Filed Pursuant to
Rule 424(b)(3)
Registration No. 333-141447

Supplement to Prospectus

Dated March 20, 2007

Isis Pharmaceuticals, Inc.


The Prospectus, dated March 20, 2007, is hereby supplemented as follows to restate, in its entirty, the “Selling Security Holders” section on pages 23-25 of the Prospectus.


 




SELLING SECURITY HOLDERS

We initially issued the notes to the initial purchasers of the notes who then resold the notes in transactions exempt from the registration requirements of the Securities Act to persons reasonably believed to be “qualified institutional buyers” (as defined in Rule 144A under the Securities Act). The selling security holders (which term includes their transferees, pledgees, donees or their successors) may from time to time offer and sell pursuant to this prospectus or any applicable prospectus supplement any or all of the notes and common stock issuable upon conversion of the notes.

No offer or sale under this prospectus may be made by a selling security holder unless that holder is listed in the table in this prospectus or until that holder has notified us and a supplement to this prospectus has been filed or an amendment to the registration statement of which this prospectus is a part has become effective. We will supplement or amend this prospectus to include additional selling security holders upon request and upon provision of all required information to us. Information concerning the selling security holders may change from time to time and any changed information will be set forth in supplements to this prospectus if and when necessary.

The following table sets forth information about each selling security holder, including the name, the number and percentage of the notes beneficially owned and being offered by the selling security holder and the number and percentage of common stock beneficially owned and being offered by the selling security holder. The percentages of common stock beneficially owned and being offered are based on the number of shares of our common stock that were outstanding as of March 12, 2007.  Unless otherwise indicated below, none of the selling security holders nor any of their affiliates, officers, directors or principal equity holders has held any position or office or has had any material relationship with us within the past three years.

Name

 

Principal Amount
of Notes
Beneficially Owned
and Offered
Hereby

 

Percentage of
Notes
Outstanding

 

Shares of Common
Stock Beneficially
Owned and
Offered Hereby

 

Percentage of
Common Stock
Outstanding

 

Absolute Strategies Fund, Forum Funds Trust

 

400,000

 

*

 

27,350

 

 

ADI Alternative Investments

 

1,000,000

 

*

 

68,376

 

 

ADI Alternative Investments c/o Casam ADI CB Arbitrage

 

1,000,000

 

*

 

68,376

 

 

ADI Alternative Investments c/o Kallista Master Fund Ltd.

 

2,000,000

 

1.2

%

136,752

 

 

Admiral Flagship Master Fund, Ltd.

 

500,000

 

*

 

34,188

 

 

Advent Convertible ARB Master

 

4,628,000

 

2.8

%

316,444

 

 

Advent Enhanced Phoenix Fund

 

2,000,000

 

1.2

%

136,752

 

 

AHFP Context

 

410,000

 

*

 

28,034

 

 

Alcon Laboratories

 

377,000

 

*

 

25,777

 

 

Altma Fund SICAV PLC in respect of the Grafton Sub Fund

 

1,020,000

 

*

 

69,743

 

 

Argent Classic Convertible Arbitrage Fund L.P.

 

850,000

 

*

 

58,119

 

 

Argent Classic Convertible Arbitrage Fund Ltd.

 

5,280,000

 

3.2

%

361,025

 

 

Argent Classic Convertible Arbitrage Fund II, L.P.

 

200,000

 

*

 

13,675

 

 

Argentum Multi-Strategy Fund Ltd. — Classic

 

80,000

 

*

 

5,470

 

 

Arlington County Employees Retirement System

 

542,000

 

*

 

37,059

 

 

Barclays Capital Securities Ltd.

