UNITED STATES

SECURITIES AND EXCHANGE
COMMISSION

Washington, D.C. 20549

SCHEDULE 13D

Item 1.

Security and Issuer

This Schedule 13D relates to the Common Stock, $0.001 par value per share (the “Common Shares”), of Isis Pharmaceuticals, Inc. (the “Issuer”), a Delaware corporation.  The principal executive offices of the Issuer are located at 1896 Rutherford Road, Carlsbad, CA 92008.

Item 2.

Identity and Background

Genzyme Corporation (“Genzyme”), a Massachusetts corporation, is a publicly-held, global biotechnology company focused on rare inherited disorders, kidney disease, cancer, transplant and immune diseases, orthopaedics and diagnostic testing.  Genzyme’s principal place of business and principal office is located at 500 Kendall Street, Cambridge, Massachusetts 02142.

To the best of Genzyme’s knowledge as of the date hereof, set forth in Schedule I to this Schedule 13D and incorporated herein by reference is the following information with respect to each director and executive officer of Genzyme:

(1)           name;

(2)           business address;

(3)           present principal occupation or employment and the name, principal business and address of any corporation or other organization in which such employment is conducted; and

(4)           citizenship.

During the last five years, neither Genzyme nor, to the best of Genzyme’s knowledge, any of its directors or executive officers has been (1) convicted in a criminal proceeding (excluding traffic violations or similar misdemeanors) or (2) a party to a civil proceeding of a judicial or administrative body of competent jurisdiction and as a result of such proceeding has been or is subject to a judgment, decree or final order enjoining future violations of, or prohibiting or mandating activities subject to, federal or state securities laws or finding any violation with respect to such laws.

Item 3.

Source and Amount of Funds or Other Consideration

On January 7, 2008 Genzyme and the Issuer entered into a Stock Purchase Agreement (the “Stock Purchase Agreement”) pursuant to which the Issuer issued and sold to Genzyme 5,000,000 shares of Common Stock for an aggregate purchase price of $150,000,000 representing a per share purchase price of $30.  The source of the funds for the purchase of the shares (the “Purchase”) was the working capital of Genzyme.

As an inducement to enter into the Stock Purchase Agreement, and in consideration thereof, Genzyme and the Issuer entered into a License and Research Agreement (the “License and Research Agreement”), dated as of the date of the Stock Purchase Agreement (the “Effective Date”).  Pursuant to the terms and conditions of the License and Research Agreement, the Issuer has granted Genzyme an exclusive worldwide license of mipomerson, which is currently in phase 3 clinical trials.  In addition, under the License and Research Agreement, for a two-year period from the Effective Date Genzyme has been granted the option to exclusively license certain Issuer drugs that become development candidates in the Issuer’s neuro-degenerative and rare disease programs.  The terms of these licenses will be negotiated in good faith by Genzyme and the Issuer.  Upon granting any such license, Genzyme will be solely responsible for the commercialization of any such licensed drug, including all funding, resourcing and decision-making, all

further clinical development, manufacturing, and regulatory approval.  All research activities prior to the identification of the development candidate will be funded by the Issuer.

A copy of the Stock Purchase Agreement is attached as Exhibit 1 to this Schedule 13D.  References to, and descriptions of, the Stock Purchase Agreement as set forth above in this Item 3 are qualified in their entirety by reference to the Stock Purchase Agreement included as Exhibit 1 to this Schedule 13D and incorporated herein in its entirety by this reference.  The information set forth and/or incorporated by reference in Item 6 is hereby incorporated by reference into this Item 3.

Item 4.

Purpose of Transaction

The information set forth and/or incorporated by reference in Item 3 is hereby incorporated by reference into this Item 4.  The purpose of the Purchase described in Item 3 is for investment purposes and the Purchase was made in the ordinary course of business and was not made for the purpose of acquiring control of the Issuer.  The purpose of entering into the License and Research Agreement is to share the risks and rewards associated with developing and commercializing certain Issuer drugs and was made in the ordinary course of business and was not made for the purpose of acquiring control of the Issuer.  However, because of the exclusive licensing relationship, a material amount of assets of the Issuer could be deemed to be transferred to Genzyme.

