as it pertains to the income tax accounting rules, we have provided a full valuation allowance for the deferred tax assets in our balance sheet as of December 31, 2016. If we determine that we are able to realize a portion or all of these deferred tax assets in the future, we will record an adjustment to increase their recorded value and a corresponding adjustment to increase income or additional paid in capital, as appropriate, in that same period.

Historically, we recognized excess tax benefits associated with share-based compensation to stockholders' equity only when realized. We followed the with-and-without approach excluding any indirect effects of the excess tax deductions to determine when we should realize excess tax benefits relating to share-based compensation. Under this approach, we did not realize our excess tax benefits related to share-based compensation until after we utilize all our other tax benefits available to us. During the year ended December 31, 2016, we realized $1.9 million of such excess tax benefits, and accordingly, we recorded a corresponding credit to additional paid-in capital.

In March 2016, the FASB issued amended guidance to simplify certain aspects of share-based payment accounting which affects how we account for unrecognized tax benefits. As of December 31, 2016, we had $82.5 million of unrealized excess tax benefits associated with share-based compensation. We adopted this amended guidance on January 1, 2017. Upon adoption we will recognize the balance of these unrecognized tax benefits as a deferred tax asset which will be offset by our full valuation allowance. The adoption of this guidance did not affect our accumulated loss.

At December 31, 2016, we had federal and California tax net operating loss carryforwards of approximately $679.8 million and $973.1 million, respectively. Our federal tax loss carryforwards will begin to expire in 2024, unless we use them before then. Our California loss carryforwards continue to expire in 2016. At December 31, 2016 we also had federal and California research and development tax credit carryforwards of approximately $189.6 million and $48.0 million, respectively. Our Federal research and development tax credit carryforwards begin to expire in 2018. Our California research and development tax credit carryforwards are available indefinitely.

We analyze filing positions in all of the federal and state 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,
	2016			2015		2014
Beginning balance of unrecognized tax benefits	$	51,257		$	27,365	$	23,964
Settlement of prior period tax positions		(4,033	)		—		—
Decrease for prior period tax positions		—			—		(1,653	)
Increase for prior period tax positions		7,928			215		—
Increase for current period tax positions		11,847			23,677		5,054
Ending balance of unrecognized tax benefits	$	66,999		$	51,257	$	27,365

Included in the balance of unrecognized tax benefits at December 31, 2016, is $46.4 million that, if recognized, would not impact our income tax benefit or effective tax rate as long as our deferred tax asset remains subject to a full 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. We did not recognize any accrued interest and penalties related to gross unrecognized tax benefits during the year ended December 31, 2016.

Due to the carryforward of unutilized net operating losses and research and development credits, we are subject to taxation in the United States and various state jurisdictions. Our tax years for 1998 and forward are subject to examination by the U.S. tax authorities and our tax years for 2003 and forward are subject to examination by the California tax authorities.

Collaborative Arrangements and Licensing Agreements

12 Months Ended

Dec. 31, 2016

Collaborative Arrangements and Licensing Agreements

6. Collaborative Arrangements and Licensing Agreements

Strategic Partnerships

AstraZeneca

Cardiometabolic and Renal Diseases Partnership

In July 2015, we and AstraZeneca formed a strategic collaboration to discover and develop antisense therapies for treating cardiovascular and metabolic diseases primarily focused on targets in the kidney and renal diseases. As part of the agreement, we granted AstraZeneca an exclusive license to a preclinical program and the option to license a drug for each target advanced under this research collaboration. Upon acceptance of a drug development candidate, AstraZeneca will be responsible for all further global development, regulatory and commercialization activities for such drug.

Under the terms of the agreement, we received a $65 million upfront payment. Since this agreement has multiple elements, we evaluated the deliverables in this arrangement and determined that none of the deliverables have stand-alone value because of the early stage of research for this collaboration. Therefore, we concluded there is one unit of accounting and we are amortizing the $65 million upfront payment through August 2021. We are eligible to receive license fees and substantive milestone payments of up to more than $4 billion as drugs under this collaboration advance, including up to $1.1 billion for the achievement of development milestones and up to $2.9 billion for regulatory milestones. In December 2016, we earned a $25 million milestone payment when we moved the first development candidate into preclinical development, IONIS-AZ4-2.5-L_Rx, our first generation 2.5 plus LIgand-Conjugated Antisense, or LICA, drug. We will earn the next milestone payment of $10 million under this collaboration if we advance a drug under our cardiometabolic research program with AstraZeneca. In addition, we are eligible to receive tiered royalties up to the low teens on sales from any product that AstraZeneca successfully commercializes under this collaboration agreement.

Oncology Partnership

In December 2012, we entered into a collaboration agreement with AstraZeneca to discover and develop antisense drugs for cancer. As part of the agreement, we granted AstraZeneca an exclusive license to develop and commercialize IONIS-STAT3-2.5_Rx for the treatment of cancer and an option to license up to three anti-cancer drugs under a separate research program. AstraZeneca is responsible for all global development, regulatory and commercialization activities for IONIS-STAT3-2.5_Rx. We and AstraZeneca have evaluated IONIS-STAT3-2.5_Rx in patients with advanced metastatic hepatocellular carcinoma and advanced lymphoma. AstraZeneca is evaluating IONIS-STAT3-2.5_Rx in combination with MEDI4736, AstraZeneca's investigational anti-PD-L1 drug, in patients with head and neck cancer and in patients with diffuse large B cell lymphoma. For the research program, we are responsible for identifying a development candidate for each of the three anti-cancer research programs. AstraZeneca has the option to license drugs resulting from each of the three anti-cancer research programs, and if AstraZeneca exercises its option for a drug, it will be responsible for all further global development, regulatory and commercialization activities for such drug. The first development candidate identified under the anti-cancer research program was IONIS-KRAS-2.5_Rx, which AstraZeneca licensed from us in December 2016. IONIS-KRAS-2.5_Rx is a Generation 2.5 antisense drug we designed to directly target KRAS, one of the most frequently mutated genes in cancer.

Under the terms of the agreement, we received $31 million in upfront payments. We recorded revenue of $11.5 million upon receipt of these payments and we have amortized $11.9 million into revenue as we have performed development activities under this collaboration. We are recognizing the remaining $7.6 million related to the option to license three drugs under the research program through February 2018. In January 2016, we and AstraZeneca amended the agreement for the research program.Under the amended terms of the agreement, we can earn an additional $5 million in milestone payments for advancing a drug under our research program.

We are eligible to receive milestone payments and license fees from AstraZeneca as programs advance in development. In addition, we are eligible to receive tiered royalties up to the low to mid-teens on sales from any drugs resulting from these programs. If AstraZeneca successfully develops IONIS-STAT3-2.5_Rx,IONIS-KRAS-2.5_Rx and two other drugs under the research program, we could receive license fees and substantive milestone payments of up to more than $750 million, including up to $226 million for the achievement of development milestones and up to $485 million for the achievement of regulatory milestones. From inception through December 2016, we have received $76 million in milestone payments and upfront fees under this oncology collaboration, not including the $15 million milestone payment and $13 million license fee we earned for IONIS-KRAS-2.5_Rx in December 2016. We will earn the next milestone payment of $17.5 million if we advance a drug under our cancer research program with AstraZeneca.

Each of our agreements with AstraZeneca will continue until the expiration of all payment obligations under the applicable agreement. In addition, the agreement, or any program under the applicable agreement, may terminate early under the following situations:

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AstraZeneca may terminate the agreement or any program at any time by providing written notice to us;

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AstraZeneca may terminate the agreement or any program by providing written notice if we undergo a change of control with a third party; and

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Either we or AstraZeneca may terminate the agreement or any program by providing written notice to the other party upon the other party's uncured failure to perform a material obligation under the agreement, or the entire agreement if the other party becomes insolvent.

During 2016, 2015 and 2014 we earned revenue of $64.9 million, $6.4 million and $27.7 million, respectively, from our relationship with AstraZeneca, which represented 19 percent, 2 percent and 13 percent, respectively, of our total revenue for those periods. Our balance sheets at December 31, 2016 and 2015 included deferred revenue of $51.5 million and $63.3 million, respectively, related to our relationship with AstraZeneca.

Biogen

We have four strategic collaborations with Biogen focused on using antisense technology to advance the treatment of neurological disorders. These collaborations combine our expertise in creating antisense drugs with Biogen's expertise in developing therapies for neurological disorders. We developed and licensed to Biogen SPINRAZA, our recently approved drug to treat pediatric and adult patients with SMA. Additionally, we and Biogen are currently developing four other drugs to treat neurodegenerative diseases under these collaborations, including IONIS-SOD1_Rx, and three drugs to treat undisclosed neurodegenerative diseases, IONIS-BIIB4_Rx,IONIS-BIIB5_Rx and IONIS-BIIB6_Rx. In addition to these drugs, we and Biogen are evaluating numerous additional targets to develop drugs to treat neurological diseases. From inception through December 2016, we have received nearly $500 million from our Biogen collaborations, not including the $60 million milestone payment we earned for the FDA’s approval of SPINRAZA that we received in February 2017.

SPINRAZA (nusinersen)

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. In December 2016, the FDA approved SPINRAZA for the treatment of SMA in pediatric and adult patients. SPINRAZA is currently under Accelerated Assessment with the EMA for marketing authorization. Biogen is responsible for all further global development, regulatory and commercialization activities and costs for SPINRAZA.

Under the terms of our collaboration agreement, we received an upfront payment of $29 million in January 2012, which we amortized through December 2016. Over the term of the collaboration, we are eligible to receive up to $346 million in a license fee and payments, including up to $121 million in substantive milestone and other payments associated with the clinical development of SPINRAZA prior to licensing and up to $150 million in substantive milestone payments if Biogen achieves pre-specified regulatory milestones. We are also eligible to receive tiered royalties up to the mid-teens on any sales of SPINRAZA. We have exclusively in-licensed patents related to SPINRAZA from Cold Spring Harbor Laboratory and the University of Massachusetts. We are obligated to pay Cold Spring Harbor Laboratory and the University of Massachusetts nominal amounts for license fees and milestone payments we receive and a low single digit royalty on sales of SPINRAZA. From inception through December 2016, we have received $259 million in payments for advancing SPINRAZA, including the $75 million license fee we received from Biogen when Biogen licensed SPINRAZA, which we recognized as revenue in the third quarter of 2016. Additionally in February 2017, we received a $60 million substantive milestone payment that we earned in December 2016. We will earn the next milestone payment of up to $50 millionif Biogen receives regulatory approval in Europe or Japan for SPINRAZA.

IONIS-DMPK-2.5_Rx

In June 2012, we and Biogen entered into a second and separate collaboration agreement to develop and commercialize a novel antisense drug, IONIS-DMPK-2.5_Rx, targeting DMPK for the treatment of myotonic dystrophy type 1, or DM1. We are responsible for global development of the drug through the completion of the first Phase 2 clinical trial. We completed a Phase 1/2 clinical study in patients with DM1. Based on the data reported in December 2016, we plan to pursue a more potent drug using our LICA technology. From inception through December 2016, we have received nearly $39 million in payments for advancing IONIS-DMPK-2.5_Rx.

Neurology

In December 2012, we and Biogen entered into a separate collaboration agreement to develop and commercialize novel antisense drugs to up to three targets to treat neurodegenerative diseases. We are responsible for the development of each of the drugs through the completion of the initial Phase 2 clinical study for such drug. Biogen has the option to license a drug from each of the three programs through the completion of the first Phase 2 study for each program. We are currently advancing IONIS-BIIB4_Rx under this collaboration. If Biogen exercises its option for a drug, it will assume all further global development, regulatory and commercialization responsibilities for that drug.

Under the terms of the agreement, we received an upfront payment of $30 million, which we are amortizing through December 2020. Over the term of the collaboration, we are eligible to receive up to $259 million in a license fee and substantive milestone payments per program. We are eligible to receive up to $59 million in development milestone payments to support research and development of each program, including amounts related to the cost of clinical trials. We are also eligible to receive up to $130 million in milestone payments per program if Biogen achieves pre-specified regulatory milestones. In addition, we are eligible to receive tiered royalties up to the mid-teens on sales from any drugs resulting from each of the three programs. From inception through December 2016, we have received $43 million in milestone payments and upfront fees under this collaboration. We will earn the next milestone payment of up to $10 million for the continued development of IONIS-BIIB4_Rx.

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 drugs resulting from this collaboration. The exclusivity for neurological diseases will last through September 2019, and may be extended for any drug development programs Biogen is pursuing under the collaboration. We will usually be responsible for drug discovery and early development of antisense drugs and Biogen will have the option to license antisense drugs 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 for a drug, it will assume all further global development, regulatory and commercialization responsibilities for that drug. We are currently advancing three drugs, IONIS-SOD1_Rx, IONIS-BIIB5_Rx, and IONIS-BIIB6_Rx under this collaboration. Biogen will be responsible for all of the drug discovery and development activities for drugs using other modalities.

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 drugs developed through this collaboration, with the specific amounts dependent upon the modality of the molecule advanced by Biogen. If we have a change of control during the first six years of the collaboration, we may be required to refund Biogen a portion of the $100 million upfront payment, with the amount of the potential refund decreasing ratably as we progress through the initial six-year term of the collaboration. We are amortizing the $100 million upfront payment through September 2019. Because the amortization period for the upfront payment will never be less than the initial six-year term of the collaboration, the amount of revenue we recognize from the upfront payment will never exceed the amount that Biogen could potentially require us to refund.

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 substantive milestone payments. We are eligible to receive up to approximately $60 million for the achievement of research and development milestones, including amounts related to the cost of clinical trials, and up to $130 million for the achievement of regulatory milestones. In addition, we are eligible to receive tiered royalties up to the mid-teens on sales from any antisense drugs developed under this collaboration. If other modalities are chosen, such as small molecules or monoclonal antibodies, we are eligible to receive up to $90 million in substantive milestone payments, including up to $35 million for the achievement of research and development milestones and up to $55 million for the achievement of regulatory milestones. In addition, we are eligible to receive tiered single-digit royalties on sales from any drugs using non-antisense modalities developed under this collaboration. From inception through December 2016, we have received $142 million in milestone payments and upfront fees under this collaboration. We will earn the next milestone payment of up to $10 million if we choose another target to advance under this collaboration.

Each of our agreements with Biogen will continue until the earlier of the date all of Biogen's options to obtain the exclusive licenses under the applicable agreement expire unexercised or, if Biogen exercises its option, until the expiration of all payment obligations under the applicable agreement. In addition, each agreement, or any program under an agreement, may terminate early under the following situations:

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Biogen may terminate the agreement or any program at any time by providing written notice to us;

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Under specific circumstances, if we are acquired by a third party with a product that directly competes with a compound being developed under the agreement, Biogen may terminate the affected program by providing written notice to us;

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If, within a specified period of time, any required clearance of a transaction contemplated by an agreement under the Hart-Scott-Rodino Antitrust Improvements Act of 1976, as amended, is not received, then either we or Biogen may terminate the affected program by providing written notice to the other party; and

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Either we or Biogen may terminate any program by providing written notice to the other party upon the other party's uncured failure to perform a material obligation under the agreement with respect to the affected program, or the entire agreement if the other party becomes insolvent.

During 2016, 2015 and 2014, we earned revenue of $207.9 million, $106.2 million and $123.2 million, respectively, from our relationship with Biogen, which represented 60 percent, 37 percent and 58 percent, respectively, of our total revenue for those periods. Our balance sheets at December 31, 2016 and 2015 included deferred revenue of $67.5 million and $91.6 million, respectively, related to our relationship with Biogen.

Research, Development and Commercialization Partners

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 patients 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. We recorded revenue of $91.2 million related to the license for IONIS-FXI_Rx in June 2015 and we recognized the majority of the remaining amount related to development activities for IONIS-FXI_Rxthrough November 2016.

In February 2017, we amended our agreement with Bayer to advance IONIS-FXI_Rx and to initiate development of IONIS-FXI-L_Rx, which Bayer licensed. In conjunction with the decision to advance these programs, we will receive a $75 million payment from Bayer. We plan to conduct a Phase 2b study evaluating IONIS-FXI_Rx in patients with end-stage renal disease on hemodialysis to finalize dose selection. Additionally, we plan to rapidly develop IONIS-FXI-L_Rx through Phase 1. Following these studies and Bayer's decision to further advance these programs, Bayer will be responsible for all global development, regulatory and commercialization activities for both drugs. We are eligible to receive additional milestone payments as each drug advances toward the market. In total over the term of our collaboration, 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 commercialization milestones. In addition, we are eligible to receive tiered royalties in the low to high 20 percent range on gross margins of both drugs combined. We will earn the next milestone payment of $10 million if we advance a program under this collaboration.

Our agreement with Bayer will continue until the expiration of all payment obligations under the agreement. In addition, the agreement, or any program under the agreement, may terminate early under the following situations:

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Bayer may terminate the agreement or any program at any time by providing written notice to us;

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Either we or Bayer may terminate the agreement or any program by providing written notice to the other party upon the other party’s uncured failure to perform a material obligation under the agreement, or the entire agreement if the other party becomes insolvent.

During 2016 and 2015 we earned revenue of $5.4 million and $93.4 million, respectively, from our relationship with Bayer, which represented two percent and 33 percent, respectively, of our total revenue for those periods. Our consolidated balance sheet at December 31, 2016 and 2015 included deferred revenue of $1.4 million and $6.7 million, respectively, related to our relationship with Bayer.

GSK

In March 2010, we entered into an alliance with GSK using our antisense drug discovery platform to discover and develop new drugs against targets for rare and serious diseases, including infectious diseases and some conditions causing blindness. Our alliance currently comprises four drugs in development, including our Phase 3 drug IONIS-TTR_Rx. We are currently conducting a Phase 3 study for IONIS-TTR_Rx and we plan to report data from this study in the second quarter of 2017. GSK has the exclusive option to license drugs resulting from this alliance after Phase 2 proof-of-concept for a license fee, including IONIS-TTR_Rx. If GSK exercises its exclusive option for any drugs resulting from this alliance, it will be responsible for all further global development, regulatory and commercialization activities for such drug.