 

5,500,000

 

3.4

%

376,068

 

 

B.C. McCabe Foundation

 

80,000

 

*

 

5,470

 

 

BNP Paribas Arbitrage(1)**

 

500,000

 

*

 

34,188

 

 

British Virgin Island Social Security Board

 

125,000

 

*

 

8,547

 

 

Calamos Market Neutral Income Fund — Calamos Investment Trust

 

5,000,000

 

3.1

%

341,880

 

 

CASAM Argent Classic Convertible Arbitrage Fund Limited

 

160,000

 

*

 

10,940

 

 

CASAM Context Offshore Advantage Fund Limited

 

380,000

 

*

 

25,982

 

 

CIBC World Markets Corp

 

1,665,000

 

1.0

%

113,846

 

 

Citadel Equity Fund, Ltd.(2)**

 

5,000,000

 

3.1

%

341,880

 

*

 

City of Shreveport (LA) Employees Retirement System

 

80,000

 

*

 

5,470

 

 

City University of New York (CUNY)

 

108,000

 

*

 

7,384

 

 

ClearBridge Asset Management Inc.(3)**

 

7,050,000

 

4.3

%

482,051

 

 

CNH CA Master Account, L.P.(4)

 

500,000

 

*

 

34,188

 

 




 

Columbia Convertible Securities Fund(5)

 

4,000,000

 

2.5

%

273,504

 

*

 

Commissioners of the Land Office

 

850,000

 

*

 

58,119

 

 

Constans Healthcare Convertible Arbitrage Fund

 

250,000

 

*

 

17,094

 

 

Context Advantage Master Fund, LP

 

3,820,000

 

2.4

%

261,196

 

 

Daimler Chrysler Corp Emp #1 Pension Plan, DTD 4/1/89(6)

 

787,000

 

*

 

53,811

 

 

Elite Classic Convertible Arbitrage Ltd.

 

160,000

 

*

 

10,940

 

 

Family Service Life Insurance Company(15)**

 

100,000

 

*

 

6,837

 

 

Federated Kaufman Fund, a portfolio of Federated Equity Funds(7)

 

19,800,000

 

12.2

%

1,353,846

 

12.7

%

Finch Tactical Plus Class B

 

170,000

 

*

 

11,623

 

 

Florida Power and Light Group Employee Pension Plan(6)

 

304,000

 

*

 

20,786

 

 

Franklin and Marshall College(6)

 

19,000

 

*

 

1,299

 

 

Froley Revy Alternative Strategies

 

600,000

 

*

 

41,025

 

 

GLG Market Neutral Fund(8)

 

6,000,000

 

3.7

%

410,256

 

 

GMIMCO Trust

 

990,000

 

*

 

67,692

 

 

Grady Hospital Foundation

 

104,000

 

*

 

7,111

 

 

The Guardian Life Insurance Company of America(15)**

 

5,000,000

 

3.1

%

341,880

 

 

The Guardian Life Insurance Company of America Pension Trust(15)**

 

400,000

 

*

 

27,350

 

 

HFRCA Opportunity Master Trust

 

205,000

 

*

 

14,017

 

 

Institutional Benchmarks Series (Master Feeder) Limited in respect of Alcor series

 

200,000

 

*

 

13,675

 

 

Intl. Truck & Engine Corp Non Contributory Retirement Plan Trust

 

635,000

 

*

 

43,418

 

 

Intl. Truck & Engine Corp Retirement Plan for Salaried Employee’s Trust

 

280,000

 

*

 

19,145

 

 

KeySpan Foundation

 

40,000

 

*

 

2,735

 

 

KeySpan Insurance Company

 

140,000

 

*

 

9,572

 

 

LDG, Limited(9)

 

222,000

 

*

 

15,179

 

 

Lord Abbett Investment Trust — LA Convertible Fund

 

3,080,000

 

1.9

%

210,598

 

 

Lyxor/Context Fund LTD

 

790,000

 

*

 

54,017

 

 

Lyxor Master Trust Fund

 

167,000

 

*

 

11,418

 

 

McMahan Securities Co. LP

 

400,000

 

*

 

27,350

 

 

Mohican VCA Master Fund Ltd

 

3,100,000

 

1.9

%

211,965

 

 

National Fuel & Gas Company Retirement Plan

 

445,000

 

*

 

30,427

 

 