Except to the extent the foregoing may be deemed a plan or proposal, Genzyme has no plans or proposals which relate to, or could result in, any of the matters referred to in paragraphs (a) through (j), inclusive, of the instructions to Item 4 of Schedule 13D. Genzyme may, at any time and from time to time, review or reconsider its position and/or change its purpose and/or formulate plans or proposals with respect thereto.

Item 5.

Interest in Securities of the Issuer

          (a) –

(c)  The information contained in Items 3, 4 and 6 is hereby incorporated herein by reference.  The following disclosure assumes that there are 87,317,938 Common Shares issued and outstanding as of the Effective Date, based on representations made in the Stock Purchase Agreement by the Issuer to Genzyme.

As of the Effective Date and taking into account the transactions described in Item 3, Genzyme beneficially owns and has sole power to vote and sole power of disposition over 5,000,000 Common Shares representing approximately 5.7% of the Common Shares outstanding.

The persons listed on Schedule 1 hereto, as the directors and executive officers of Genzyme, may be deemed to share voting and dispositive power with respect to 5,000,000 Common Shares currently held by Genzyme, representing approximately 5.7% of the Common Shares outstanding.  The persons listed on Schedule I hereto, however, disclaim beneficial ownership of such Common Shares, and this statement shall not be construed as an admission that any person listed on Schedule I hereto is the beneficial owner for any purpose of the Common Shares covered by this Schedule 13D disclosure.

           (d)

To the best of Genzyme’s knowledge as of the date hereof, neither Genzyme nor any of its directors and executive officers named in Schedule I hereto has or knows any other person who has the right to receive or the power to direct the receipt of dividends from, or the proceeds from the sale of, any Common Shares beneficially owned by Genzyme.

          (e)

Not applicable.

Item 6.

Contracts, Arrangements, Understandings or Relationships with Respect to Securities of the Issuer

The information set forth and/or incorporated by reference in Items 2 through 5 is hereby incorporated by reference into this Item 6.

As described in Item 3, on January 7, 2008, Genzyme entered into the Stock Purchase Agreement and the License and Research Agreement with the Issuer.  The Stock Purchase Agreement contains customary representations and warranties and indemnification provisions.  The Stock Purchase Agreement also requires the Issuer to file a registration statement with the Securities and Exchange Commission (the “SEC”) covering the resale of the Registrable Securities (as defined in the Stock Purchase Agreement) within 30 days after the closing of the transactions contemplated by the Stock Purchase Agreement and to effect such registration within 90 days if such registration statement is not reviewed by the SEC or within 120 days if it is reviewed by the SEC.  Pursuant to the Stockholders Agreement, Genzyme is also subject to certain standstill restrictions, including restrictions on acquiring Issuer securities, participating in any solicitation of proxies to vote Issuer securities, or publicly proposing any business combination or similar transaction with the Issuer.  The standstill provisions continue in effect until the earlier of (a) the ten-year anniversary of the License and Research Agreement or (b) the date on which Genzyme holds less than 2% of the Issuer’s outstanding common stock, unless a tender or exchange offer is commenced by a third party or a change of control of the Issuer is announced.  Pursuant to the terms and conditions of the Stock Purchase Agreement, Genzyme also agreed not to sell the shares acquired until the earlier of (a) the four-year anniversary of the effective date of the License and Research Agreement, (b) the first commercial sale of a product under the License and Research Agreement, or (c) the termination or reversion of the product license granted to Genzyme under the License and Research Agreement.  In addition, after the expiration of such holding period, Genzyme will not sell more than 500,000 of the Common Shares acquired in any thirty-day period.

Item 7.

Material to Be Filed as Exhibits

Exhibit No.

Description

1

Stock Purchase Agreement, between Genzyme Corporation and Isis Pharmaceuticals, Inc., dated January 7, 2008.

Dated: January 15, 2008

GENZYME CORPORATION

By:

 /s/ Peter Wirth

Name: Peter Wirth

Title: Chief Legal Officer & Executive Vice President, Legal &

          Corporate Development