In October 2012, we and GSK amended the original agreement to reflect an accelerated clinical development plan for IONIS-TTR_Rx. We have completed enrollment in the Phase 3 study we are conducting in patients with TTR familial amyloid polyneuropathy, or FAP. From inception through December 2016, we have earned $70 million from GSK related to the development of IONIS-TTR_Rx, primarily in milestone payments. In addition, under the amended agreement, we and GSK increased the regulatory and commercial milestone payments we can earn should IONIS-TTR_Rx receive marketing authorization and meet pre-agreed sales targets.

In addition to IONIS-TTR_Rx, we have three drugs in development with GSK, including two antisense drugs we designed to reduce the production of viral proteins associated with hepatitis B virus, or HBV, infection; IONIS-HBV_Rx and IONIS-HBV-L_Rx, a follow-on drug using our LICA technology. GSK is currently developing IONIS-HBV_Rx and IONIS-HBV-L_Rx, and if GSK exercises its exclusive option for either of these drugs, it will be responsible for all further global development, regulatory and commercialization activities. We are also developing IONIS-GSK4-L_Rx which is an antisense drug we designed to treat an ocular disease.

Under the terms of the agreement, we received $38 million in upfront and expansion payments, which we are amortizing through September 2017. Under our agreement, if GSK successfully develops all four drugs for one or more indications and achieves pre-agreed sales targets, we could receive license fees and substantive milestone payments of up to nearly $900 million, including up to $157.5 million for the achievement of development milestones, up to $338.5 million for the achievement of regulatory milestones and up to $255 million for the achievement of commercialization milestones. Through December 2016, we have received $155 million in milestone payments and upfront fees under this alliance with GSK. We will earn the next milestone payment of up to $1.5 million if we further advance a program under this collaboration and we will earn a payment of $45 million if GSK licenses IONIS-TTR_Rx. In addition, we are eligible to receive tiered royalties up to the mid-teens on sales from any product that GSK successfully commercializes under this alliance.

Our alliance with GSK will continue until the earlier of the date that all of GSK's options to obtain the exclusive licenses under the agreement expire unexercised or, if GSK exercises its option, until the expiration of all payment obligations under the agreement. In addition, the agreement, or any program under the agreement, may terminate early under the following situations:

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GSK may terminate any program, other than the IONIS-TTR_Rx program, at any time by providing written notice to us;

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GSK may terminate the IONIS-TTR_Rx program by providing written notice to us after reviewing specific data from the Phase 3 study for the program; and

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Either we or GSK may terminate any program by providing written notice to the other party upon the other party's uncured failure to perform a material obligation under the agreement with respect to the affected program, or the entire agreement if the other party becomes insolvent.

During 2016, 2015 and 2014, we earned revenue of $12.3 million, $33.3 million and $37.3 million respectively, from our relationship with GSK, which represented four percent, 12 percent and 17 percent, respectively, of our total revenue for those years. Our balance sheets at December 31, 2016 and 2015 included deferred revenue of $2.1 million and $4.9 million, respectively, related to our relationship with GSK.

Janssen Biotech, Inc., a pharmaceutical company of Johnson & Johnson

In December 2014, we entered into a collaboration agreement with Janssen Biotech, Inc. to discover and develop antisense drugs that can be locally administered, including oral delivery, to treat autoimmune disorders of the gastrointestinal tract. Janssen has the option to license drugs from us through the designation of a development candidate for up to three programs. Prior to option exercise we are responsible for the discovery activities to identify a development candidate. If Janssen exercises an option for one of the programs, it will be responsible for the global development, regulatory and commercial activities under that program. Under the terms of the agreement, we received $35 million in upfront payments, which we are amortizing through December 2018. We are eligible to receive up to nearly $800 million in license fees and substantive milestone payments for these programs, including up to $175 million for the achievement of development milestones, up to $420 million for the achievement of regulatory milestones and up to $180 million for the achievement of commercialization milestones. Through December 2016, we have received $47 million, including the $10 million license fee we earned in July 2016 when Janssen licensed IONIS-JBI1-2.5_Rx from us, which we recognized as revenue in the third quarter of 2016. We also earned a $5 million milestone payment in December 2016 when Janssen selected a development candidate for a second program. In addition, we are eligible to receive tiered royalties up to the near teens on sales from any drugs resulting from this collaboration. We will earn the next milestone payment of $5 million if Janssen chooses another target to advance under this collaboration.

Our agreement with Janssen will continue until the earlier of the date that all of Janssen’s options to obtain the exclusive licenses under the agreement expire unexercised or, if Janssen exercises its option, until the expiration of all payment obligations under the agreement. In addition, the agreement, or any program under the agreement, may terminate early under the following situations:

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Janssen may terminate the agreement or any program at any time by providing written notice to us; and

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Either we or Janssen may terminate any program by providing written notice to the other party upon the other party’s uncured failure to perform a material obligation under the agreement, or the entire agreement if the other party becomes insolvent.

During 2016 and 2015 we earned revenue of $27.3 million and $8.9 million, respectively, from our relationship with Janssen. During 2014 we did not earn any revenue from our relationship with Janssen. Our balance sheet at December 31, 2016 and 2015 included deferred revenue of $17.5 million and $26.3 million, respectively, related to our relationship with Janssen.

Novartis

In January 2017, we and Akcea initiated a collaboration with Novartis to develop and commercialize AKCEA-APO(a)-L_Rx and AKCEA-APOCIII-L_Rx. Under the collaboration, option and license agreement, Novartis has an exclusive option to develop and commercialize these drugs. Akcea is responsible for completing a Phase 2 dose ranging study and conducting an end-of-Phase 2 meeting with the FDA for each drug. If Novartis exercises an option for one of these drugs, Novartis will be responsible for all further global development, regulatory and commercialization activities for each drug.

Akcea will receive a $75 million upfront payment, of which Akcea will retain $60 million and will pay us $15 million as a sublicense fee under our license agreement with Akcea. Beginning in 2017, we and Akcea will recognize revenue from this collaboration with Novartis. If Novartis exercises its option for a drug, Novartis will pay Akcea a license fee equal to $150 million for each drug it licenses. In addition, Akcea is eligible to receive up to $600 million and $530 million in milestone payments related to AKCEA-APO(a)-L_Rx and AKCEA-APOCIII-L_Rx, respectively. Akcea retains the right to co-commercialize any such drug through its specialized sales force focused on lipid specialists in selected markets. Akcea is also eligible to receive tiered royalties in the mid-teens to low 20 percent range on net sales of AKCEA-APO(a)-L_Rx and AKCEA-APOCIII-L_Rx. Akcea will pay 50 percent of these license fees, milestone payments and royalties to us as a sublicense fee.

The agreement with Novartis will continue until the earlier of the date that all of Novartis’ options to obtain the exclusive licenses under the agreement expire unexercised or, if Novartis exercises its options, until the expiration of all payment obligations under the agreement. In addition, the agreement as a whole or with respect to any drug under the agreement, may terminate early under the following situations:

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Novartis may terminate the agreement as a whole or with respect to any drug at any time by providing written notice to us;

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Either we or Novartis may terminate the agreement with respect to any drug by providing written notice to the other party in good faith that we or Novartis has determined that the continued development or commercialization of the drug presents safety concerns that pose an unacceptable risk or threat of harm in humans or would violate any applicable law, ethical principles, or principles of scientific integrity;

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Either we or Novartis may terminate the agreement for a drug by providing written notice to the other party upon the other party’s uncured failure to perform a material obligation related to the drug under the agreement, or the entire agreement if the other party becomes insolvent; and

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We may terminate the agreement if Novartis disputes or assists a third party to dispute the validity of any or our patents.

Additionally, in January 2017, we and Akcea entered into a stock purchase agreement, or SPA, with Novartis. Under the SPA, Novartis purchased 1,631,435 shares of our common stock for $100 million. Additionally, the SPA requires Novartis to purchase an additional $50 million of common stock in the future. The additional purchase will be for either our stock or Akcea’s stock.

Roche

In April 2013, we formed an alliance with Hoffman-La Roche Inc. and F. Hoffmann-La Roche Ltd., collectively Roche, to develop treatments for Huntington's disease, or HD, based on our antisense technology. Roche has the option to license the drugs from us through the completion of the first Phase 1 trial. Under the agreement, we are responsible for the discovery and development of an antisense drug targeting huntingtin, or HTT, protein. We are currently evaluating a drug targeting HTT, IONIS-HTT_Rx, in a Phase 1/2 clinical study in patients with early stage HD. If Roche exercises its option, it will be responsible for global development, regulatory and commercialization activities for any drug arising out of the collaboration. Under the terms of the agreement, we received an upfront payment of $30 million in April 2013, which we are amortizing through April 2017. In December 2016, we updated development activities for IONIS-HTT_Rx and as a result we are eligible for an additional $3 million payment. We are eligible to receive up to $365 million in a license fee and substantive 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 commercialization milestones. In addition, we are eligible to receive up to $136.5 million in milestone payments for each additional drug successfully developed. We are also eligible to receive tiered royalties up to the mid-teens on any sales of any product resulting from this alliance. Through December 2016, we have received $53.6 million in milestone payments and upfront fees under this alliance with Roche. We will earn the next milestone payment of $10 million if Roche initiates a Phase 2 trial for IONIS-HTT_Rx.

Our alliance with Roche will continue until the earlier of the date Roche's option to obtain the exclusive license under the agreement expires unexercised or, if Roche exercises its option, until the expiration of all payment obligations under the agreement. In addition, the agreement may terminate early under the following situations:

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Roche may terminate the agreement at any time by providing written notice to us; and

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Either we or Roche may terminate the agreement by providing written notice to the other party upon the other party's uncured failure to perform a material obligation under the agreement or if the other party becomes insolvent.

During 2016, 2015 and 2014, we earned revenue of $7.1 million, $31.2 million and $8.7 million, respectively from our relationship with Roche, which represented two percent, 11 percent and four percent, respectively, of our total revenue for those years. Our balance sheet at December 31, 2016 and 2015 included deferred revenue of $1.7 million and $8.8 million, respectively related to our relationship with Roche.

Satellite Company Partnerships

Achaogen, Inc.

In 2006, we exclusively licensed to Achaogen, Inc. specific know-how, patents and patent applications relating to aminoglycosides. In connection with the license, Achaogen issued to us $1.5 million of Achaogen stock. Achaogen is developing plazomicin, an aminoglycoside Achaogen discovered based on the technology we licensed to Achaogen. If Achaogen successfully develops and commercializes two drugs under our agreement, we will receive payments totaling up to $49.3 million for the achievement of key clinical, regulatory and sales events. In December 2016, Achaogen announced positive data for its CARE Phase 3 study for plazomicin and that its EPIC Phase 3 study met its primary endpoints. Achaogen plans to submit an NDA, which will include EPIC and CARE data, to the FDA in the second half of 2017 and also plans to submit an MAA to the EMA in 2018. Through December 2016, we have earned $7 million in milestone payments from Achaogen, including a $4 million milestone payment we earned in September 2014 when Achaogen initiated a Phase 3 study of plazomicin. We will earn the next milestone payment of $7.5 million if Achaogen obtains regulatory approval for plazomicin in a major market. We are also eligible to receive low single digit royalties on sales of drugs resulting from the program. Achaogen is solely responsible for the continued development and commercialization of plazomicin.

During 2016 and 2015, we did not earn any revenue from our relationship with Achaogen. During 2014, we earned revenue of $4 million from our relationship with Achaogen and we sold all of the Achaogen stock we owned resulting in net proceeds of $1.3 million.

Alnylam Pharmaceuticals, Inc.

In March 2004, we entered into an alliance with Alnylam to develop and commercialize RNAi therapeutics. Under the terms of the agreement, we exclusively licensed to Alnylam our patent estate relating to antisense motifs and mechanisms and oligonucleotide chemistry for double-stranded RNAi therapeutics in exchange for a $5 million technology access fee, participation in fees from Alnylam’s partnering programs, as well as future milestone and royalty payments from Alnylam. For each drug Alnylam develops under this alliance, we may receive up to $3.4 million in milestone payments, including up to $1.1 million for the achievement of development milestones and $2.3 million for regulatory milestones. We will earn the next milestone payment of $0.4 million if Alnylam initiates a Phase 1 study for a drug in Alnylam’s pipeline. We also have the potential to earn royalties on drug sales and a portion of payments that Alnylam receives from licenses of our technology it grants to its partners, plus royalties. We retained rights to 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 drugs targeting a limited number of therapeutic targets on a nonexclusive basis. If we develop or commercialize an RNAi-based drug using Alnylam’s technology, we will pay Alnylam up to $3.4 million in milestone payments for specified development and regulatory events, plus royalties. To date, we do not have an RNAi-based drug in development.

In 2015, we and Alnylam entered into an alliance in which we formed an intellectual property cross-license under which 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. Through December 2016, we have received over $70 million from Alnylam.

During 2016, 2015 and 2014, we earned revenue from our relationship with Alnylam totaling $1.1 million, $1.3 million and $9.9 million, respectively.

Antisense Therapeutics Limited

In 2001, we licensed ATL1102 and ATL1103 to ATL, an Australian company publicly traded on the Australian Stock Exchange. ATL completed a Phase 2a efficacy and safety trial and has also completed a chronic toxicology study in primates to support a potential Phase 2b trial of ATL1102 in patients with multiple sclerosis, or MS. In addition, ATL is currently developing ATL1103 for growth and sight disorders. We are eligible to receive royalties on sales of ATL1102 and ATL1103. We may also receive a portion of the fees ATL receives if it licenses ATL1102 or ATL1103. At December 31, 2016 and 2015, we owned less than 10 percent of ATL’s equity. During 2016, 2015 and 2014, we did not earn any revenue from our relationship with ATL.

Atlantic Pharmaceuticals Limited

In March 2007, we licensed alicaforsen to Atlantic Pharmaceuticals, a UK-based specialty pharmaceutical company founded in 2006. Atlantic Pharmaceuticals is developing alicaforsen for the treatment of ulcerative colitis, or UC, and other inflammatory diseases. Atlantic Pharmaceuticals is initially developing alicaforsen for pouchitis, a UC indication, followed by UC and other inflammatory diseases. In January 2017, Atlantic announced that it received agreement from the FDA to initiate a rolling submission of its NDA for alicaforsen. In exchange for the exclusive, worldwide license to alicaforsen, we received a $2 million upfront payment from Atlantic Pharmaceuticals in the form of equity. Under the agreement, we could receive milestone payments totaling up to $1.4 million for the achievement of regulatory milestones for multiple indications. We will earn the next milestone payment of $0.6 million if Atlantic Pharmaceuticals submits an NDA for alicaforsen with the FDA. In 2010, Atlantic Pharmaceuticals began supplying alicaforsen under international named patient supply regulations for patients with inflammatory bowel disease, or IBD, for which we receive royalties.

In 2010, 2013 and 2016, we agreed to sell Atlantic Pharmaceuticals alicaforsen drug substance in return for shares of Atlantic Pharmaceuticals’ common stock. Additionally, in 2013 we received an advance payment in the form of equity for the initial royalties that we will earn from Atlantic Pharmaceuticals. We recorded a full valuation allowance for all of the equity we received from Atlantic Pharmaceuticals, including the upfront payment, because realization of value from the equity is uncertain. At December 31, 2016 and 2015, we owned approximately 9 percent and 11 percent, respectively, of Atlantic Pharmaceuticals’ equity. Because the payments were made in equity, we did not record any revenue. During 2016 we did not earn any revenue and during 2015 and 2014, our revenue was negligible from our relationship with Atlantic Pharmaceuticals.

Dynacure, SAS

In October 2016, we entered into a collaboration with Dynacure to discover, develop and commercialize an antisense drug for the treatment of neuromuscular diseases. We and Dynacure will share research responsibilities and to identify a drug candidate. Upon exercising its option to license the drug, Dynacure will assume all responsibility for development and commercialization. Under the terms of the agreement, we obtained a 15 percent equity ownership in Dynacure. If Dynacure advances a target under this collaboration, we could receive cash or equity up to more than $210 million in a license fee and milestone payments including up to $34.5 million for the achievement of development milestones, up to $111 million for the achievement of regulatory milestones and up to $60 million for the achievement of commercialization milestones. In addition, we are eligible to receive royalties on future product sales of the drug under this collaboration. We will receive an additional equity position in Dynacure if Dynacure initiates a Phase 1 study for a target under this collaboration. During 2016, we did not earn any revenue from our relationship with Dynacure.

OncoGenex Technologies Inc., a subsidiary of OncoGenex Pharmaceuticals Inc.

In January 2005, we entered into an agreement with OncoGenex to allow for the development of an antisense anti-cancer drug, apatorsen. OncoGenex and collaborators are evaluating apatorsen in multiple Phase 2 studies in patients with cancer. OncoGenex is responsible for all development costs and activities. OncoGenex will pay us milestone payments totaling up to $5.8 million for the achievement of key development and regulatory milestones, including up to $1.3 million for the achievement of development milestones and up to $4.5 million for the achievement of regulatory milestones. In addition, we are eligible to receive royalties on future product sales of apatorsen. We will earn the next milestone payment of $1.3 million if OncoGenex initiates a Phase 3 study for apatorsen.

In early 2017, OncoGenex Pharmaceuticals, Inc. entered into a definitive merger agreement under which OncoGenex will acquire Achieve Life Sciences in an all-stock transaction. The merger is expected to close mid-2017. Upon closing OncoGenex Pharmaceuticals, Inc. will be renamed Achieve Life Sciences, Inc.

During 2016 we earned $1.4 million in revenue from our relationship with OncoGenex. During 2015 and 2014, we did not earn any revenue from our relationship with OncoGenex.

Regulus Therapeutics Inc.

In September 2007, we and Alnylam established Regulus as a company focused on the discovery, development and commercialization of microRNA-targeting therapeutics. We and Alnylam retain rights to develop and commercialize, on pre-negotiated terms, microRNA therapeutic products that Regulus decides not to develop either by itself or with a partner. Regulus is addressing therapeutic opportunities that arise from alterations in microRNA expression. Since microRNAs may act as master regulators of the genome, affecting the expression of multiple genes in a disease pathway, microRNA therapeutics define a new platform for drug discovery and development. MicroRNAs may also prove to be an attractive new tool for characterizing diseases. Regulus focuses its drug discovery and development efforts in numerous therapeutic areas, including cancer, fibrosis, and viral infections. Regulus currently has three drugs in clinical development. Regulus is evaluating RG-101 in a Phase 2 study in patients with HCV and in a Phase 1 study in patients with severe renal insufficiency or end-stage renal disease. Regulus is also evaluating RG-012 in a Phase 1 study to treat patients with Alport syndrome. Regulus and AstraZeneca are also evaluating RG-125 in a Phase 1 study for the treatment of NASH in patients with type 2 diabetes or pre-diabetes. We are eligible to receive royalties on any future product sales of these drugs.

