LICENSE AND RESEARCH AGREEMENT

Exhibit 10.1

CONFIDENTIAL TREATMENT REQUESTED

UNDER 17 C.F.R §§ 200.80(b)4, AND 240.24b-2

Execution Version

LICENSE AND RESEARCH AGREEMENT

This License and Research Agreement (together with all Exhibits, Schedules and other attachments hereto, this “Agreement”), is dated as of the 7th day of January, 2008 (the “Execution Date”), by and between Genzyme Corporation, a Massachusetts corporation (“Genzyme”) and Isis Pharmaceuticals, Inc., a Delaware corporation (“Isis”).  Genzyme and Isis each may be referred to herein individually as a “Party” or collectively as the “Parties.”

WITNESSETH:

WHEREAS, simultaneously with this Agreement, Isis and Genzyme will enter into that certain Stock Purchase Agreement of even date herewith in the form attached hereto as Exhibit A (the “Stock Purchase Agreement”) pursuant to which Genzyme is purchasing the Shares;

WHEREAS, Isis possesses certain intellectual property with respect to certain oligonucleotide-based therapeutic compounds;

WHEREAS, Isis desires to grant to Genzyme, and Genzyme desires to obtain, a license under certain Isis intellectual property to advance mipomersen, formerly known as ISIS 301012, and related compounds targeting apoB, through human clinical trials and ultimately commercialize it as a product; and

WHEREAS, Isis and Genzyme desire to enter into a research agreement under which Isis will conduct research related to certain gene targets selected by Genzyme.

NOW, THEREFORE, in consideration of the Parties’ willingness to enter into the Stock Purchase Agreement and the respective covenants, representations, warranties and agreements set forth herein, the Parties hereto agree as follows:

ARTICLE 1.
DEFINITIONS

For purposes of this Agreement, the following capitalized terms will have the following meanings.  Capitalized terms used without definition in this Agreement will have the meanings ascribed to them in the Product Term Sheet and the Research Term Sheet.

1.1.                              “AAA” has the meaning set forth in Section 6.2.2 (Binding Arbitration With Respect to Agreement Terms).

1.2.                              “Action” has the meaning set forth in Section 6.3.1 (Jurisdiction).

1.3.                              “Additional Third Party Agreement” has the meaning set forth in Section 2.1.6 (Additional Rights after Effective Date).

1.4.                              “Affiliate” of an entity means any other entity that, directly or indirectly, through one or more intermediaries, controls, is controlled by, or is under common control with such first entity. For purposes of this definition only, “control” (and, with correlative

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meanings, the terms “controlled by” and “under common control with”) means the possession of the actual power to direct the management or policies of an entity, whether through the ownership of voting securities or by contract relating to voting rights or corporate governance.  In addition, [***] will not be considered an Affiliate of Isis.

1.5.                              “apoB” means apolipoprotein B.

1.6.                              “Bankruptcy Code” has the meaning set forth in Section 8.14 (Rights in Bankruptcy).

1.7.                              “Confidential Information” has the meaning set forth in Section 8.1.1 (Non-Disclosure).

1.8.                              “Control” or “Controlled” means, with respect to any Know-How, Patent or other intellectual property right or Regulatory Materials, possession by a Party (including its Affiliates) of the right (whether by ownership, license or otherwise) to grant to the other Party a license or a sublicense under such Know-How, Patent or other intellectual property right or access to Regulatory Materials without violating the terms of any agreement or other arrangement with any Third Party.

1.9.                              “Diligence Period” means the period beginning on the Execution Date and ending on the earlier of (a) the date that is [***] after the Execution Date or (b) the date the Parties enter into the More Detailed Product Agreement.  The Parties’ goal is to conclude diligence and enter into the More Detailed Product Agreement by [***].

1.10.                        “Disclosure Schedule” means the schedule (dated as of the Execution Date and updated pursuant to Section 5.4 (Right to Update Disclosure Schedule Prior to Effective Date)) delivered by Isis to Genzyme that includes exceptions to Isis’ representations and warranties in Section 5.2 (Product Representations and Warranties) and Section 5.3 (Research Representations and Warranties) hereof.

1.11.                        “Dispute” has the meaning set forth in Section 6.1.1 (Escalation).

1.12.                        “Effective Date” has the meaning set forth in Section 7.1.2 (Effective Date).

1.13.                        “Encumbered Follow-On Product” has the meaning set forth in Section 2.2 (Follow-On Product).

1.14.                        “Executives” has the meaning set forth in Section 6.1.1 (Escalation).

1.15.                        “Follow-On Product” means all pharmaceutical compositions, formulations, dosage forms, delivery systems and presentations that contain [***] (alone or with other active ingredients) other than Mipomersen.

1.16.                        “Follow-On Product Encumbrances” has the meaning set forth in Section 2.2.2.