NFS — SCI Funeral and Merchandise Fixed Common Trust

 

30,000

 

*

 

2,051

 

 

Occidental Petroleum Corporation

 

250,000

 

*

 

17,094

 

 

The Northwestern Mutual Life Insurance Company — General Account(10)**

 

2,250,000

 

1.4

%

153,846

 

 

The Northwestern Mutual Life Insurance Company —
Group Annuity Separate Account(10)**

 

250,000

 

*

 

17,094

 

 

NYC Teachers’ Variable Annuity Fund

 

1,400,000

 

*

 

95,726

 

 

Philadelphia Board of Pensions

 

550,000

 

*

 

37,606

 

 

Police & Fire Retirement System of the City of Detroit

 

416,000

 

*

 

28,444

 

 

Polygon Global Opportunities Master Fund(11)

 

1,000,000

 

*

 

68,376

 

 

ProMutual

 

685,000

 

*

 

46,837

 

 

Rampart Enhanced Convertible Investors, LLC(6)

 

140,000

 

*

 

9,572

 

 

San Francisco City and County ERS

 

1,071,000

 

*

 

73,230

 

 

SCI Cemetary Merchandise Common Trust

 

20,000

 

*

 

1,367

 

 

SCI Pre-Need Common Trust Fund

 

20,000

 

*

 

1,367

 

 

Stark Master Fund Ltd.(12)**

 

6,500,000

 

4.0

%

444,444

 

 

Sterling Invest Co.

 

1,675,000

 

1.0

%

114,529

 

 

Total Fina Elf Finance USA, Inc.

 

245,000

 

*

 

16,752

 

 

TQA Master Fund Ltd.(9)

 

1,425,000

 

*

 

97,435

 

 

TQA Master Plus Fund, Ltd.(9)(13)

 

885,000

 

*

 

60,512

 

*

 

Trustmark Insurance Company

 

267,000

 

*

 

18,256

 

 

Vermont Mutual Insurance Company

 

140,000

 

*

 

9,572

 

 

Vicis Capital Master Fund

 

9,000,000

 

5.5

%

615,384

 

 

Wachovia Securities International Ltd(14)**

 

500,000

 

*

 

34,188

 

 

Worldwide Transactions Limited

 

210,000

 

*

 

14,358

 

 

Xavex Convertible Arbitrage 10 Fund

 

270,000

 

*

 

18,461

 

 

 

Zurich Institutional Benchmarks Master Fund Ltd. c/o TQA Investors, LLC(9)

 

468,000

 

*

 

32,000

 

 


*                    Less than 1%

**             The selling security holder has represented to us that the notes held by them were purchased in the ordinary course of business and that at the time of purchase of the notes held by them, they did not have any agreements or understandings, directly or indirectly, with any person to distribute the notes held by them or the common stock issuable upon conversion of the notes held by them.

(1)             BNP Paribas Security Corp. is an affiliate of BNP Paribus Arbitrage, a registered broker-dealer.

(2)             Citadel Equity Fund, Ltd. also beneficially owns 630 shares of our common stock, which are not included for sale under this prospectus.  The broker-dealers are under common control with Citadel Equity Fund Ltd. and is directly owned by Citadel Equity Fund.  The broker dealers are: Aragon Investments Ltd., Palofax Trading LLC, Citadel Trading Group, LLC and Citadel Derivatives Group, LLC.  Citadel Limited Partnership (“CLP”) is the trading manager of Citadel Equity Fund Ltd. and consequently has investment discretion over securities held by Citadel Equity Fund Ltd.  Citadel Investment Group, LLC (“CIG”) controls CLP.  Kenneth C. Griffin controls CIG and therefore has ultimate investment discretion over securities held by Citadel Equity Fund Ltd. CLP, CIG, and Mr. Griffin each disclaim beneficial ownership of the shares held by Citadel Equity Fund Ltd.