During 2016, 2015 and 2014, we did not earn any revenue from our relationship with Regulus. During 2016, we sold a portion of our Regulus stock for proceeds of $4.5 million. During 2015 and 2014, we sold a portion of our Regulus stock, resulting in a gain of $20.2 million and $19.9 million, respectively, and proceeds of $25.5 million and $22.9 million, respectively. As of December 31, 2016, we owned approximately 1.1 million shares, with a net carrying value of $2.4 million. In January 2017, we sold our remaining investment in Regulus.

The University of Texas MD Anderson Cancer Center

In May 2016, we entered into a collaboration agreement with the University of Texas MD Anderson Cancer Center to identify cancer targets and create novel antisense drugs to treat cancer together. In the collaboration, we and MD Anderson will work together to validate novel “undruggable” cancer targets selected based on human genomic data. We will lead the drug discovery efforts against mutually agreed upon novel targets and MD Anderson will lead development activities through clinical proof of concept. Following clinical proof of concept, we and MD Anderson plan to identify a partner to complete development and to commercialize each drug with us leading business development efforts. Under the five-year collaboration, we and MD Anderson will evenly share costs specific to our collaboration.

External Project Funding

CHDI Foundation, Inc.

Starting in November 2007, CHDI provided financial and scientific support to our Huntington’s disease drug discovery program through our development collaboration. In April 2013, we formed an alliance with Roche to develop treatments for Huntington’s disease. Under the terms of our agreement with CHDI, we will reimburse CHDI for a portion of its support of our Huntington’s disease program out of the payments we receive from Roche. We made payments of $5 million and $3 million to CHDI in 2015 and 2013, respectively, associated with the progression of our Huntington’s disease program. If we achieve pre-specified milestones under our collaboration with Roche, we will make additional research related payments to CHDI up to $4 million, upon completion of our Phase 1/2 study of IONIS-HTT_Rx. If Roche licenses IONIS-HTT_Rx,we will make an additional payment to CHDI.

During 2016 and 2014, we did not earn any revenue from our relationship with CHDI. During 2015, our revenue earned from our relationship with CHDI was negligible.

Cystic Fibrosis Foundation

In August 2016, we entered into a collaboration agreement with the Cystic Fibrosis Foundation to discover and advance a drug for the treatment of Cystic Fibrosis. Under this agreement, we received upfront payments of $1 million and we are eligible to receive additional milestone payments up to $2 million. Under the agreement, we and the Cystic Fibrosis Foundation will evenly share the first $3 million of costs specific to our collaboration. We will pay the Cystic Fibrosis Foundation up to $18 million in payments upon achieving specific regulatory and sales events if we advance a drug under our collaboration. We will earn the next milestone payment of $0.5 million if we further advance IONIS-ENAC-2.5_Rx.

During 2016 we earned $0.6 million from our relationship with the Cystic Fibrosis Foundation.

The Ludwig Institute; Center for Neurological Studies

In October 2005, we entered into a collaboration agreement with the Ludwig Institute, the Center for Neurological Studies and researchers from these institutions to discover and develop antisense drugs for amyotrophic lateral sclerosis, or ALS, and other neurological diseases. Under this agreement, we agreed to pay the Ludwig Institute and Center for Neurological Studies modest milestone payments and royalties on any antisense drugs resulting from the collaboration.

Intellectual Property Sale and Licensing Agreements

Sales of Intellectual Property

Abbott Molecular Inc.

In January 2009, we sold our former subsidiary, Ibis Biosciences, to Abbott Molecular Inc., or AMI, pursuant to a stock purchase agreement for a total acquisition price of $215 million plus the earn out payments described below.

Under the stock purchase agreement, we are eligible to receive earn out payments from AMI equal to a percentage of Ibis’ revenue related to sales of Ibis systems, which AMI launched in 2014 as IRIDICA, including instruments, assay kits and successor products. Once cumulative net sales reach $140 million, and through December 31, 2025, we are eligible to earn out payments in any year that net sales exceed $50 million for the applicable year. The earn out payments will equal five percent of Ibis’ cumulative net sales over $140 million and up to $2.1 billion, and three percent of Ibis’ cumulative net sales over $2.1 billion. AMI may reduce these earn out payments from five percent to as low as 2.5 percent and from three percent to as low as 1.5 percent, respectively, upon the occurrence of certain events. During 2016, 2015 and 2014, we did not earn any revenue from our relationship with AMI.

Kastle Therapeutics

In May 2016, we entered into an agreement with Kastle under which Kastle acquired the global rights to develop and commercialize Kynamro. Kynamro is approved in the United States for use in patients with homozygous familial hypercholesterolemia to reduce low density lipoprotein-cholesterol, apolipoprotein B, total cholesterol and non-high density lipoprotein-cholesterol as an adjunct to lipid lowering medications and diet. We previously licensed Kynamro to Sanofi Genzyme. As a result, Sanofi Genzyme earns a three percent royalty on sales of Kynamro and three percent of non-royalty cash payments we receive from Kastle. Under the terms of our agreement with Kastle, we are eligible to receive up to $95 million, which includes a $15 million upfront payment we received in May 2016, a $10 million payment we are entitled to receive in May 2019 and up to $70 million in sales milestones. In December 2016, we amended our agreement with Kastle. As a result of the amendment, through 2017, Kastle will only pay us the three percent royalty we owe Sanofi Genzyme on sales of Kynamro. Beginning in 2018, we will be eligible to earn tiered royalties on global sales of Kynamro that average in the mid to low teens, increasing slightly in years 2020 and 2021. In addition in May 2016, we received a 10 percent common equity position in Kastle. Because realization of our equity position is uncertain, we recorded a full valuation allowance.

During 2016, we earned revenue of $15.1 million from our relationship with Kastle.

In-Licensing Arrangements

University of Massachusetts

We have a license agreement with the University of Massachusetts under which we acquired an exclusive license to the University of Massachusetts’ patent rights related to SPINRAZA. We are obligated to pay the University of Massachusetts nominal amounts for license fees and milestone payments we receive and a low single digit royalty on sales of SPINRAZA.

Cold Spring Harbor Laboratory

We have a collaboration and license agreement with the Cold Spring Harbor Laboratory under which we acquired an exclusive license to the Cold Spring Harbor Laboratory’s patent rights related to SPINRAZA. If we successfully develop and commercialize a drug incorporating the technology we licensed from the Cold Spring Harbor Laboratory, we will pay a portion of any sublicense revenue and post licensing milestone payments we receive in consideration for sublicensing the Cold Spring Harbor Laboratory’s technology up to $11.3 million and a low single digit royalty on sales of SPINRAZA. During 2016, we paid Cold Spring Harbor Laboratory $3.4 million.

Segment Information and Concentration of Business Risk

12 Months Ended

Dec. 31, 2016

Segment Information and Concentration of Business Risk [Abstract]

Segment Information and Concentration of Business Risk

7. Segment Information and Concentration of Business Risk

In 2015, we began reporting our financial results in two reportable segments, Ionis Core, and Akcea Therapeutics, our wholly owned subsidiary. Segment loss from operations includes revenue less operating expenses attributable to each segment.

In our Ionis Core segment, we are exploiting a novel drug discovery platform we created to generate a broad pipeline of first-in-class or best-in-class drugs for us and our partners. Our Ionis Core segment generates revenue from a multifaceted partnering strategy.

We formed Akcea to develop and commercialize drugs to treat patients with serious cardiometabolic diseases caused by lipid disorders. Moving our lipid drugs into a company that we own ensures that our core focus at Ionis remains on innovation while allowing us to maintain control over and retain more value from our lipid drugs. Through 2016, Akcea had not earned any revenue, however in 2017, Akcea will begin recognizing revenue related to its collaboration with Novartis.

The following is our segment information for 2016, 2015 and 2014 (in thousands).

2016	Ionis Core		Akcea Therapeutics			Elimination of Intercompany Activity			Total
Revenue:
Research and development	$	338,546	$	—		$	(12,648	)	$	325,898
Licensing and royalty		20,722		—			—			20,722
Total segment revenue	$	359,268	$	—		$	(12,648	)	$	346,620
Income (loss) from operations	$	37,196	$	(83,512	)	$	—		$	(46,316	)

2015	Ionis Core			Akcea Therapeutics			Elimination of Intercompany Activity			Total
Revenue:
Research and development	$	284,135		$	—		$	(2,775	)	$	281,360
Licensing and royalty		2,343			—			—			2,343
Total segment revenue	$	286,478		$	—		$	(2,775	)	$	283,703
Loss from operations	$	(23,014	)	$	(52,748	)	$	—		$	(75,762	)

2014	Ionis Core			Akcea Therapeutics			Total
Revenue:
Research and development	$	202,514		$	—		$	202,514
Licensing and royalty		11,647			—			11,647
Total segment revenue	$	214,161		$	—		$	214,161
Loss from operations	$	(26,033	)	$	(21,697	)	$	(47,730	)

The following table shows our total assets by segment at December 31, 2016 and 2015 (in thousands), respectively.

Total Assets	Ionis Core		Akcea Therapeutics		Elimination of Intercompany Activity			Total
December 31, 2016	$	1,067,770	$	10,684	$	(165,987	)	$	912,467
December 31, 2015	$	994,191	$	66,068	$	(112,359	)	$	947,900

We have historically funded our operations from collaborations with corporate partners and a relatively small number of partners have accounted for a significant percentage of our revenue. Revenue from significant partners, which is defined as 10 percent or more of our total revenue, was as follows:

	2016		2015		2014
Partner A		60 %		37 %		58 %
Partner B		19 %		2 %		13 %
Partner C		4 %		12 %		17 %
Partner D		2 %		33 %		0 %
Partner E		2 %		11 %		4 %

Contracts receivables at December 31, 2016 and December 31, 2015 were comprised of approximately 92 percent and 99 percent for each year from two significant partners, respectively.

- Definition

The entire disclosure for reporting segments including data and tables. Reportable segments include those that meet any of the following quantitative thresholds a) it's reported revenue, including sales to external customers and intersegment sales or transfers is 10 percent or more of the combined revenue, internal and external, of all operating segments b) the absolute amount of its reported profit or loss is 10 percent or more of the greater, in absolute amount of 1) the combined reported profit of all operating segments that did not report a loss or 2) the combined reported loss of all operating segments that did report a loss c) its assets are 10 percent or more of the combined assets of all operating segments.

+ References

Reference 1: http://www.xbrl.org/2003/role/presentationRef
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-Name Accounting Standards Codification
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Reference 2: http://www.xbrl.org/2003/role/presentationRef
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Reference 3: http://www.xbrl.org/2003/role/presentationRef
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Reference 6: http://www.xbrl.org/2003/role/presentationRef
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Reference 14: http://www.xbrl.org/2003/role/presentationRef
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+ Details

Employment Benefits	12 Months Ended
Employment Benefits	Dec. 31, 2016
Employment Benefits [Abstract]
Employment Benefits	8. Employment Benefits We have an employee 401(k) salary deferral plan, covering all employees. Employees may make contributions by withholding a percentage of their salary up to the IRS annual limit $18,000 and $24,000 in 2016 for employees under 50 years old and employees 50 years old or over, respectively. We made approximately $1.7 million, $1.5 million and $1.0 million in matching contributions for the years ended December 31, 2016, 2015 and 2014, respectively.

Legal Proceedings	12 Months Ended
Legal Proceedings	Dec. 31, 2016
Legal Proceedings [Abstract]
Legal Proceedings	9. 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. Gilead Litigation In August 2013, Gilead Sciences Inc. filed a suit in the United States District Court of Northern District of California related to United States Patent Nos. 7,105,499 and 8,481,712, which are jointly owned by Merck Sharp & Dohme Corp. and Ionis Pharmaceuticals, Inc. In the suit, Gilead asked the court to determine that Gilead's activities do not infringe any valid claim of the named patents and that the patents are not valid. We and Merck Sharp & Dohme Corp. filed our answer denying Gilead's noninfringement and invalidity contentions, contending that Gilead's commercial sale and offer for sale of sofosbuvir prior to the expiration of the '499 and '712 patents infringes those patents, and requesting monetary damages to compensate for such infringement. In the trial for this case held in March 2016, the jury upheld all ten of the asserted claims of the patents-in-suit. The jury then decided that we and Merck are entitled to four percent of $5 billion in past sales of sofosbuvir. Gilead has stated it would appeal the jury’s finding of validity. In the meantime, Gilead asserted two additional non-jury defenses: waiver and unclean hands. Although the judge rejected the waiver defense, she granted Gilead’s motion claiming that the patents are unenforceable against it under the doctrine of unclean hands. We believe this ruling is contrary to the relevant law and the facts of the case. Accordingly, in July 2016, together with Merck we appealed the decision. Gilead cross-appealed on the issue of validity. The appeal is pending before the Court of Appeals for the Federal Circuit. Under our agreement with Merck, Merck is responsible for the costs of this suit.

Quarterly Financial Data (Unaudited)

12 Months Ended

Dec. 31, 2016

Quarterly Financial Data (Unaudited) [Abstract]

Quarterly Financial Data (Unaudited)

10. Quarterly 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 quarterly data for the years ended December 31, 2016 and 2015 are as follows (in thousands, except per share data).

2016 Quarters	First Quarter			Second Quarter			Third Quarter		Fourth Quarter
Revenue	$	36,874		$	38,470		$	110,927	$	160,349
Operating expenses	$	91,526		$	87,397		$	94,819	$	119,194
Income (loss) from operations	$	(54,652	)	$	(48,927	)	$	16,108	$	41,155
Net income (loss)	$	(62,917	)	$	(56,855	)	$	7,351	$	25,865
Basic net income (loss) per share (1)	$	(0.52	)	$	(0.47	)	$	0.06	$	0.21
Diluted net income (loss) per share (1) (2) (3)	$	(0.52	)	$	(0.47	)	$	0.06	$	0.21

2015 Quarters	First Quarter			Second Quarter		Third Quarter			Fourth Quarter
Revenue	$	62,583		$	120,428	$	49,121		$	51,571
Operating expenses	$	71,913		$	75,782	$	97,259		$	114,511
Income (loss) from operations	$	(9,330	)	$	44,646	$	(48,138	)	$	(62,940	)
Net income (loss)	$	(16,717	)	$	35,648	$	(35,776	)	$	(71,433	)
Basic net income (loss) per share (1)	$	(0.14	)	$	0.30	$	(0.30	)	$	(0.59	)
Diluted net income (loss) per share (1) (4)	$	(0.14	)	$	0.29	$	(0.30	)	$	(0.59	)

(1)	We computed net income (loss) per share independently for each of the quarters presented. Therefore, the sum of the quarterly net income (loss) per share will not necessarily equal the total for the year.

(2)

For the three months ended December 31, 2016, we had net income. 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. Diluted common equivalent shares for the three months ended December 31, 2016 consisted of the following (in thousands):

Three Months Ended December 31, 2016	Income (Numerator)		Shares (Denominator)		Per-Share Amount

Income available to common shareholders	$	25,865		121,340	$	0.21
Effect of diluted securities:
Shares issuable upon exercise of stock options		—		2,189
Shares issuable upon restricted stock award issuance		—		403
Shares issuable related to our ESPP		—		21
Income available to common shareholders, plus assumed conversions	$	25,865		123,953	$	0.21

For the three months ended December 31, 2016, the calculation excludes the 1 percent and 2¾ percent notes because the effect on diluted earnings per share would be anti-dilutive.

(3)

For the three months ended September 30, 2016, we had net income. 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. Diluted common equivalent shares for the three months ended September 30, 2016 consisted of the following (in thousands):

Three Months Ended September 30, 2016	Income (Numerator)		Shares (Denominator)		Per-Share Amount

Income available to common shareholders	$	7,351		120,989	$	0.06
Effect of diluted securities:
Shares issuable upon exercise of stock options		—		2,129
Shares issuable upon restricted stock award issuance		—		202
Shares issuable related to our ESPP		—		58
Income available to common shareholders, plus assumed conversions	$	7,351		123,378	$	0.06

For the three months ended September 30, 2016, the calculation excludes the 1 percent and 2¾ percent notes because the effect on diluted earnings per share would be anti-dilutive.

(4)

For the three months ended June 30, 2015, we had net income. 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. Diluted common equivalent shares for the three months ended June 30, 2015 consisted of the following (in thousands):

Three Months Ended June 30, 2015	Income (Numerator)		Shares (Denominator)		Per-Share Amount

Income available to common shareholders	$	35,648		119,742	$	0.30
Effect of diluted securities:
Shares issuable upon exercise of stock options		—		3,974
Shares issuable upon restricted stock award issuance		—		376
Shares issuable related to our ESPP		—		4
Shares issuable related to our 2¾ percent notes		1,047		3,683
Income available to common shareholders, plus assumed conversions	$	36,695		127,779	$	0.29

For the three months ended June 30, 2015, the calculation excludes the 1 percent notes because the effect on diluted earnings per share was anti-dilutive.

Organization and Significant Accounting Policies (Policies)

12 Months Ended

Dec. 31, 2016

Organization and Significant Accounting Policies [Abstract]

Basis of Presentation

Basis of presentation

Organization and Business Activity

Organization and business activity

Basic and Diluted Net Loss per Share

Basic and diluted net loss per share



percent convertible senior notes;



2¾ percent convertible senior notes;



Dilutive stock options;



Unvested restricted stock units; and



Employee Stock Purchase Plan, or ESPP.

Revenue Recognition

Arrangements with multiple deliverables

Identifying deliverables and units of accounting



The exclusive license we granted to Bayer to develop and commercialize IONIS-FXI_Rx for the treatment of thrombosis;



The development services we agreed to perform for IONIS-FXI_Rx; and



The initial supply of API.