1.17.                        “General Representations and Warranties” has the meaning set forth in Section 5.1 (Representations and Warranties of Both Parties).

1.18.                        “HSR” means the Hart-Scott-Rodino Antitrust Improvements Act of 1976, as amended.

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1.19.                        “In-Licensed Third Party IP” means Patents or Know-How Controlled by Isis that are in-licensed by Isis pursuant to a Third Party Agreement.

1.20.                        “Isis Core Technology Patents” means all Patents, other than the Product-Specific Patents or Isis Manufacturing and Analytical Patents, Controlled by Isis or any of its Affiliates as of the Execution Date hereof or during the term of the Product License that are necessary or useful for the development and commercialization of Product, including the Patents identified on Schedule 1.20.

1.21.                        “Isis Manufacturing and Analytical Know-How” means Know-How other than Product Know-How Controlled by Isis or its Affiliates as of the Execution Date hereof or during the term of the Product License that relates to the synthesis or analysis of Products independent of sequence or chemical modification.

1.22.                        “Isis Manufacturing and Analytical Patents” means Patents Controlled by Isis or its Affiliates as of the Execution Date hereof or during the term of the Product License that claim methods and materials used in the synthesis or analysis of Products independent of sequence or chemical modification, including the Patents identified on Schedule 1.22.  Isis Manufacturing and Analytical Patents do not include the Product-Specific Patents and the Isis Core Technology Patents.

1.23.                        “Isis Manufacturing and Analytical Technology” means the Isis Manufacturing and Analytical Know-How and Isis Manufacturing and Analytical Patents solely to the extent necessary or useful to manufacture a Product.(1)

1.24.                        “Know-How” means technical information and materials, including technology, software, instrumentation, devices, data, compositions, formulas, biological materials, assays, constructs, compounds, discoveries, inventions, procedures, processes, practices, protocols, methods, techniques, results of experimentation or testing, knowledge, trade secrets, skill and experience, whether or not patentable or copyrightable.

1.25.                        “Licensed IP” means the Licensed Patents, the Product Know-How and the Isis Manufacturing and Analytical Know-How; provided, however, that (a) for any such Know-How or Patent that becomes Controlled by Isis after the Execution Date pursuant to an Additional Third Party Agreement, the provisions of Section 2.1.6 (Additional Rights after Effective Date) will govern whether such Know-How or Patent will be

(1) As part of its collaboration with other pharmaceutical partners, Isis has an arrangement where Isis can share manufacturing technology improvements made by such pharmaceutical partners with other Third Parties so long as such Third Parties similarly agree to share their manufacturing technology improvements.  Genzyme may decide to participate in this arrangement if Genzyme wishes.

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included as Licensed IP, and (b) with respect to any Follow-On Product, the provisions of Section 2.2 (Follow-On Product) will govern the extent to which In-Licensed Third Party IP will be included in Licensed IP.

1.26.                        “Licensed Patent(s)” means the Product-Specific Patents, Isis Core Technology Patents and the Isis Manufacturing and Analytical Patents.

1.27.                        “Mipomersen” means mipomersen sodium, formerly known as ISIS 301012.

1.28.                        “More Detailed Product Agreement” has the meaning set forth in Section 2.1.2 (More Detailed Product Agreement).

1.29.                        “More Detailed Research Agreement” has the meaning set forth in Section 2.3 (Research Option Agreement).

1.30.                        “Patent(s)” means (a) patents and patent applications in any country or jurisdiction, (b) all priority applications, divisionals, continuations, substitutions, and continuations-in-part of any of the foregoing, and (c) all patents issuing on any of the foregoing patent applications, together with all registrations, reissues, renewals, re-examinations, confirmations, supplementary protection certificates, and extensions of any of (a), (b) or (c).

1.31.                        “Permitted Licenses” means licenses granted by Isis after the Execution Date to any Third Party under the Isis Core Technology Patents or the Isis Manufacturing and Analytical Technology (but not under the Product-Specific Patents or for use of [***] to (a) use oligonucleotides (or supply oligonucleotides to end users) in quantities not to exceed [***](2) per oligonucleotide per end user solely to conduct Pre-Clinical Research, or (b) enable such Third Party to [***], where such Third Party is primarily engaged in providing contract manufacturing or services and is not engaged in drug discovery, development or commercialization.  Notwithstanding the foregoing, Permitted Licenses do not include any licenses that allow (i) a Third Party to make, use or sell an oligonucleotide having the same [***] as a Product or Isis’ preferred [***], (ii) a Third Party to manufacture any nucleic acid that [***] apoB that will be incorporated into a therapeutic product for use in human clinical trials or for commercial sale or (iii) Isis to directly supply to a Third Party any [***] apoB.

1.32.                        “Pre-Clinical Research” means pre-clinical research including gene function, gene expression and target validation research using cells and animals, which may include small pilot toxicology studies but excludes pharmacokinetic and toxicology studies

(2) Quantity subject to confirmation by the Parties during the Diligence Period.