(3)             Selling Security Holder is under common control with Legg Mason Investors Services, LLC (“LMIS”), a limited purpose broker-dealer affiliate.  LMIS serves as a principal underwriter for certain mutual funds managed by investment advisory affiliates of Legg Mason Inc.




(4)             CNH Partners, LLC is Investment Advisor of the Selling Securityholder and has sole voting and dispositive power over the securities.  Investment principals for the Advisor are Robert Krail, Mark Mitchell and Todd Pulvino.

(5)             Columbia Convertible Securities Fund also beneficially owns $1,960,000 principal amount of our 5.5% convertible subordinated notes due 2009, which are convertible into approximately 117,894 shares of our common stock.  Neither of these securities are included for sale under this prospectus.

(6)             Palisade Capital Management, LLC acts as an Investment Advisor.

(7)    Federated Kaufman Fund also beneficially owns 9,274,660 shares of our common stock and 1,176,470 shares of our common stock issuable upon exercise of warrants.  Neither of these securities are included for sale under this prospectus.

(8)             GLG Market Neutral Fund is a publicly owned company listed on the Irish Stock Exchange.  GLG Partners LP, and English limited partnership, acts as the investment manager of the fund and has voting and dispositive power over the securities held by the fund.  The general partner of GLG Partners LP is GLG Partners Limited, an English limited company.  The shareholders of GLG Partners Limited are Noam Gottesman, Pierre Lagrange, Jonathan Green, Philippe Jabre and Lehman Brothers (Cayman) Limited, a subsidiary of Lehman Brothers Holdings, Inc., a publicly-held entity.  The managing directors of GLG Partners Limited are Noam Gottesman, Pierre Lagrange and Emmanual Roman and, as a result, each has voting and dispositive power over the securities held by the fund.  GLG Partners LP, GLG Partners Limited, Noam Gottesman, Pierre Lagrange and Emmanual Roman disclaim beneficial ownership of the securities held by the Fund, except for their pecuniary interest therein.

(9)             TQA Investors LLC has sole investment power and shared voting power.  Its members are: John Idone, Paul Bucci and Darren Langis and Andrew Anderson.

(10)       The following NASD members are affiliated with Northwestern Mutual: Northwestern Mutual Investment Services, LLC, Russell Institutional Services, Russell Implementation Services, Inc., Russell Fund Distributiors, Inc., and Todd Securities, LLC

(11)       Polygon Investment Partner LLP and Polygon Investment Partners LP (the “Investment Manager”), Polygon Investments Ltd. (the “Manager”), Alexander E. Jackson, Reade E. Griffith, and Patrick G. G. Dear share voting and dispositive power of the securities held by Polygon Global Opportunities Master Fund.  The Investment Mangers, the Manger, Alexander E. Jackson, Reade E. Griffith, and Patrick G. G. Dear disclaim beneficial ownership of the securities held by Polygon Global Opportunities Master Fund.

(12)       Stark Master Fund Ltd. is an affiliate of Reliant Trading, a registered broker-dealer.

(13)       TQA Master Plus Fund, Ltd also beneficially owns 10,000 shares of our common stock, which are not included for sale under this prospectus.

(14)       Wachovia Securities Intl. Ltd and Wachovia Capital Markets LLC are subsidiaries of Wachovia Corporation.

(15)  Park Avenue Securities LLC and Guardian Investor Services LLC are broker dealers which are indirect, wholly owned subsidiaries of The Guardian Life Insurance Company of America.

We prepared this table based on the information supplied to us by the selling security holders named in the table and we have not sought to verify such information.

The selling security holders listed in the above table may have sold or transferred, in transactions exempt from the registration requirements of the Securities Act, some or all of their notes since the date on which the information in the above table was provided to us. Information about the selling security holders may change over time.

Because the selling security holders may offer all or some of the notes or the shares of common stock issuable upon conversion of the notes from time to time, we cannot estimate the amount of the notes or shares of common stock that will be held by the selling security holders upon the termination of any particular offering by a selling security holder. See “Plan of Distribution.”

The date of this Prospectus Supplement is April 6, 2007