Measurement and allocation of arrangement consideration



Estimated future product sales;



Estimated royalties on future product sales;



Contractual milestone payments;



Expenses we expect to incur;



Income taxes; and



An appropriate discount rate.



The number of internal hours 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 drug product we will use.

For purposes of determining BESP of the services we performed and the API we delivered in our Bayer transaction, accounting guidance required us to include a markup for a reasonable profit margin.

Based on the units of accounting under the agreement, we allocated the $100 million upfront payment from Bayer as follows:



$91.2 million to the IONIS-FXI_Rx exclusive license;



$4.3 million for development services; and



$4.5 million for the delivery of API.

Timing of revenue recognition

The following are the periods over which we are recognizing revenue for each of our units of accounting under our Bayer agreement:



We recognized the portion of the consideration attributed to the IONIS-FXI_Rx license immediately in the second quarter of 2015 because we delivered the license and earned the revenue;



We recognized the amount attributed to the development services for IONIS-FXI_Rx over the period of time we performed the services; and



We are recognizing the amount attributed to the API supply as we deliver it to Bayer.

Multiple agreements



Milestone payments

During the first step of the development stage, we or our partners study our drugs in Investigational New Drug, or IND,

Development milestones in our partnerships may include the following types of events:



Designation of a development candidate. Following the designation of a development candidate, IND-enabling animal studies for a new development candidate generally take 12 to 18 months to complete;



Initiation of a Phase 1 clinical trial. Generally, Phase 1 clinical trials take one to two years to complete;



Initiation or completion of a Phase 2 clinical trial. Generally, Phase 2 clinical trials take one to three years to complete;



Initiation or completion of a Phase 3 clinical trial. Generally, Phase 3 clinical trials take two to four years to complete.

Regulatory milestones in our partnerships may include the following types of events:



Commercialization milestones in our partnerships may include the following types of events:



First commercial sale in a particular market, such as in the United States or Europe.



Substantive uncertainty exists as to the achievement of the milestone event at the inception of the arrangement;



The amount of the milestone payment appears reasonable either in relation to the effort expended or to the enhancement of the value of the delivered items;



There is no future performance required to earn the milestone; and



The consideration is reasonable relative to all deliverables and payment terms in the arrangement.

Option to license

Licensing and royalty revenue

Research, Development and Patent Expenses

Research, development and patent expenses

Based on existing patents, estimated amortization expense related to patents in each of the next five years is as follows:

Years Ending December 31,	Amortization (in millions)
2017	$	1.4
2018	$	1.3
2019	$	1.2
2020	$	1.1
2021	$	1.0

Concentration of Credit Risk

Concentration of credit risk

Cash, Cash Equivalents and Short-Term Investments

Cash, cash equivalents and short-term investments

Inventory Valuation

Inventory valuation

Property, Plant and Equipment

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):

			December 31,
	Estimated Useful Lives (in years)		2016			2015
Computer software, laboratory, manufacturing and other equipment	3 to 10		$	63,287		$	56,822
Building and building systems	25 to 40			48,909			48,163
Land improvements		20		2,853			2,853
Leasehold improvements	5 to 20			41,736			39,061
Furniture and fixtures	5 to 10			5,937			5,842
				162,722			152,741
Less accumulated depreciation				(80,075	)		(72,706	)
				82,647			80,035
Land				10,198			10,198
Total			$	92,845		$	90,233

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

Fair Value of Financial Instruments

Fair value of financial instruments

Long-Lived Assets

Long-lived assets

Use of Estimates

Use of estimates

Stock-Based Compensation Expense

Stock-based compensation expense

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 vest annually over a four-year period.

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

Accumulated Other Comprehensive Income (Loss)

Accumulated other comprehensive income (loss)

	Year Ended December 31,
	2016			2015			2014
Beginning balance accumulated other comprehensive (loss) income	$	(13,565	)	$	39,747		$	21,080
Unrealized (losses) gains on securities, net of tax (1)		(17,219	)		(33,101	)		40,079
Amounts reclassified from accumulated other comprehensive (loss) income (2)		447			(20,211	)		(21,412	)
Currency translation adjustment		(21	)		—			—
Net other comprehensive (loss) income for the period		(16,793	)		(53,312	)		18,667
Ending balance accumulated other comprehensive (loss) income	$	(30,358	)	$	(13,565	)	$	39,747

(1)	Other comprehensive income includes income tax expense of $12.8 million for the year ended December 31, 2014. There was no tax expense for other comprehensive income for the years ended December 31, 2016 or 2015.

(2)

Convertible Debt

Convertible debt

Segment Information

Segment information

Fair Value Measurements

Fair value measurements

	At December 31, 2016		Quoted Prices in Active Markets (Level 1)		Significant Other Observable Inputs (Level 2)
Cash equivalents (1)	$	54,137	$	54,137	$	—
Corporate debt securities (2)		396,221		—		396,221
Debt securities issued by U.S. government agencies (2)		55,179		—		55,179
Debt securities issued by the U.S. Treasury (2)		29,286		29,286		—
Debt securities issued by states of the U.S. and political subdivisions of the states (3)		109,111		—		109,111
Investment in Regulus Therapeutics Inc.		2,414		2,414		—
Total	$	646,348	$	85,837	$	560,511

	At December 31, 2015		Quoted Prices in Active Markets (Level 1)		Significant Other Observable Inputs (Level 2)
Cash equivalents (1)	$	88,902	$	88,902	$	—
Corporate debt securities (2)		438,426		—		438,426
Debt securities issued by U.S. government agencies (2)		89,253		—		89,253
Debt securities issued by the U.S. Treasury (2)		2,601		2,601		—
Debt securities issued by states of the U.S. and political subdivisions of the states (4)		127,656		—		127,656
Investment in Regulus Therapeutics Inc.		24,792		24,792		—
Total	$	771,630	$	116,295	$	655,335

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

(2)	Included in short-term investments on our consolidated balance sheet.

(3) $9.3 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) $7.5 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.

The following is a summary of our investments measured at fair value on a recurring basis using significant unobservable inputs (Level 3) for the year ended December 31, 2015 (in thousands):

	Year Ended December 31,
	2015
Beginning balance of Level 3 investments	$	81,881
Transfers into Level 3 investments		—
Total gains (losses) included in accumulated other comprehensive income (loss)		22,377
Transfers out of Level 3 investments		(104,258	)
Ending balance of Level 3 investments	$	—

Impact of Recently Issued Accounting Standards

Impact of recently issued accounting standards

Organization and Significant Accounting Policies (Tables)

12 Months Ended

Dec. 31, 2016

Organization and Significant Accounting Policies [Abstract]

Amortization Expense for Patents

Based on existing patents, estimated amortization expense related to patents in each of the next five years is as follows:

Years Ending December 31,	Amortization (in millions)
2017	$	1.4
2018	$	1.3
2019	$	1.2
2020	$	1.1
2021	$	1.0

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):

			December 31,
	Estimated Useful Lives (in years)		2016			2015
Computer software, laboratory, manufacturing and other equipment	3 to 10		$	63,287		$	56,822
Building and building systems	25 to 40			48,909			48,163
Land improvements		20		2,853			2,853
Leasehold improvements	5 to 20			41,736			39,061
Furniture and fixtures	5 to 10			5,937			5,842
				162,722			152,741
Less accumulated depreciation				(80,075	)		(72,706	)
				82,647			80,035
Land				10,198			10,198
Total			$	92,845		$	90,233

Changes in Accumulated Other Comprehensive Income (Loss)

	Year Ended December 31,
	2016			2015			2014
Beginning balance accumulated other comprehensive (loss) income	$	(13,565	)	$	39,747		$	21,080
Unrealized (losses) gains on securities, net of tax (1)		(17,219	)		(33,101	)		40,079
Amounts reclassified from accumulated other comprehensive (loss) income (2)		447			(20,211	)		(21,412	)
Currency translation adjustment		(21	)		—			—
Net other comprehensive (loss) income for the period		(16,793	)		(53,312	)		18,667
Ending balance accumulated other comprehensive (loss) income	$	(30,358	)	$	(13,565	)	$	39,747

(1)	Other comprehensive income includes income tax expense of $12.8 million for the year ended December 31, 2014. There was no tax expense for other comprehensive income for the years ended December 31, 2016 or 2015.

(2)

Assets Measured at Fair Value on a Recurring Basis

	At December 31, 2016		Quoted Prices in Active Markets (Level 1)		Significant Other Observable Inputs (Level 2)
Cash equivalents (1)	$	54,137	$	54,137	$	—
Corporate debt securities (2)		396,221		—		396,221
Debt securities issued by U.S. government agencies (2)		55,179		—		55,179
Debt securities issued by the U.S. Treasury (2)		29,286		29,286		—
Debt securities issued by states of the U.S. and political subdivisions of the states (3)		109,111		—		109,111
Investment in Regulus Therapeutics Inc.		2,414		2,414		—
Total	$	646,348	$	85,837	$	560,511

	At December 31, 2015		Quoted Prices in Active Markets (Level 1)		Significant Other Observable Inputs (Level 2)
Cash equivalents (1)	$	88,902	$	88,902	$	—
Corporate debt securities (2)		438,426		—		438,426
Debt securities issued by U.S. government agencies (2)		89,253		—		89,253
Debt securities issued by the U.S. Treasury (2)		2,601		2,601		—
Debt securities issued by states of the U.S. and political subdivisions of the states (4)		127,656		—		127,656
Investment in Regulus Therapeutics Inc.		24,792		24,792		—
Total	$	771,630	$	116,295	$	655,335

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

(2)	Included in short-term investments on our consolidated balance sheet.

(3) $9.3 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) $7.5 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.

Reconciliation of Assets Measured at Fair Value on a Recurring Basis Using Significant Unobservable Inputs (Level 3)

The following is a summary of our investments measured at fair value on a recurring basis using significant unobservable inputs (Level 3) for the year ended December 31, 2015 (in thousands):

	Year Ended December 31,
	2015
Beginning balance of Level 3 investments	$	81,881
Transfers into Level 3 investments		—
Total gains (losses) included in accumulated other comprehensive income (loss)		22,377
Transfers out of Level 3 investments		(104,258	)
Ending balance of Level 3 investments	$	—

Investments (Tables)

12 Months Ended

Dec. 31, 2016

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, 2016:

One year or less		55 %
After one year but within two years		32 %
After two years but within three and a half years		13 %
Total		100 %

Summary of Investments

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

			Gross Unrealized
December 31, 2016	Cost (1)		Gains		Losses			Estimated Fair Value
Available-for-sale securities:
Corporate debt securities	$	195,087	$	25	$	(161	)	$	194,951
Debt securities issued by U.S. government agencies		26,548		—		(10	)		26,538
Debt securities issued by the U.S. Treasury		29,298		2		(14	)		29,286
Debt securities issued by states of the U.S. and political subdivisions of the states (2)		72,775		2		(134	)		72,643
Total securities with a maturity of one year or less		323,708		29		(319	)		323,418
Corporate debt securities		202,408		36		(1,174	)		201,270
Debt securities issued by U.S. government agencies		28,807		1		(167	)		28,641
Debt securities issued by states of the U.S. and political subdivisions of the states		36,816		1		(349	)		36,468
Total securities with a maturity of more than one year		268,031		38		(1,690	)		266,379
Total available-for-sale securities	$	591,739	$	67	$	(2,009	)	$	589,797
Equity securities:
Regulus Therapeutics Inc.	$	2,133	$	281	$	—		$	2,414
Total equity securities	$	2,133	$	281	$	—		$	2,414
Total available-for-sale and equity securities	$	593,872	$	348	$	(2,009	)	$	592,211

			Gross Unrealized
December 31, 2015	Cost (1)		Gains		Losses			Estimated Fair Value
Available-for-sale securities:
Corporate debt securities	$	181,670	$	5	$	(250	)	$	181,425
Debt securities issued by U.S. government agencies		50,559		1		(19	)		50,541
Debt securities issued by the U.S. Treasury		2,604		—		(3	)		2,601
Debt securities issued by states of the U.S. and political subdivisions of the states (2)		79,414		18		(88	)		79,344
Total securities with a maturity of one year or less		314,247		24		(360	)		313,911
Corporate debt securities		258,703		3		(1,705	)		257,001
Debt securities issued by U.S. government agencies		38,956		—		(244	)		38,712
Debt securities issued by states of the U.S. and political subdivisions of the states		48,552		3		(243	)		48,312
Total securities with a maturity of more than one year		346,211		6		(2,192	)		344,025
Total available-for-sale securities	$	660,458	$	30	$	(2,552	)	$	657,936
Equity securities:
Regulus Therapeutics Inc.	$	7,162	$	17,630	$	—		$	24,792
Total equity securities	$	7,162	$	17,630	$	—		$	24,792
Total available-for-sale and equity securities	$	667,620	$	17,660	$	(2,552	)	$	682,728

(1)

Our available-for-sale securities are held at amortized cost.

(2)

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

Temporarily Impaired Investments

Investments we consider to be temporarily impaired at December 31, 2016 are as follows (in thousands):

			Less than 12 months of Temporary Impairment					More than 12 months of Temporary Impairment					Total Temporary Impairment
	Number of Investments		Estimated Fair Value		Unrealized Losses			Estimated Fair Value		Unrealized Losses			Estimated Fair Value		Unrealized Losses
Corporate debt securities		255	$	280,393	$	(1,197	)	$	32,753	$	(138	)	$	313,146	$	(1,335	)
Debt securities issued by U.S. government agencies		29		43,851		(177	)		—		—			43,851		(177	)
Debt securities issued by the U.S. Treasury		2		18,782		(14	)		—		—			18,782		(14	)
Debt securities issued by states of the U.S. and political subdivisions of the states		135		80,896		(398	)		6,934		(85	)		87,830		(483	)
Total temporarily impaired securities		421	$	423,922	$	(1,786	)	$	39,687	$	(223	)	$	463,609	$	(2,009	)

Long-Term Obligations and Commitments (Tables)

12 Months Ended

Dec. 31, 2016

Long-Term Obligations and Commitments [Abstract]

Long-Term Obligations

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

	December 31,
	2016			2015
1 percent convertible senior notes	$	500,511		$	339,847
2¾ percent convertible senior notes		124			49,523
Long-term financing liability for leased facility		72,359			72,217
Fixed rate note with Morgan Stanley		12,500			—
Leases and other obligations		3,611			2,856
Total	$	589,105		$	464,443
Less: current portion		(1,185	)		(515	)
Total Long-Term Obligations	$	587,920		$	463,928

Convertible Notes

	1 Percent Convertible Senior Notes
Outstanding balance	$	685.5
Original issue date ($500 million of principal)	November 2014
Additional issue date ($185.5 million of principal)	December 2016
Maturity date	November 2021
Interest rate	1 percent
Conversion price per share	$	66.81
Total shares of common stock subject to conversion		10.3

	1 Percent Convertible Senior Notes Issued in November 2014	1 Percent Convertible Senior Notes Issued in December 2016
Nonconvertible debt borrowing rate	7.4 percent	6.8 percent
Effective interest rate	7.8 percent	7.2 percent
Amortization period of debt discount	7 years	5 years

	December 31,
	2016		2015

Fair value of outstanding notes	$	700,969	$	555,000
Principal amount of convertible notes outstanding	$	685,450	$	500,000
Unamortized portion of debt discount	$	175,699	$	152,786
Long-term debt	$	500,511	$	339,847
Carrying value of equity component	$	219,011	$	174,770

Maturity Schedules

Annual debt and other obligation maturities, including fixed and determinable interest, at December 31, 2016 are as follows (in thousands):

2017	$	7,271
2018		7,211
2019		19,801
2020		6,915
2021		692,365
Thereafter		840
Subtotal	$	734,403
Less: current portion		(52	)
Less: fixed and determinable interest		(35,959	)
Less: unamortized portion of debt discount		(175,721	)
Plus: Deferred rent		2,130
Total	$	524,801

Future Minimum Payments Under Operating Leases

Annual future minimum payments under operating leases as of December 31, 2016 are as follows (in thousands):

	Operating Leases
2017	$	1,954
2018		1,690
2019		1,474
2020		1,527
2021		1,411
Thereafter		14,714
Total minimum payments	$	22,770

Future Rent Payments for Research and Development Facility Lease Obligation

Annual future rent payments as of December 31, 2016 for our primary research and development facility are as follows (in thousands):

	Future Rent Payments
2017	$	6,550
2018		6,943
2019		6,943
2020		7,359
2021		7,359
Thereafter		83,846
Total minimum payments	$	119,000

- 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

Reference 1: http://www.xbrl.org/2003/role/presentationRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 210
-SubTopic 10
-Section S99
-Paragraph 1
-Subparagraph (SX 210.5-02.22)
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Reference 2: http://www.xbrl.org/2003/role/presentationRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 505
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Reference 3: http://www.xbrl.org/2003/role/presentationRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 942
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-Paragraph 3
-URI http://asc.fasb.org/extlink&oid=6479336&loc=d3e64711-112823

Reference 4: http://www.xbrl.org/2003/role/presentationRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 235
-SubTopic 10
-Section S99
-Paragraph 1
-Subparagraph (SX 210.4-08.(e),(f))
-URI http://asc.fasb.org/extlink&oid=26873400&loc=d3e23780-122690

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-Name Accounting Standards Codification
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-SubTopic 30
-Section 55
-Paragraph 8
-URI http://asc.fasb.org/extlink&oid=64930739&loc=d3e28878-108400

Reference 6: http://www.xbrl.org/2003/role/presentationRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 505
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-Section 50
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Reference 7: http://www.xbrl.org/2003/role/presentationRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 505
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Reference 8: http://www.xbrl.org/2003/role/presentationRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 835
-SubTopic 30
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-Paragraph 1A
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Reference 9: http://www.xbrl.org/2003/role/presentationRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 835
-SubTopic 30
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-URI http://asc.fasb.org/extlink&oid=64930785&loc=d3e28551-108399

Reference 10: http://www.xbrl.org/2003/role/presentationRef
-Publisher FASB
-Name Accounting Standards Codification
-Topic 505
-SubTopic 10
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-Paragraph 7
-URI http://asc.fasb.org/extlink&oid=6928386&loc=d3e21521-112644

+ Details

Stockholders' Equity (Tables)

12 Months Ended

Dec. 31, 2016

Restricted Stock Unit Activity

Stock Option Activity

The following table summarizes the stock option activity for the year ended December 31, 2016 (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, 2015		8,041		$	33.21
Granted		2,428		$	54.79
Exercised		(994	)	$	12.63
Cancelled/forfeited/expired		(297	)	$	53.65
Outstanding at December 31, 2016		9,178		$	40.48		4.46		$	122,738
Exercisable at December 31, 2016		4,898		$	28.73		3.40		$	107,969

The following table summarizes the RSU activity for the year ended December 31, 2016 (in thousands, except per share data):

	Number of Shares			Weighted Average Grant Date Fair Value Per Share
Non-vested at December 31, 2015		751		$	47.47
Granted		346		$	41.79
Vested		(270	)	$	39.22
Cancelled/forfeited		(49	)	$	49.38
Non-vested at December 31, 2016		778		$	47.68

Stock-Based Compensation Expense

	Year Ended December 31,
	2016			2015			2014
Research, development and patents		$	55,099		$	43,638		$	25,843
General and administrative			17,009			15,676			5,540
Total		$	72,108		$	59,314		$	31,383

Weighted-Average Assumptions - ESPP

ESPP:

	December 31,
	2016	2015	2014
Risk-free interest rate	0.4 %	0.1 %	0.1 %
Dividend yield	0.0 %	0.0 %	0.0 %
Volatility	86.4 %	51.7 %	60.1 %
Expected life	6 months	6 months	6 months

Employee Stock Options [Member]

Weighted-Average Assumptions

For the years ended December 31, 2016, 2015 and 2014, we used the following weighted-average assumptions in our Black-Scholes calculations:

Employee Stock Options:

	December 31,
	2016	2015	2014
Risk-free interest rate	1.5 %	1.5 %	1.7 %
Dividend yield	0.0 %	0.0 %	0.0 %
Volatility	58.7 %	53.8 %	50.1 %
Expected life	4.5 years	4.5 years	4.7 years

Board of Director Stock Options [Member]

Weighted-Average Assumptions

Board of Director Stock Options:

	December 31,
	2016	2015	2014
Risk-free interest rate	1.3 %	2.1 %	2.2 %
Dividend yield	0.0 %	0.0 %	0.0 %
Volatility	53.1 %	52.2 %	54.2 %
Expected life	6.5 years	6.9 years	6.9 years

Income Taxes (Tables)

12 Months Ended

Dec. 31, 2016

Income Taxes [Abstract]

Provision for Income Taxes

The provisions for income taxes on income from continuing operations were as follows (in thousands):

	Year Ended December 31,
	2016		2015			2014
Current:
Federal	$	1,067	$	379		$	263
State		1,867		(7	)		(4,295	)
Total current		2,934		372			(4,032	)

Deferred:
Federal		—		—			(8,948	)
State		—		—			(2,427	)
Total deferred		—		—			(11,375	)
Income tax expense (benefit)	$	2,934	$	372		$	(15,407	)

Reconciliation Between Effective and Statutory Tax Rate

The reconciliation between our effective tax rate on loss from continuing operations and the statutory U.S. tax rate is as follows (in thousands):

	Year Ended December 31,
	2016					2015					2014
Pre-tax loss	$	(83,622	)			$	(87,906	)			$	(54,391	)

Statutory rate		(29,268	)	35.0	%		(30,767	)	35.0	%		(19,035	)	35.0	%
State income tax net of federal benefit		(276	)	0.3	%		1		0.0	%		(3,125	)	5.7	%
Net change in valuation allowance		55,927		(66.9	)%		69,499		(79.1	)%		29,547		(54.3	)%
Loss on debt extinguishment		—		0.0	%		—		0.0	%		2,406		(4.4	)%
Tax credits		(26,954	)	32.2	%		(41,284	)	47.0	%		(23,628	)	43.4	%
California franchise tax refund		—		0.0	%		—		0.0	%		(2,795	)	5.1	%
Deferred tax true-up		2,591		(3.1	)%		1,496		(1.7	)%		977		(1.8	)%
Other		914		(1.1	)%		1,427		(1.6	)%		246		(0.5	)%
Effective rate	$	2,934		(3.5	)%	$	372		(0.4	)%	$	(15,407	)	28.2	%

Deferred Tax Assets and Liabilities

Significant components of our deferred tax assets and liabilities as of December 31, 2016 and 2015 are as follows (in thousands):

	Year Ended December 31,
	2016			2015
Deferred Tax Assets:
Net operating loss carryovers	$	194,372		$	218,493
R&D credits		193,845			153,601
Deferred revenue		54,203			45,110
Stock-based compensation		48,209			31,093
Other		26,228			19,655
Total deferred tax assets	$	516,857		$	467,952

Deferred Tax Liabilities:
Convertible debt	$	(62,669	)	$	(55,928	)
Unrealized gain in other comprehensive income		-			(5,288	)
Intangible and capital assets		(2,030	)		(2,643	)
Net deferred tax asset	$	452,158		$	404,093
Valuation allowance		(452,158	)		(404,093	)

Net deferreds	$	—		$	—

Gross Unrecognized Tax Benefits

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

	Year Ended December 31,
	2016			2015		2014
Beginning balance of unrecognized tax benefits	$	51,257		$	27,365	$	23,964
Settlement of prior period tax positions		(4,033	)		—		—
Decrease for prior period tax positions		—			—		(1,653	)
Increase for prior period tax positions		7,928			215		—
Increase for current period tax positions		11,847			23,677		5,054
Ending balance of unrecognized tax benefits	$	66,999		$	51,257	$	27,365

Segment Information and Concentration of Business Risk (Tables)

12 Months Ended

Dec. 31, 2016

Segment Information and Concentration of Business Risk [Abstract]

Segment Information

The following is our segment information for 2016, 2015 and 2014 (in thousands).

2016	Ionis Core		Akcea Therapeutics			Elimination of Intercompany Activity			Total
Revenue:
Research and development	$	338,546	$	—		$	(12,648	)	$	325,898
Licensing and royalty		20,722		—			—			20,722
Total segment revenue	$	359,268	$	—		$	(12,648	)	$	346,620
Income (loss) from operations	$	37,196	$	(83,512	)	$	—		$	(46,316	)

2015	Ionis Core			Akcea Therapeutics			Elimination of Intercompany Activity			Total
Revenue:
Research and development	$	284,135		$	—		$	(2,775	)	$	281,360
Licensing and royalty		2,343			—			—			2,343
Total segment revenue	$	286,478		$	—		$	(2,775	)	$	283,703
Loss from operations	$	(23,014	)	$	(52,748	)	$	—		$	(75,762	)

2014	Ionis Core			Akcea Therapeutics			Total
Revenue:
Research and development	$	202,514		$	—		$	202,514
Licensing and royalty		11,647			—			11,647
Total segment revenue	$	214,161		$	—		$	214,161
Loss from operations	$	(26,033	)	$	(21,697	)	$	(47,730	)

The following table shows our total assets by segment at December 31, 2016 and 2015 (in thousands), respectively.

Total Assets	Ionis Core		Akcea Therapeutics		Elimination of Intercompany Activity			Total
December 31, 2016	$	1,067,770	$	10,684	$	(165,987	)	$	912,467
December 31, 2015	$	994,191	$	66,068	$	(112,359	)	$	947,900

Revenue from Significant Partners

	2016		2015		2014
Partner A		60 %		37 %		58 %
Partner B		19 %		2 %		13 %
Partner C		4 %		12 %		17 %
Partner D		2 %		33 %		0 %
Partner E		2 %		11 %		4 %

Quarterly Financial Data (Unaudited) (Tables)

12 Months Ended

Dec. 31, 2016

Quarterly Financial Data (Unaudited) [Abstract]

Quarterly Financial Data

2016 Quarters	First Quarter			Second Quarter			Third Quarter		Fourth Quarter
Revenue	$	36,874		$	38,470		$	110,927	$	160,349
Operating expenses	$	91,526		$	87,397		$	94,819	$	119,194
Income (loss) from operations	$	(54,652	)	$	(48,927	)	$	16,108	$	41,155
Net income (loss)	$	(62,917	)	$	(56,855	)	$	7,351	$	25,865
Basic net income (loss) per share (1)	$	(0.52	)	$	(0.47	)	$	0.06	$	0.21
Diluted net income (loss) per share (1) (2) (3)	$	(0.52	)	$	(0.47	)	$	0.06	$	0.21

2015 Quarters	First Quarter			Second Quarter		Third Quarter			Fourth Quarter
Revenue	$	62,583		$	120,428	$	49,121		$	51,571
Operating expenses	$	71,913		$	75,782	$	97,259		$	114,511
Income (loss) from operations	$	(9,330	)	$	44,646	$	(48,138	)	$	(62,940	)
Net income (loss)	$	(16,717	)	$	35,648	$	(35,776	)	$	(71,433	)
Basic net income (loss) per share (1)	$	(0.14	)	$	0.30	$	(0.30	)	$	(0.59	)
Diluted net income (loss) per share (1) (4)	$	(0.14	)	$	0.29	$	(0.30	)	$	(0.59	)

(1)	We computed net income (loss) per share independently for each of the quarters presented. Therefore, the sum of the quarterly net income (loss) per share will not necessarily equal the total for the year.

(2)

Three Months Ended December 31, 2016	Income (Numerator)		Shares (Denominator)		Per-Share Amount

Income available to common shareholders	$	25,865		121,340	$	0.21
Effect of diluted securities:
Shares issuable upon exercise of stock options		—		2,189
Shares issuable upon restricted stock award issuance		—		403
Shares issuable related to our ESPP		—		21
Income available to common shareholders, plus assumed conversions	$	25,865		123,953	$	0.21

For the three months ended December 31, 2016, the calculation excludes the 1 percent and 2¾ percent notes because the effect on diluted earnings per share would be anti-dilutive.

(3)

Three Months Ended September 30, 2016	Income (Numerator)		Shares (Denominator)		Per-Share Amount

Income available to common shareholders	$	7,351		120,989	$	0.06
Effect of diluted securities:
Shares issuable upon exercise of stock options		—		2,129
Shares issuable upon restricted stock award issuance		—		202
Shares issuable related to our ESPP		—		58
Income available to common shareholders, plus assumed conversions	$	7,351		123,378	$	0.06

For the three months ended September 30, 2016, the calculation excludes the 1 percent and 2¾ percent notes because the effect on diluted earnings per share would be anti-dilutive.

(4)

Three Months Ended June 30, 2015	Income (Numerator)		Shares (Denominator)		Per-Share Amount

Income available to common shareholders	$	35,648		119,742	$	0.30
Effect of diluted securities:
Shares issuable upon exercise of stock options		—		3,974
Shares issuable upon restricted stock award issuance		—		376
Shares issuable related to our ESPP		—		4
Shares issuable related to our 2¾ percent notes		1,047		3,683
Income available to common shareholders, plus assumed conversions	$	36,695		127,779	$	0.29

For the three months ended June 30, 2015, the calculation excludes the 1 percent notes because the effect on diluted earnings per share was anti-dilutive.

Organization and Significant Accounting Policies, Basic and Diluted Net Loss per Share (Details)	Dec. 31, 2016	Sep. 30, 2016	Dec. 31, 2015	Jun. 30, 2015	Dec. 31, 2014
1 Percent Convertible Senior Notes [Member]
Basic and Diluted Net Loss per Share [Abstract]
Interest rate on convertible senior notes	1.00%	1.00%	1.00%	1.00%	1.00%
2 3/4 Percent Convertible Senior Notes [Member]
Basic and Diluted Net Loss per Share [Abstract]
Interest rate on convertible senior notes	2.75%	2.75%	2.75%	2.75%	2.75%

Organization and Significant Accounting Policies, Revenue Recognition (Details) $ in Thousands	1 Months Ended					3 Months Ended								12 Months Ended
	Jun. 30, 2015 USD ($)	Sep. 30, 2013 USD ($)	Dec. 31, 2012 USD ($) Target	Jun. 30, 2012 USD ($)	Jan. 31, 2012 USD ($)	Dec. 31, 2016 USD ($)	Sep. 30, 2016 USD ($)	Jun. 30, 2016 USD ($)	Mar. 31, 2016 USD ($)	Dec. 31, 2015 USD ($)	Sep. 30, 2015 USD ($)	Jun. 30, 2015 USD ($) AccountingUnit	Mar. 31, 2015 USD ($)	Dec. 31, 2016 USD ($) Drug Category Stage Partner	Dec. 31, 2015 USD ($)	Dec. 31, 2014 USD ($)
Revenue Recognition [Abstract]
Number of categories of milestone events \| Category														3
Number of stages of life-cycle of drugs \| Stage														3
Number of partners that exercised option to license drugs \| Partner														3
Number of drugs licensed under option in collaboration agreements \| Drug														3
Revenue earned						$ 160,349	$ 110,927	$ 38,470	$ 36,874	$ 51,571	$ 49,121	$ 120,428	$ 62,583	$ 346,620	$ 283,703	$ 214,161
AstraZeneca, Biogen and Janssen [Member]
Revenue Recognition [Abstract]
Revenue earned														$ 98,000
Minimum [Member]
Revenue Recognition [Abstract]
Period to complete IND-enabling animal studies														12 months
Period to complete Phase 1 clinical trial														1 year
Period to complete Phase 2 clinical trial														1 year
Period to complete Phase 3 clinical trial														2 years
Period to prepare and submit regulatory filings														6 months
Period to obtain marketing authorization from applicable regulatory agency														1 year
Pre-specified product sales threshold included in commercialization milestones														$ 1,000,000
Maximum [Member]
Revenue Recognition [Abstract]
Period to complete IND-enabling animal studies														18 months
Period to complete Phase 1 clinical trial														2 years
Period to complete Phase 2 clinical trial														3 years
Period to complete Phase 3 clinical trial														4 years
Period to prepare and submit regulatory filings														12 months
Period to obtain marketing authorization from applicable regulatory agency														2 years
Bayer [Member]
Revenue Recognition [Abstract]
Upfront payment received												$ 100,000
Number of units of accounting \| AccountingUnit												3
Upfront payment allocated to exclusive license	$ 91,200											$ 91,200
Upfront payment allocated to ongoing development services	4,300											4,300
Upfront payment allocated to delivery of API	4,500											$ 4,500
Assumed percentage change in estimated selling price												10.00%
Percentage change in earned revenue based on assumed change in estimated selling price												1.00%
Amount by which earned revenue would change based on assumed change in estimated selling price												$ 900
Revenue earned	$ 91,200													$ 5,400	93,400
Collaboration Agreements with Biogen [Member]
Revenue Recognition [Abstract]
Revenue earned														$ 207,900	$ 106,200	$ 123,200
Collaboration Agreements with Biogen [Member] \| Minimum [Member]
Revenue Recognition [Abstract]
Number of drugs that can be licensed under option in collaboration agreements \| Drug														1
SPINRAZA [Member]
Revenue Recognition [Abstract]
Upfront payment recorded as deferred revenue					$ 29,000
DMPK [Member]
Revenue Recognition [Abstract]
Upfront payment recorded as deferred revenue				$ 12,000
Neurology [Member]
Revenue Recognition [Abstract]
Upfront payment recorded as deferred revenue			$ 30,000
Number of targets \| Target			3
Strategic Neurology [Member]
Revenue Recognition [Abstract]
Upfront payment recorded as deferred revenue		$ 100,000
Term of collaboration agreement														6 years

Organization and Significant Accounting Policies, Research, Development and Patent Expenses (Details) - USD ($) $ in Millions	12 Months Ended
	Dec. 31, 2016	Dec. 31, 2015	Dec. 31, 2014
Research, Development and Patent Expenses [Abstract]
Research and development expenses	$ 340.4	$ 319.5	$ 238.9
Patents [Member]
Patents [Abstract]
Estimated useful life	10 years 1 month 6 days
Cost	$ 28.8	27.5
Accumulated amortization	8.4	8.2
Estimated Amortization Expense [Abstract]
2017	1.4
2018	1.3
2019	1.2
2020	1.1
2021	1.0
Patent expenses	3.9	2.8	2.9
Non-cash charges related to write-down	2.3	1.1	1.3
Collaborative Agreements [Member]
Research, Development and Patent Expenses [Abstract]
Research and development expenses	$ 187.1	$ 161.7	$ 85.6

Organization and Significant Accounting Policies, Cash, Cash Equivalents and Short-term Investments (Details)	Dec. 31, 2016 Company
Cash, Cash Equivalents and Short-term Investments [Abstract]
Number of publicly-held companies in which there is an equity ownership interest of less than 20%	2
Number of privately-held companies in which there is an equity ownership interest of less than 20%	3

Organization and Significant Accounting Policies, Inventory Valuation (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2016	Dec. 31, 2015	Dec. 31, 2014
Inventory Valuation [Abstract]
Inventory write-off	$ 0	$ 0	$ 0
Inventories	$ 7,489	$ 6,899

Organization and Significant Accounting Policies, Property, Plant and Equipment (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2016	Dec. 31, 2015
Property, Plant and Equipment [Abstract]
Less accumulated depreciation	$ (80,075)	$ (72,706)
Property, plant and equipment, net	92,845	90,233
Property, Plant and Equipment, Excluding Land [Member]
Property, Plant and Equipment [Abstract]
Property, plant and equipment	162,722	152,741
Property, plant and equipment, net	82,647	80,035
Computer Software, Laboratory, Manufacturing and Other Equipment [Member]
Property, Plant and Equipment [Abstract]
Property, plant and equipment	$ 63,287	56,822
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 and Building Systems [Member]
Property, Plant and Equipment [Abstract]
Property, plant and equipment	$ 48,909	48,163
Building and Building Systems [Member] \| Minimum [Member]
Property, Plant and Equipment [Abstract]
Estimated useful lives	25 years
Building 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	$ 2,853	2,853
Estimated useful lives	20 years
Leasehold Improvements [Member]
Property, Plant and Equipment [Abstract]
Property, plant and equipment	$ 41,736	39,061
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	20 years
Furniture and Fixtures [Member]
Property, Plant and Equipment [Abstract]
Property, plant and equipment	$ 5,937	5,842
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	$ 10,198	$ 10,198

Organization and Significant Accounting Policies, Long-Lived Assets (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2016	Dec. 31, 2015	Dec. 31, 2014
Long-Lived Assets [Abstract]
Charges related to write-down of intangible assets	$ 2,297	$ 1,881	$ 1,305

Organization and Significant Accounting Policies, Stock-based Compensation Expense (Details)	12 Months Ended
	Dec. 31, 2016
RSUs [Member]
Stock-Based Compensation [Abstract]
Vesting period	4 years

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

12 Months Ended

Dec. 31, 2016

Dec. 31, 2015

Dec. 31, 2014

Accumulated Other Comprehensive Income (Loss) [Roll Forward]

Beginning balance

$ 200,790

Net other comprehensive (loss) income for the period

(16,793)

$ (53,312)

$ 18,667

Ending balance

99,565

200,790

Income tax expense included in other comprehensive income

12,800

Gain on investment in Regulus Therapeutics Inc.

20,211

19,902

Accumulated Other Comprehensive (Loss) Income [Member]

Accumulated Other Comprehensive Income (Loss) [Roll Forward]

Beginning balance

(13,565)

39,747

21,080

Ending balance

(30,358)

(13,565)

39,747

Unrealized (Losses) Gains on Securities [Member]

Accumulated Other Comprehensive Income (Loss) [Roll Forward]

Unrealized (losses) gains, net of tax

^[1]

(17,219)

(33,101)

40,079

Amounts reclassified from accumulated other comprehensive (loss) income

^[2]

447

(20,211)

(21,412)

Currency Translation Adjustment [Member]

Accumulated Other Comprehensive Income (Loss) [Roll Forward]

Unrealized (losses) gains, net of tax

$ (21)

$ 0

[1]	Other comprehensive income includes income tax expense of $12.8 million for the year ended December 31, 2014. There was no tax expense for other comprehensive income for the years ended December 31, 2016 or 2015.
[2]	Amounts for 2015 are included in the separate line called "Gain on investment in Regulus Therapeutics Inc." on our Consolidated Statement of Operations. For 2014, $19.9 million is included in a separate line called "Gain on investment in Regulus Therapeutics Inc.", with the remaining amount included in a separate line called "Gain on investments, net" on our Consolidated Statement of Operations.

Organization and Significant Accounting Policies, Segment Information (Details)	12 Months Ended
	Dec. 31, 2016 Segment
Segment Information [Abstract]
Number of operating segments	2

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

Dec. 31, 2016

Dec. 31, 2015

Organization and Significant Accounting Policies [Abstract]

Transfers from Level 1 to Level 2

$ 0

Transfers from Level 2 to Level 1

592,211

682,728

2,414

24,792

Recurring Basis [Member]

Cash equivalents

^[1]

54,137

88,902

2,414

24,792

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

646,348

771,630

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

^[2]

396,221

438,426

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

^[2]

55,179

89,253

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

^[2]

29,286

2,601

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

109,111

^[3]

127,656

^[4]

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

9,300

7,500

Cash equivalents

54,137

88,902

2,414

24,792

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

85,837

116,295

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

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

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]

29,286

2,601

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

Cash equivalents

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

560,511

655,335

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

396,221

438,426

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

55,179

89,253

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]

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

109,111

127,656

$ 0

[1]	Included in cash and cash equivalents on our consolidated balance sheet.
[2]	Included in short-term investments on our consolidated balance sheet.
[3]	$9.3 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]	$7.5 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.

Organization and Significant Accounting Policies, Fair Value Measurements Using Significant Unobservable Inputs (Level 3) (Details) - Equity Securities [Member] $ in Thousands	12 Months Ended
	Dec. 31, 2015 USD ($)
Unobservable Inputs (Level 3) [Roll Forward]
Beginning balance of Level 3 investments	$ 81,881
Transfers into Level 3 investments	0
Total gains (losses) included in accumulated other comprehensive income (loss)	22,377
Transfers out of Level 3 investments	(104,258)
Ending balance of Level 3 investments	$ 0

Investments, Contract Maturity of Available-for-Sale Securities (Details) $ in Thousands	12 Months Ended
	Dec. 31, 2016 USD ($) Company	Dec. 31, 2015 USD ($)	Dec. 31, 2014 USD ($)
Contract Maturity of Available-for-Sale Securities [Abstract]
One year or less	55.00%
After one year but within two years	32.00%
After two years but within three and a half years	13.00%
Total	100.00%
Percentage of available-for-sale securities with a maturity of less than two years	87.00%
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% \| Company	3
Number of publicly-held companies in which there is an equity ownership interest of less than 20% \| Company	2
Gain on investments, net		$ 20,300	$ 21,200
Gain on investment in Regulus Therapeutics Inc.	$ 0	20,211	$ 19,902
Investment in Regulus Therapeutics Inc.	$ 2,414	$ 24,792

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

Dec. 31, 2016

Dec. 31, 2015

$ 593,872

$ 667,620

348

17,660

(2,009)

(2,552)

Securities with Maturity of One Year or Less [Member]

592,211

682,728

^[1]

323,708

314,247

(319)

(360)

Securities with Maturity of More than One Year [Member]

323,418

313,911

^[1]

268,031

346,211

(1,690)

(2,192)

Available-for-sale Securities [Member]

266,379

344,025

^[1]

591,739

660,458

(2,009)

(2,552)

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

589,797

657,936

^[1]

195,087

181,670

(161)

(250)

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

194,951

181,425

^[1]

202,408

258,703

(1,174)

(1,705)

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

201,270

257,001

^[1]

26,548

50,559

(10)

(19)

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

26,538

50,541

^[1]

28,807

38,956

(167)

(244)

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

28,641

38,712

^[1]

29,298

2,604

(14)

(3)

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]

29,286

2,601

^[1],[2]

72,775

79,414

(134)

(88)

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]

72,643

79,344

^[1]

36,816

48,552

(349)

(243)

Equity Securities [Member]

36,468

48,312

2,133

7,162

281

17,630

Equity Securities [Member] | Regulus Therapeutics Inc. [Member]

2,414

24,792

2,133

7,162

281

17,630

Collaborative Arrangement and Licensing Agreement [Abstract]

$ 2,414

$ 24,792

[1]	Our available-for-sale securities are held at amortized cost.
[2]	Includes investments classified as cash equivalents on our consolidated balance sheet.

Investments, Investments Temporarily Impaired (Details) $ in Thousands	Dec. 31, 2016 USD ($) Investment
Temporarily Impaired Investments [Abstract]
Number of investments \| Investment	421
Estimated fair value, less than 12 months of temporary impairment	$ 423,922
Unrealized losses, less than 12 months of temporary impairment	(1,786)
Estimated fair value, more than 12 months of temporary impairment	39,687
Unrealized losses, more than 12 months of temporary impairment	(223)
Estimated fair value, total temporary impairment	463,609
Unrealized losses, total temporary impairment	$ (2,009)
Corporate Debt Securities [Member]
Temporarily Impaired Investments [Abstract]
Number of investments \| Investment	255
Estimated fair value, less than 12 months of temporary impairment	$ 280,393
Unrealized losses, less than 12 months of temporary impairment	(1,197)
Estimated fair value, more than 12 months of temporary impairment	32,753
Unrealized losses, more than 12 months of temporary impairment	(138)
Estimated fair value, total temporary impairment	313,146
Unrealized losses, total temporary impairment	$ (1,335)
Debt Securities issued by U.S. Government Agencies [Member]
Temporarily Impaired Investments [Abstract]
Number of investments \| Investment	29
Estimated fair value, less than 12 months of temporary impairment	$ 43,851
Unrealized losses, less than 12 months of temporary impairment	(177)
Estimated fair value, more than 12 months of temporary impairment	0
Unrealized losses, more than 12 months of temporary impairment	0
Estimated fair value, total temporary impairment	43,851
Unrealized losses, total temporary impairment	$ (177)
Debt Securities issued by the U.S. Treasury [Member]
Temporarily Impaired Investments [Abstract]
Number of investments \| Investment	2
Estimated fair value, less than 12 months of temporary impairment	$ 18,782
Unrealized losses, less than 12 months of temporary impairment	(14)
Estimated fair value, more than 12 months of temporary impairment	0
Unrealized losses, more than 12 months of temporary impairment	0
Estimated fair value, total temporary impairment	18,782
Unrealized losses, total temporary impairment	$ (14)
Debt Securities issued by States of the U.S. and Political Subdivisions of the States [Member]
Temporarily Impaired Investments [Abstract]
Number of investments \| Investment	135
Estimated fair value, less than 12 months of temporary impairment	$ 80,896
Unrealized losses, less than 12 months of temporary impairment	(398)
Estimated fair value, more than 12 months of temporary impairment	6,934
Unrealized losses, more than 12 months of temporary impairment	(85)
Estimated fair value, total temporary impairment	87,830
Unrealized losses, total temporary impairment	$ (483)

Long-Term Obligations and Commitments, Long-Term Obligations (Details) - USD ($) $ in Thousands	Dec. 31, 2016	Dec. 31, 2015
Long-Term Obligations [Abstract]
Total long-term obligations, including current portion	$ 589,105	$ 464,443
Less: current portion	(1,185)	(515)
Total Long-Term Obligations	587,920	463,928
1 Percent Convertible Senior Notes [Member]
Long-Term Obligations [Abstract]
Total long-term obligations, including current portion	500,511	339,847
2 3/4 Percent Convertible Senior Notes [Member]
Long-Term Obligations [Abstract]
Total long-term obligations, including current portion	124	49,523
Long-term Financing Liability for Leased Facility [Member]
Long-Term Obligations [Abstract]
Total long-term obligations, including current portion	72,359	72,217
Fixed Rate Note with Morgan Stanley [Member]
Long-Term Obligations [Abstract]
Total long-term obligations, including current portion	12,500	0
Leases and Other Obligations [Member]
Long-Term Obligations [Abstract]
Total long-term obligations, including current portion	$ 3,611	$ 2,856

Long-Term Obligations and Commitments, Convertible Notes (Details) $ / shares in Units, $ in Thousands	1 Months Ended		12 Months Ended
	Dec. 31, 2016 USD ($) $ / shares	Nov. 30, 2014 USD ($)	Dec. 31, 2016 USD ($) shares $ / shares	Dec. 31, 2015 USD ($)	Dec. 31, 2014 USD ($)	Sep. 30, 2016	Jun. 30, 2015
Convertible Notes [Abstract]
Proceeds from issuance of 1 percent convertible senior notes, net of issuance costs			$ 0	$ 0	$ 487,035
Loss on early retirement of debt			(3,983)	0	(8,292)
Amortization of debt discount and debt issuance costs			$ 25,100	$ 23,200	$ 9,600
1 Percent Convertible Senior Notes [Member]
Convertible Notes [Abstract]
Maturity date			Nov. 30, 2021
Interest rate	1.00%		1.00%	1.00%	1.00%	1.00%	1.00%
Conversion price per share (in dollars per share) \| $ / shares	$ 66.81		$ 66.81
Total shares of common stock subject to conversion (in shares) \| shares			10,300,000
Percentage of principal amount used a purchase price upon occurrence of fundamental change			100.00%
Principal amount of convertible notes outstanding	$ 685,450		$ 685,450	$ 500,000
Unamortized portion of liability component	175,699		175,699	152,786
Long-term debt	500,511		500,511	339,847
Carrying value of equity component	219,011		219,011	174,770
1 Percent Convertible Senior Notes [Member] \| Level 2 [Member]
Convertible Notes [Abstract]
Fair value of outstanding notes	$ 700,969		$ 700,969	$ 555,000
1 Percent Convertible Senior Notes Issued in November 2014 [Member]
Convertible Notes [Abstract]
Face amount of offering		$ 500,000
Proceeds from issuance of 1 percent convertible senior notes, net of issuance costs		487,000
Issue date			Nov. 30, 2014
Nonconvertible debt borrowing rate			7.40%
Effective interest rate	7.80%		7.80%
Amortization period of debt discount			7 years
1 Percent Convertible Senior Notes Issued in December 2016 [Member]
Convertible Notes [Abstract]
Face amount of offering	$ 185,500		$ 185,500
Issue date			Dec. 31, 2016
Nonconvertible debt borrowing rate			6.80%
Effective interest rate	7.20%		7.20%
Amortization period of debt discount			5 years
2 3/4 Percent Convertible Senior Notes [Member]
Convertible Notes [Abstract]
Principal amount repurchased	$ 61,100	140,000	$ 61,100		$ 140,000
Repurchase of convertible senior notes		441,900
Loss on early retirement of debt	$ 3,983	8,292
Interest rate	2.75%		2.75%	2.75%	2.75%	2.75%	2.75%
Principal amount of convertible notes outstanding		$ 61,200
Long-term debt	$ 124		$ 124	$ 49,523

Long-Term Obligations and Commitments, Financing Arrangements (Details) $ in Millions	12 Months Ended
	Dec. 31, 2016 USD ($)
Fixed Rate Note with Morgan Stanley [Member]
Financing Arrangements [Abstract]
Outstanding borrowings	$ 12.5
Interest rate	2.31%
Maturity date	Sep. 30, 2019
Morgan Stanley [Member] \| Revolving Line of Credit [Member]
Financing Arrangements [Abstract]
Term of agreement	5 years
Maximum borrowing capacity	$ 30.0
Commitment fee percentage on unused capacity	0.25%
Morgan Stanley [Member] \| Revolving Line of Credit [Member] \| LIBOR [Member]
Financing Arrangements [Abstract]
Term of variable rate	1 month
Basis spread on variable rate	1.25%
Term of fixed rate elected	one, two, three, four, six, or twelve months

Long-Term Obligations and Commitments, Maturity Schedules (Details) - USD ($) $ in Thousands	Dec. 31, 2016	Dec. 31, 2015
Annual Debt and Other Obligation Maturities [Abstract]
Less: current portion	$ (1,185)	$ (515)
Total	587,920	$ 463,928
Long-Term Obligations, Excluding Financing Liability for Leased Facility [Member]
Annual Debt and Other Obligation Maturities [Abstract]
2017	7,271
2018	7,211
2019	19,801
2020	6,915
2021	692,365
Thereafter	840
Total minimum payments	734,403
Less: current portion	(52)
Less: fixed and determinable interest	(35,959)
Less: unamortized portion of debt discount	(175,721)
Plus: Deferred rent	2,130
Total	$ 524,801

Long-Term Obligations and Commitments, Operating Leases (Details) - Office and Laboratory Space [Member] $ in Thousands	12 Months Ended
	Dec. 31, 2016 USD ($) Building Option	Dec. 31, 2015 USD ($)	Dec. 31, 2014 USD ($)
Operating Leases [Abstract]
Number of buildings in Carlsbad, California \| Building	3
Annual Future Minimum Payments Under Operating Leases [Abstract]
2017	$ 1,954
2018	1,690
2019	1,474
2020	1,527
2021	1,411
Thereafter	14,714
Total minimum payments	22,770
Rent expense	2,000	$ 2,000	$ 1,800
Deferred rent	$ 2,100	$ 2,000
Manufacturing Facility [Member]
Operating Leases [Abstract]
Number of options to extend lease \| Option	4
Term of lease extension	5 years
Building [Member]
Operating Leases [Abstract]
Number of options to extend lease \| Option	2
Term of lease extension	5 years
Building [Member] \| Akcea Therapeutics [Member]
Operating Leases [Abstract]
Term of lease	3 years

Long-Term Obligations and Commitments, Research and Development Facility Lease Obligation (Details) $ in Thousands	1 Months Ended	12 Months Ended
	Mar. 31, 2010 USD ($)	Dec. 31, 2016 USD ($) Option	Dec. 31, 2015 USD ($)
Research and Development Facility Lease Obligation [Abstract]
Net book value		$ 92,845	$ 90,233
Accumulated depreciation		$ 80,075	72,706
Primary Research and Development Facility [Member]
Research and Development Facility Lease Obligation [Abstract]
Number of options to extend lease \| Option		4
Term of lease extension		5 years
Net book value		$ 60,000	62,200
Accumulated depreciation		12,100	$ 9,900
Purchase price of land	$ 10,100
Annual Future Rent Payments [Abstract]
2017		6,550
2018		6,943
2019		6,943
2020		7,359
2021		7,359
Thereafter		83,846
Total minimum payments		$ 119,000

Stockholders' Equity, Preferred and Common Stock (Details) - USD ($) $ in Millions	12 Months Ended
	Dec. 31, 2016	Dec. 31, 2015	Dec. 31, 2014
Common Stock [Abstract]
Common stock, shares authorized to issue (in shares)	300,000,000	300,000,000
Common stock, shares issued (in shares)	121,636,273	120,351,480
Common stock, shares outstanding (in shares)	121,636,273	120,351,480
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)	121,636,273	120,351,480
Common stock, shares outstanding (in shares)	121,636,273	120,351,480
Common shares reserved for future issuance (in shares)	14,703,837
Number of shares issued for stock option exercises, vesting of restricted stock units, and ESPP purchases (in shares)	1,285,000	1,908,000	1,972,000
Net proceeds from stock option exercises, vesting of restricted stock units, and ESPP purchases	$ 13.7	$ 24.9	$ 23.1

Stockholders' Equity, Stock Plans (Details)	1 Months Ended	12 Months Ended
Stockholders' Equity, Stock Plans (Details)	Jun. 30, 2009 shares	Dec. 31, 2016 Installment $ / shares shares	Dec. 31, 2015 shares	Jun. 30, 2015 shares	May 31, 2015 shares
Stock Options [Member]
Stock Plans [Abstract]
Number of options outstanding (in shares)		9,178,000	8,041,000
Number of options exercisable (in shares)		4,898,000
Restricted Stock Units [Member]
Stock Plans [Abstract]
Vesting period		4 years
1989 Stock Option Plan [Member]
Stock Plans [Abstract]
Number of shares authorized (in shares)		20,000,000
Vesting period		4 years
Award term		7 years
Number of options outstanding (in shares)		2,732,089
Number of options exercisable (in shares)		2,542,372
Number of shares available for grant (in shares)		25,552
1989 Stock Option Plan [Member] \| One Year from Date of Grant [Member]
Stock Plans [Abstract]
Vesting percentage		25.00%
2011 Equity Incentive Plan [Member]
Stock Plans [Abstract]
Number of shares authorized (in shares)				11,000,000	5,500,000
Number of options outstanding (in shares)		5,830,078
Number of options exercisable (in shares)		1,827,264
Number of shares available for grant (in shares)		3,661,538
Number of awards outstanding (in shares)		737,113
2011 Equity Incentive Plan [Member] \| Stock Options [Member] \| Minimum [Member]
Stock Plans [Abstract]
Vesting period		2 years
2011 Equity Incentive Plan [Member] \| Restricted Stock Units [Member]
Stock Plans [Abstract]
Vesting period		4 years
2011 Equity Incentive Plan [Member] \| Restricted Stock Units [Member] \| Minimum [Member]
Stock Plans [Abstract]
Vesting period		3 years
2002 Non-Employee Directors' Stock Option Plan [Member]
Stock Plans [Abstract]
Number of shares authorized (in shares)				2,000,000	1,200,000
Award term		10 years
Number of options outstanding (in shares)		615,812
Number of options exercisable (in shares)		368,877
Number of shares available for grant (in shares)		747,869
Number of awards outstanding (in shares)		41,151
2002 Non-Employee Directors' Stock Option Plan [Member] \| One Year from Date of Grant [Member]
Stock Plans [Abstract]
Number of equal annual installments over which options become exercisable \| Installment		4
Employee Stock Purchase Plan [Member]
Stock Plans [Abstract]
Number of shares authorized (in shares)		3,374,596
Number of shares available for grant (in shares)		585,713
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%
Purchase period		6 months
Holding period for purchased stock		6 months
Shares purchased and issued under ESPP (in shares)		46,051
Purchase price (in dollars per share) \| $ / shares		$ 30.47

Stockholders' Equity, Stock Option Activity (Details) - Stock Options [Member] - USD ($) $ / shares in Units, shares in Thousands, $ in Thousands	12 Months Ended
	Dec. 31, 2016	Dec. 31, 2015	Dec. 31, 2014
Number of Shares [Abstract]
Outstanding at beginning of period (in shares)	8,041
Granted (in shares)	2,428
Exercised (in shares)	(994)
Cancelled/forfeited/expired (in shares)	(297)
Outstanding at end of period (in shares)	9,178	8,041
Exercisable at end of period (in shares)	4,898
Weighted Average Exercise Price Per Share [Abstract]
Outstanding at beginning of period (in dollars per share)	$ 33.21
Granted (in dollars per share)	54.79
Exercised (in dollars per share)	12.63
Cancelled/forfeited/expired (in dollars per share)	53.65
Outstanding at end of period (in dollars per share)	40.48	$ 33.21
Exercisable at end of period (in dollars per share)	$ 28.73
Average Remaining Contractual Term, Aggregate Intrinsic Value and Other [Abstract]
Average remaining contractual term, outstanding at end of period	4 years 5 months 16 days
Average remaining contractual term, exercisable at end of period	3 years 4 months 24 days
Aggregate intrinsic value, outstanding at end of period	$ 122,738
Aggregate intrinsic value, exercisable at end of period	$ 107,969
Weighted average fair value of options granted (in dollars per share)	$ 26.72	$ 27.44	$ 17.54
Intrinsic value of options exercised	$ 28,000	$ 84,700	$ 62,800
Cash received from exercise of stock options	$ 12,600	$ 23,600	$ 22,400
Weighted-average fair value of options exercised (in dollars per share)	$ 40.83
Unrecognized Compensation Expense [Abstract]
Unrecognized compensation expense related to non-vested stock options	$ 48,100
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, 2016	Dec. 31, 2015	Dec. 31, 2014
Number of Shares [Abstract]
Non-vested at beginning of period (in shares)	751
Granted (in shares)	346
Vested (in shares)	(270)
Cancelled/forfeited (in shares)	(49)
Non-vested at end of period (in shares)	778	751
Weighted Average Grant Date Fair Value per Share [Abstract]
Non-vested at beginning of period (in dollars per share)	$ 47.47
Granted (in dollars per share)	41.79	$ 65.69	$ 44.94
Vested (in dollars per share)	39.22
Cancelled/forfeited (in dollars per share)	49.38
Non-vested at end of period (in dollars per share)	$ 47.68	$ 47.47
Unrecognized Compensation Expense [Abstract]
Unrecognized compensation cost related to non-vested RSUs	$ 13.3
Weighted average period for recognition	1 year 2 months 12 days

Stockholders' Equity, Stock-based Compensation Expense (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2016	Dec. 31, 2015	Dec. 31, 2014
Stock-Based Compensation [Abstract]
Stock-based compensation expense	$ 72,108	$ 59,314	$ 31,383
Research, Development and Patents [Member]
Stock-Based Compensation [Abstract]
Stock-based compensation expense	55,099	43,638	25,843
General and Administrative [Member]
Stock-Based Compensation [Abstract]
Stock-based compensation expense	17,009	15,676	$ 5,540
Akcea Therapeutics [Member]
Stock-Based Compensation [Abstract]
Stock-based compensation expense	$ 10,100	$ 6,500

Stockholders' Equity, Stock-based Valuation Information (Details)	12 Months Ended
	Dec. 31, 2016	Dec. 31, 2015	Dec. 31, 2014
Employee Stock Options [Member]
Weighted-Average Assumptions [Abstract]
Risk-free interest rate	1.50%	1.50%	1.70%
Dividend yield	0.00%	0.00%	0.00%
Volatility	58.70%	53.80%	50.10%
Expected life	4 years 6 months	4 years 6 months	4 years 8 months 12 days
Board of Director Stock Options [Member]
Weighted-Average Assumptions [Abstract]
Risk-free interest rate	1.30%	2.10%	2.20%
Dividend yield	0.00%	0.00%	0.00%
Volatility	53.10%	52.20%	54.20%
Expected life	6 years 6 months	6 years 10 months 24 days	6 years 10 months 24 days
Employee Stock Purchase Plan (ESPP) [Member]
Weighted-Average Assumptions [Abstract]
Risk-free interest rate	0.40%	0.10%	0.10%
Dividend yield	0.00%	0.00%	0.00%
Volatility	86.40%	51.70%	60.10%
Expected life	6 months	6 months	6 months

Income Taxes, Provision for Income Taxes (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2016	Dec. 31, 2015	Dec. 31, 2014
Current [Abstract]
Federal	$ 1,067	$ 379	$ 263
State	1,867	(7)	(4,295)
Total current	2,934	372	(4,032)
Deferred [Abstract]
Federal	0	0	(8,948)
State	0	0	(2,427)
Total deferred	0	0	(11,375)
Income tax expense (benefit)	$ 2,934	$ 372	(15,407)
Tax benefit related to unrealized gains on investments in available-for-sale securities recorded in continuing operations			(12,800)
Tax expense related to unrealized gains on investments in available-for-sale securities recorded in other comprehensive income			$ 12,800

Income Taxes, Reconciliation of Effective Tax Rate (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2016	Dec. 31, 2015	Dec. 31, 2014
Reconciliation Between Effective and Statutory Tax Rate [Abstract]
Pre-tax loss	$ (83,622)	$ (87,906)	$ (54,391)
Statutory rate	(29,268)	(30,767)	(19,035)
State income tax net of federal benefit	(276)	1	(3,125)
Net change in valuation allowance	55,927	69,499	29,547
Loss on debt extinguishment	0	0	2,406
Tax credits	(26,954)	(41,284)	(23,628)
California franchise tax refund	0	0	(2,795)
Deferred tax true-up	2,591	1,496	977
Other	914	1,427	246
Income tax expense (benefit)	$ 2,934	$ 372	$ (15,407)
Reconciliation Between Effective and Statutory Tax Rate Percentage [Abstract]
Statutory rate	35.00%	35.00%	35.00%
State income tax net of federal benefit	0.30%	0.00%	5.70%
Net change in valuation allowance	(66.90%)	(79.10%)	(54.30%)
Loss on debt extinguishment	0.00%	0.00%	(4.40%)
Tax credits	32.20%	47.00%	43.40%
California franchise tax refund	0.00%	0.00%	5.10%
Deferred tax true-up	(3.10%)	(1.70%)	(1.80%)
Other	(1.10%)	(1.60%)	(0.50%)
Effective rate	(3.50%)	(0.40%)	28.20%

Income Taxes, Deferred Tax Assets and Liabilities (Details) - USD ($) $ in Thousands	12 Months Ended
	Dec. 31, 2016	Dec. 31, 2015	Dec. 31, 2014
Deferred Tax Assets [Abstract]
Net operating loss carryovers	$ 194,372	$ 218,493
R&D credits	193,845	153,601
Deferred revenue	54,203	45,110
Stock-based compensation	48,209	31,093
Other	26,228	19,655
Total deferred tax assets	516,857	467,952
Deferred Tax Liabilities [Abstract]
Convertible debt	(62,669)	(55,928)
Unrealized gain in other comprehensive income	0	(5,288)
Intangible and capital assets	(2,030)	(2,643)
Net deferred tax asset	452,158	404,093
Valuation allowance	(452,158)	(404,093)
Net deferreds	0	0
Excess tax benefits from shared-based compensation awards	1,861	$ 396	$ 1,463
Unrealized excess tax benefits associated with share-based compensation	$ 82,500

Income Taxes, Tax Credit Carryforward (Details) $ in Millions	Dec. 31, 2016 USD ($)
Research and Development [Member] \| Federal [Member]
Tax Credit Carryforward [Abstract]
Tax credit carryforwards	$ 189.6
Research and Development [Member] \| California [Member]
Tax Credit Carryforward [Abstract]
Tax credit carryforwards	48.0
Federal [Member]
Operating Loss Carryforwards [Abstract]
Net operating loss carryforwards	679.8
California [Member]
Operating Loss Carryforwards [Abstract]
Net operating loss carryforwards	$ 973.1

Income Taxes, Gross Unrecognized Tax Benefits (Details) - USD ($)	12 Months Ended
	Dec. 31, 2016	Dec. 31, 2015	Dec. 31, 2014
Gross Unrecognized Tax Benefits [Roll Forward]
Beginning balance of unrecognized tax benefits	$ 51,257,000	$ 27,365,000	$ 23,964,000
Settlement of prior period tax positions	(4,033,000)	0	0
Decrease for prior period tax positions	0	0	(1,653,000)
Increase for prior period tax positions	7,928,000	215,000	0
Increase for current period tax positions	11,847,000	23,677,000	5,054,000
Ending balance of unrecognized tax benefits	66,999,000	$ 51,257,000	$ 27,365,000
Unrecognized tax benefits that would reduce effective tax rate	46,400,000
Interest and penalties on unrecognized tax benefits	$ 0

Collaborative Arrangements and Licensing Agreements, Strategic Partnerships - AstraZeneca (Details) $ in Thousands	1 Months Ended			3 Months Ended								12 Months Ended
	Dec. 31, 2016 USD ($)	Jul. 31, 2015 USD ($)	Dec. 31, 2012 USD ($)	Dec. 31, 2016 USD ($)	Sep. 30, 2016 USD ($)	Jun. 30, 2016 USD ($)	Mar. 31, 2016 USD ($)	Dec. 31, 2015 USD ($)	Sep. 30, 2015 USD ($)	Jun. 30, 2015 USD ($)	Mar. 31, 2015 USD ($)	Dec. 31, 2016 USD ($) AccountingUnit Drug Program	Dec. 31, 2015 USD ($)	Dec. 31, 2014 USD ($)
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue earned				$ 160,349	$ 110,927	$ 38,470	$ 36,874	$ 51,571	$ 49,121	$ 120,428	$ 62,583	$ 346,620	$ 283,703	$ 214,161
Collaboration Agreements with AstraZeneca [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Deferred revenue	$ 51,500			51,500				$ 63,300				51,500	63,300
Revenue earned												$ 64,900	$ 6,400	$ 27,700
Collaboration Agreements with AstraZeneca [Member] \| Revenue [Member] \| Strategic Partner [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Concentration percentage												19.00%	2.00%	13.00%
Cardiometabolic and Renal Diseases Partnership [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Upfront payment received		$ 65,000
Number of units of accounting \| AccountingUnit												1
Minimum potential amount of payments receivable for license fees and substantive milestones	4,000,000			4,000,000								$ 4,000,000
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
Milestone payment earned	25,000
Next prospective milestone	10,000			10,000								10,000
Oncology Partnership [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Minimum potential amount of payments receivable for license fees and substantive milestones	750,000			750,000								750,000
Maximum amount of payments receivable for development milestones	226,000			226,000								226,000
Maximum amount of payments receivable for regulatory milestones	485,000			485,000								485,000
Milestone payment earned	15,000		$ 11,500
Next prospective milestone	17,500			17,500								$ 17,500
Number of drugs that can be licensed under option in collaboration agreement \| Drug												3
Number of anti-cancer research programs covered by collaboration agreement \| Program												3
Cumulative upfront fees received	31,000			31,000								$ 31,000
Upfront fee amortized into revenue	11,900			11,900								11,900
Deferred revenue	7,600			7,600								7,600
Milestone payment to be earned	5,000			5,000								5,000
Cumulative payments received	76,000			$ 76,000								$ 76,000
License fee earned	$ 13,000

Collaborative Arrangements and Licensing Agreements, Strategic Partnerships - Biogen (SPINRAZA) (Details) $ in Thousands	1 Months Ended			3 Months Ended								12 Months Ended
	Feb. 28, 2017 USD ($)	Dec. 31, 2016 USD ($)	Jan. 31, 2012 USD ($)	Dec. 31, 2016 USD ($)	Sep. 30, 2016 USD ($)	Jun. 30, 2016 USD ($)	Mar. 31, 2016 USD ($)	Dec. 31, 2015 USD ($)	Sep. 30, 2015 USD ($)	Jun. 30, 2015 USD ($)	Mar. 31, 2015 USD ($)	Dec. 31, 2016 USD ($) Drug Agreement	Dec. 31, 2015 USD ($)	Dec. 31, 2014 USD ($)
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue earned				$ 160,349	$ 110,927	$ 38,470	$ 36,874	$ 51,571	$ 49,121	$ 120,428	$ 62,583	$ 346,620	$ 283,703	$ 214,161
Biogen [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue earned					$ 75,000
Collaboration Agreements with Biogen [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of strategic collaboration agreements \| Agreement												4
Number of additional drugs in clinical development to treat neurological diseases \| Drug												4
Number of drugs in clinical development to treat undisclosed neurodegenerative diseases \| Drug												3
Cumulative payments received		$ 500,000		500,000								$ 500,000
Revenue earned												207,900	$ 106,200	$ 123,200
SPINRAZA [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received		259,000		259,000								259,000
Milestone payment earned		60,000
Upfront payment recorded as deferred revenue			$ 29,000
Maximum amount of payments receivable for license fee and substantive milestones		346,000		346,000								346,000
Maximum amount of payments receivable for development milestones		121,000		121,000								121,000
Maximum amount of payments receivable for regulatory milestones		150,000		150,000								150,000
Next prospective milestone		$ 50,000		$ 50,000								$ 50,000
SPINRAZA [Member] \| Subsequent Event [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Milestone payment received	$ 60,000

Collaborative Arrangements and Licensing Agreements, Strategic Partnerships - Biogen (IONIS-DMPK-2.5) (Details) $ in Millions	Dec. 31, 2016 USD ($)
IONIS-DMPK-2.5 [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received	$ 39

Collaborative Arrangements and Licensing Agreements, Strategic Partnerships - Biogen (Neurology) (Details) - Neurology [Member] $ in Millions	1 Months Ended	12 Months Ended
	Dec. 31, 2012 USD ($) Target	Dec. 31, 2016 USD ($) Program
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of targets \| Target	3
Number of programs under which drugs are to be developed and commercialized \| Program		3
Upfront payment recorded as deferred revenue	$ 30
Maximum amount of payments receivable per program for license fees and substantive milestone payments		$ 259
Maximum amount of payments receivable per program for development milestones		59
Maximum amount of payments receivable per program for regulatory milestones		130
Cumulative payments received		43
Next prospective milestone		$ 10

Collaborative Arrangements and Licensing Agreements, Strategic Partnerships - Biogen (Strategic Neurology) (Details) $ in Thousands	1 Months Ended	3 Months Ended								12 Months Ended
	Sep. 30, 2013 USD ($)	Dec. 31, 2016 USD ($)	Sep. 30, 2016 USD ($)	Jun. 30, 2016 USD ($)	Mar. 31, 2016 USD ($)	Dec. 31, 2015 USD ($)	Sep. 30, 2015 USD ($)	Jun. 30, 2015 USD ($)	Mar. 31, 2015 USD ($)	Dec. 31, 2016 USD ($) Drug	Dec. 31, 2015 USD ($)	Dec. 31, 2014 USD ($)
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue earned		$ 160,349	$ 110,927	$ 38,470	$ 36,874	$ 51,571	$ 49,121	$ 120,428	$ 62,583	$ 346,620	$ 283,703	$ 214,161
Collaboration Agreements with Biogen [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received		500,000								500,000
Revenue earned										207,900	106,200	$ 123,200
Deferred revenue		67,500				$ 91,600				$ 67,500	$ 91,600
Collaboration Agreements with Biogen [Member] \| Revenue [Member] \| Strategic Partner [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Concentration percentage										60.00%	37.00%	58.00%
Strategic Neurology [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of drugs currently being advanced \| Drug										3
Upfront payment recorded as deferred revenue	$ 100,000
Term of collaboration agreement										6 years
Cumulative payments received		142,000								$ 142,000
Next prospective milestone		10,000								10,000
Strategic Neurology [Member] \| Antisense Molecule [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Maximum amount of payments receivable for license fee and substantive milestones		260,000								260,000
Maximum amount of payments receivable for development milestones		60,000								60,000
Maximum amount of payments receivable for regulatory milestones		130,000								130,000
Strategic Neurology [Member] \| Other Modalities [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Maximum amount of payments receivable for license fee and substantive milestones		90,000								90,000
Maximum amount of payments receivable for development milestones		35,000								35,000
Maximum amount of payments receivable for regulatory milestones		$ 55,000								$ 55,000

Collaborative Arrangements and Licensing Agreements, Research, Development and Commercialization Partners - Bayer (Details) - USD ($) $ in Thousands	1 Months Ended	3 Months Ended								12 Months Ended
	Jun. 30, 2015	Dec. 31, 2016	Sep. 30, 2016	Jun. 30, 2016	Mar. 31, 2016	Dec. 31, 2015	Sep. 30, 2015	Jun. 30, 2015	Mar. 31, 2015	Dec. 31, 2016	Dec. 31, 2015	Dec. 31, 2014	Feb. 28, 2017
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue earned		$ 160,349	$ 110,927	$ 38,470	$ 36,874	$ 51,571	$ 49,121	$ 120,428	$ 62,583	$ 346,620	$ 283,703	$ 214,161
Bayer [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Upfront payment received								$ 100,000
Revenue earned	$ 91,200									5,400	93,400
Maximum amount of payments receivable for license fee and substantive milestones		385,000								385,000
Maximum amount of payments receivable for development milestones		125,000								125,000
Maximum amount of payments receivable for regulatory milestones		110,000								110,000
Next prospective milestone		10,000								10,000
Deferred revenue		$ 1,400				$ 6,700				$ 1,400	$ 6,700
Bayer [Member] \| Revenue [Member] \| Strategic Partner [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Concentration percentage										2.00%	33.00%
Bayer [Member] \| Subsequent Event [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Payment receivable due for advancement of programs													$ 75,000
Bayer [Member] \| Minimum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Royalty percentage received on gross margins of both drugs combined										20.00%

Collaborative Arrangements and Licensing Agreements, Research, Development and Commercialization Partners - GSK (Details) $ in Thousands	1 Months Ended	3 Months Ended								12 Months Ended
	Mar. 31, 2010 USD ($)	Dec. 31, 2016 USD ($)	Sep. 30, 2016 USD ($)	Jun. 30, 2016 USD ($)	Mar. 31, 2016 USD ($)	Dec. 31, 2015 USD ($)	Sep. 30, 2015 USD ($)	Jun. 30, 2015 USD ($)	Mar. 31, 2015 USD ($)	Dec. 31, 2016 USD ($) Drug	Dec. 31, 2015 USD ($)	Dec. 31, 2014 USD ($)
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue earned		$ 160,349	$ 110,927	$ 38,470	$ 36,874	$ 51,571	$ 49,121	$ 120,428	$ 62,583	$ 346,620	$ 283,703	$ 214,161
GSK [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of drugs currently in development \| Drug										4
Cumulative payments received		155,000								$ 155,000
Number of drugs currently in clinical development with IONIS-TTR \| Drug										3
Number of antisense drugs in development \| Drug										2
Upfront payment received	$ 38,000
Maximum amount of payments receivable for license fee and substantive milestones		900,000								$ 900,000
Maximum amount of payments receivable for development milestones		157,500								157,500
Maximum amount of payments receivable for regulatory milestones		338,500								338,500
Maximum amount of payments receivable for commercialization milestones		255,000								255,000
Next prospective milestone		1,500								1,500
Next prospective license fee		45,000								45,000
Revenue earned										12,300	33,300	$ 37,300
Deferred revenue		2,100				$ 4,900				$ 2,100	$ 4,900
GSK [Member] \| Revenue [Member] \| Strategic Partner [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Concentration percentage										4.00%	12.00%	17.00%
GSK [Member] \| IONIS-TTR [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Cumulative payments received		$ 70,000								$ 70,000

Collaborative Arrangements and Licensing Agreements, Research, Development and Commercialization Partners - Janssen Biotech, Inc. (Details) $ in Thousands	1 Months Ended			3 Months Ended								12 Months Ended
	Dec. 31, 2016 USD ($)	Jul. 31, 2016 USD ($)	Dec. 31, 2014 USD ($)	Dec. 31, 2016 USD ($)	Sep. 30, 2016 USD ($)	Jun. 30, 2016 USD ($)	Mar. 31, 2016 USD ($)	Dec. 31, 2015 USD ($)	Sep. 30, 2015 USD ($)	Jun. 30, 2015 USD ($)	Mar. 31, 2015 USD ($)	Dec. 31, 2016 USD ($) Program	Dec. 31, 2015 USD ($)	Dec. 31, 2014 USD ($)
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue earned				$ 160,349	$ 110,927	$ 38,470	$ 36,874	$ 51,571	$ 49,121	$ 120,428	$ 62,583	$ 346,620	$ 283,703	$ 214,161
Janssen Biotech, Inc. [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of programs under which drugs are to be developed and commercialized \| Program												3
Upfront payment recorded as deferred revenue			$ 35,000
Maximum amount of payments receivable for license fee and substantive milestones	$ 800,000			800,000								$ 800,000
Maximum amount of payments receivable for development milestones	175,000			175,000								175,000
Maximum amount of payments receivable for regulatory milestones	420,000			420,000								420,000
Maximum amount of payments receivable for commercialization milestones	180,000			180,000								180,000
Cumulative payments received	47,000			47,000								47,000
License fee received		$ 10,000
Revenue earned					$ 10,000							27,300	8,900	$ 0
Milestone payment earned	5,000
Next prospective milestone	5,000			5,000								5,000
Deferred revenue	$ 17,500			$ 17,500				$ 26,300				$ 17,500	$ 26,300

Collaborative Arrangements and Licensing Agreements, Research, Development and Commercialization Partners - Novartis (Details) - Novartis [Member] - Subsequent Event [Member] $ in Millions	1 Months Ended
	Jan. 31, 2017 USD ($) shares
Collaborative Arrangement and Licensing Agreement [Abstract]
Shares issued (in shares) \| shares	1,631,435
Proceeds from sale of common stock	$ 100
Additional amount of common stock required to be purchased in the future	50
Akcea [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Upfront payment received	75
Portion of upfront payment retained	60
Portion of upfront payment paid as a sublicense fee	15
License fee receivable per drug	$ 150
Percentage of license fees, milestone payments and royalties paid as sublicense fee	50.00%
Akcea [Member] \| AKCEA-APO(a)-L [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Maximum amount of payments receivable for milestones	$ 600
Royalty percentage received on sales of drug	20.00%
Akcea [Member] \| AKCEA-APOCIII-L [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Maximum amount of payments receivable for milestones	$ 530
Royalty percentage received on sales of drug	20.00%

Collaborative Arrangements and Licensing Agreements, Research, Development and Commercialization Partners - Roche (Details) - USD ($) $ in Thousands	1 Months Ended	3 Months Ended								12 Months Ended
	Apr. 30, 2013	Dec. 31, 2016	Sep. 30, 2016	Jun. 30, 2016	Mar. 31, 2016	Dec. 31, 2015	Sep. 30, 2015	Jun. 30, 2015	Mar. 31, 2015	Dec. 31, 2016	Dec. 31, 2015	Dec. 31, 2014
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue earned		$ 160,349	$ 110,927	$ 38,470	$ 36,874	$ 51,571	$ 49,121	$ 120,428	$ 62,583	$ 346,620	$ 283,703	$ 214,161
Roche [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Upfront payment recorded as deferred revenue	$ 30,000
Payment receivable due for updated development activities		3,000								3,000
Maximum amount of payments receivable for license fee and substantive milestones		365,000								365,000
Maximum amount of payments receivable for development milestones		70,000								70,000
Maximum amount of payments receivable for regulatory milestones		170,000								170,000
Maximum amount of payments receivable for commercialization milestones		80,000								80,000
Maximum amount of payment receivable for each additional drug developed		136,500								136,500
Cumulative payments received		53,600								53,600
Next prospective milestone		10,000								10,000
Revenue earned										7,100	31,200	$ 8,700
Deferred revenue		$ 1,700				$ 8,800				$ 1,700	$ 8,800
Roche [Member] \| Revenue [Member] \| Strategic Partner [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Concentration percentage										2.00%	11.00%	4.00%

Collaborative Arrangements and Licensing Agreements, Satellite Company Collaborations - Achaogen, Inc. (Details) $ in Thousands	1 Months Ended	3 Months Ended								12 Months Ended
	Sep. 30, 2014 USD ($)	Dec. 31, 2016 USD ($)	Sep. 30, 2016 USD ($)	Jun. 30, 2016 USD ($)	Mar. 31, 2016 USD ($)	Dec. 31, 2015 USD ($)	Sep. 30, 2015 USD ($)	Jun. 30, 2015 USD ($)	Mar. 31, 2015 USD ($)	Dec. 31, 2016 USD ($) Drug	Dec. 31, 2015 USD ($)	Dec. 31, 2014 USD ($)	Dec. 31, 2006 USD ($)
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue earned		$ 160,349	$ 110,927	$ 38,470	$ 36,874	$ 51,571	$ 49,121	$ 120,428	$ 62,583	$ 346,620	$ 283,703	$ 214,161
Achaogen, Inc. [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Upfront fee in the form of equity securities													$ 1,500
Number of drugs to be developed and commercialized \| Drug										2
Maximum amount of payments receivable for development, regulatory and commercialization milestones		49,300								$ 49,300
Cumulative payments received		7,000								7,000
Milestone payment earned	$ 4,000
Next prospective milestone		$ 7,500								7,500
Revenue earned										$ 0	$ 0	4,000
Net proceeds from sale of stock												$ 1,300

Collaborative Arrangements and Licensing Agreements, Satellite Company Collaborations - Alnylam Pharmaceuticals, Inc. (Details) $ in Thousands	1 Months Ended	3 Months Ended								12 Months Ended
	Mar. 31, 2004 USD ($)	Dec. 31, 2016 USD ($)	Sep. 30, 2016 USD ($)	Jun. 30, 2016 USD ($)	Mar. 31, 2016 USD ($)	Dec. 31, 2015 USD ($)	Sep. 30, 2015 USD ($)	Jun. 30, 2015 USD ($)	Mar. 31, 2015 USD ($)	Dec. 31, 2016 USD ($)	Dec. 31, 2015 USD ($) Target Program	Dec. 31, 2014 USD ($)
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue earned		$ 160,349	$ 110,927	$ 38,470	$ 36,874	$ 51,571	$ 49,121	$ 120,428	$ 62,583	$ 346,620	$ 283,703	$ 214,161
Alnylam Pharmaceuticals, Inc. [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Upfront payment recorded as deferred revenue	$ 5,000
Maximum amount of payments receivable per drug for milestone payments		3,400								3,400
Maximum amount of payments receivable per drug for development milestones		1,100								1,100
Maximum amount of payments receivable per drug for regulatory milestones		2,300								2,300
Next prospective milestone		400								400
Maximum amount of payments payable for development and regulatory milestones		3,400								3,400
Number of therapeutic programs \| Program											4
Number of therapeutic targets granted to Ionis \| Target											4
Number of other unnamed therapeutic targets granted to Ionis \| Target											2
Number of therapeutic targets granted by Ionis \| Target											4
Cumulative payments received		$ 70,000								70,000
Revenue earned										$ 1,100	$ 1,300	$ 9,900

Collaborative Arrangements and Licensing Agreements, Satellite Company Collaborations - Antisense Therapeutics Limited (Details) - USD ($)	3 Months Ended								12 Months Ended
	Dec. 31, 2016	Sep. 30, 2016	Jun. 30, 2016	Mar. 31, 2016	Dec. 31, 2015	Sep. 30, 2015	Jun. 30, 2015	Mar. 31, 2015	Dec. 31, 2016	Dec. 31, 2015	Dec. 31, 2014
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue earned	$ 160,349,000	$ 110,927,000	$ 38,470,000	$ 36,874,000	$ 51,571,000	$ 49,121,000	$ 120,428,000	$ 62,583,000	$ 346,620,000	$ 283,703,000	$ 214,161,000
Antisense Therapeutics Limited [Member] \| Maximum [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Ownership interest percentage	10.00%				10.00%				10.00%	10.00%
Antisense Therapeutics Limited [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue earned									$ 0	$ 0	$ 0

Collaborative Arrangements and Licensing Agreements, Satellite Company Collaborations - Atlantic Pharmaceuticals Limited (Details) - USD ($)

1 Months Ended

3 Months Ended

12 Months Ended

Mar. 31, 2007

Dec. 31, 2016

Sep. 30, 2016

Jun. 30, 2016

Mar. 31, 2016

Dec. 31, 2015

Sep. 30, 2015

Jun. 30, 2015

Mar. 31, 2015

Dec. 31, 2016

Dec. 31, 2015

Dec. 31, 2014

Dec. 31, 2013

Dec. 31, 2010

Atlantic Pharmaceuticals Limited [Member]

$ 160,349,000

$ 110,927,000

$ 38,470,000

$ 36,874,000

$ 51,571,000

$ 49,121,000

$ 120,428,000

$ 62,583,000

$ 346,620,000

$ 283,703,000

$ 214,161,000

Collaborative Arrangement and Licensing Agreement [Abstract]

Ownership interest percentage

9.00%

11.00%

9.00%

11.00%

Atlantic Pharmaceuticals Limited [Member]

Collaborative Arrangement and Licensing Agreement [Abstract]

Upfront fee in the form of equity securities

$ 2,000,000

Maximum amount of payments receivable for regulatory milestones

$ 1,400,000

Next prospective milestone

$ 600,000

600,000

Collaborative Arrangement and Licensing Agreement [Abstract]

$ 0

^[1]

$ 0

^[1]

$ 0

[1]	Revenue from this relationship was negligible for the year.

Collaborative Arrangements and Licensing Agreements, Satellite Company Collaborations - Dynacure, SAS (Details) - USD ($)	3 Months Ended								12 Months Ended
	Dec. 31, 2016	Sep. 30, 2016	Jun. 30, 2016	Mar. 31, 2016	Dec. 31, 2015	Sep. 30, 2015	Jun. 30, 2015	Mar. 31, 2015	Dec. 31, 2016	Dec. 31, 2015	Dec. 31, 2014
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue earned	$ 160,349,000	$ 110,927,000	$ 38,470,000	$ 36,874,000	$ 51,571,000	$ 49,121,000	$ 120,428,000	$ 62,583,000	$ 346,620,000	$ 283,703,000	$ 214,161,000
Dynacure, SAS [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Ownership interest percentage	15.00%								15.00%
Maximum amount of payments receivable for license fee and substantive milestones	$ 210,000,000								$ 210,000,000
Maximum amount of payments receivable for development milestones	34,500,000								34,500,000
Maximum amount of payments receivable for regulatory milestones	111,000,000								111,000,000
Maximum amount of payments receivable for commercialization milestones	$ 60,000,000								60,000,000
Revenue earned									$ 0

Collaborative Arrangements and Licensing Agreements, Satellite Company Collaborations - OncoGenex Technologies Inc. (Details) - USD ($) $ in Thousands	3 Months Ended								12 Months Ended
	Dec. 31, 2016	Sep. 30, 2016	Jun. 30, 2016	Mar. 31, 2016	Dec. 31, 2015	Sep. 30, 2015	Jun. 30, 2015	Mar. 31, 2015	Dec. 31, 2016	Dec. 31, 2015	Dec. 31, 2014
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue earned	$ 160,349	$ 110,927	$ 38,470	$ 36,874	$ 51,571	$ 49,121	$ 120,428	$ 62,583	$ 346,620	$ 283,703	$ 214,161
OncoGenex Technologies Inc. [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Maximum amount of payments receivable for development and regulatory milestones	5,800								5,800
Maximum amount of payments receivable for development milestones	1,300								1,300
Maximum amount of payments receivable for regulatory milestones	4,500								4,500
Next prospective milestone	$ 1,300								1,300
Revenue earned									$ 1,400	$ 0	$ 0

Collaborative Arrangements and Licensing Agreements, Satellite Company Collaborations - Regulus Therapeutics Inc. (Details) $ in Thousands, shares in Millions	3 Months Ended								12 Months Ended
	Dec. 31, 2016 USD ($) shares	Sep. 30, 2016 USD ($)	Jun. 30, 2016 USD ($)	Mar. 31, 2016 USD ($)	Dec. 31, 2015 USD ($)	Sep. 30, 2015 USD ($)	Jun. 30, 2015 USD ($)	Mar. 31, 2015 USD ($)	Dec. 31, 2016 USD ($) Drug shares	Dec. 31, 2015 USD ($)	Dec. 31, 2014 USD ($)
Collaborative Arrangement and Licensing Agreement [Abstract]
Revenue earned	$ 160,349	$ 110,927	$ 38,470	$ 36,874	$ 51,571	$ 49,121	$ 120,428	$ 62,583	$ 346,620	$ 283,703	$ 214,161
Net carrying value	$ 2,414				$ 24,792				$ 2,414	24,792
Regulus Therapeutics Inc. [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Number of drugs currently in development \| Drug									3
Revenue earned									$ 0	0	0
Proceeds from sale of stock									$ 4,467	25,527	22,949
Gain on sale of stock										$ 20,211	$ 19,902
Common stock owned (in shares) \| shares	1.1								1.1
Net carrying value	$ 2,414								$ 2,414

Collaborative Arrangements and Licensing Agreements, Satellite Company Collaborations - The University of Texas MD Anderson Cancer Center (Details)	12 Months Ended
	Dec. 31, 2016
The University of Texas MD Anderson Cancer Center [Member]
Collaborative Arrangement and Licensing Agreement [Abstract]
Term of collaboration agreement	5 years

Collaborative Arrangements and Licensing Agreements, External Project Funding (Details) - USD ($)

1 Months Ended

3 Months Ended

12 Months Ended

Aug. 31, 2016

Dec. 31, 2016

Sep. 30, 2016

Jun. 30, 2016

Mar. 31, 2016

Dec. 31, 2015

Sep. 30, 2015

Jun. 30, 2015

Mar. 31, 2015

Dec. 31, 2016

Dec. 31, 2015

Dec. 31, 2014

Dec. 31, 2013

Research and development expense

$ 340,400,000

$ 319,500,000

$ 238,900,000

CHDI Foundation, Inc. [Member]

$ 160,349,000

$ 110,927,000

$ 38,470,000

$ 36,874,000

$ 51,571,000

$ 49,121,000

$ 120,428,000

$ 62,583,000

346,620,000

283,703,000

214,161,000

Collaborative Arrangement and Licensing Agreement [Abstract]

Research and development expense

5,000,000

$ 3,000,000

Maximum amount of payments payable for pre-specified milestones

4,000,000

Cystic Fibrosis Foundation [Member]

$ 0

^[1]

$ 0

Collaborative Arrangement and Licensing Agreement [Abstract]