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required to meet the regulations for filing an IND, clinical development and commercialization.

1.33.                        “Product” means all pharmaceutical compositions, formulations, dosage forms, delivery systems and presentations that contain Mipomersen or any Follow-On Product, including all pharmaceutically acceptable salts, solvates, hydrates, hemihydrates, metabolites, pro-drug forms, stereoisomers, enantiomers, racemates and all optically active forms thereof.

1.34.                        “Product Know-How” means Know-How Controlled by Isis on the Execution Date or during the term of the Product License relating to or otherwise necessary for the development and commercialization of Product.  Product Know-How does not include the Isis Manufacturing and Analytical Know How.

1.35.                        “Product License” has the meaning set forth in Section 2.1 (Grant).

1.36.                        “Product Representations and Warranties” has the meaning set forth in Section 5.2 (Product Representations and Warranties).

1.37.                        “Product-Specific Patents” means Patents Controlled by Isis or any of its Affiliates as of the Execution Date and during the term of the Product License claiming or covering (a) [***] apoB; (b) the sequence of apoB; (c) the specific composition of matter of a Product; and (d) methods of using Product as a therapeutic, methods of using Product to modulate apoB, and methods of using the product to inhibit expression of apoB, including the Patents identified on Schedule 1.37; provided, however, that if a Patent satisfies the criteria set forth above but also applies to gene targets other than apoB, such Patent will be considered an Isis Core Technology Patent.

1.38.                        “Product Term Sheet” means the term sheet attached hereto as Exhibit B.

1.39.                        “Regulatory Materials” means any regulatory submissions, notifications, registrations, approvals and/or other filings and correspondence made to or with a regulatory authority in any country or jurisdiction in the Territory, and any other records required to be maintained for possible audit by a regulatory authority that may be necessary or useful to develop, manufacture, market, sell or otherwise commercialize Product in the Territory.

1.40.                        “Research Option Agreement” has the meaning set forth in Section 2.3 (Research OptionAgreement).

1.41.                        “Research Term Sheet” means the term sheet attached hereto as Exhibit C.

1.42.                        “SEC” means Securities and Exchange Commission.

1.43.                        “Shares” means the shares of Isis’ Common Stock purchased by Genzyme pursuant to the Stock Purchase Agreement.

1.44.                        “Territory” means worldwide.

1.45.                        “Third Party” means a person or entity other than the Parties and their respective

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Affiliates.

1.46.                        “Third Party Agreement” means any agreements pursuant to which Isis obtains rights applicable to the development or commercialization of Product or Follow-On Product.

ARTICLE 2.
LICENSE AND RESEARCH AGREEMENTS

2.1.                              Product License.

2.1.1.                     Grant.  Isis hereby grants to Genzyme an exclusive license, (with the limited right to sublicense as set forth in Section 2.1.3 (Limited Right to Sublicense)), under the Licensed IP to research, develop, make, have made, use, sell, offer for sale, have sold, import and export Products in the Territory for therapeutic purposes on the terms and conditions set forth in the Product Term Sheet and this Agreement (the “Product License”).  Notwithstanding the foregoing, (a) the exclusive license to the Isis Core Technology Patents will be subject to the licenses granted by Isis to Third Parties identified on Schedule 2.1.1 and Isis’ right to grant Permitted Licenses, and (b) with respect to any Follow-On Product, the provisions of Section 2.2 (Follow-On Product) will govern the extent to which In-Licensed Third Party IP is included within Licensed IP.

2.1.2.                     More Detailed Product Agreement.  The Parties agree that the Product Term Sheet and this Agreement contain all material terms of the Product License and will form a legally binding and enforceable license and co-development agreement without need for execution of further documentation or any further action by any Party.  The Parties also recognize that it may be desirable to agree upon other more detailed customary terms and conditions with respect to the Product License.  Accordingly, as soon as reasonably practicable after the Effective Date, the Parties will negotiate and enter into a more detailed written license and co-development agreement that will include the terms set forth in the Product Term Sheet and any additional terms and conditions that are customary and reasonable for agreements of this type that may be agreed to by the Parties, including provisions relating to intellectual property ownership, prosecution and enforcement, regulatory interactions and approvals, term and termination, indemnification and confidentiality (the “More Detailed Product Agreement”).

2.1.3.                     Limited Right to Sublicense.

(a)                                  The licenses granted to Genzyme under the Licensed IP are sublicensable only in connection with a sublicense of a Product to any Affiliate of Genzyme or to any Third Party, in each case for the continued research, development or commercialization of such Product in accordance with the terms of the Product License.

(b)                                 Notwithstanding the foregoing, the licenses granted to Genzyme under the Isis Manufacturing and Analytical Technology are sublicensable to a Third Party [***] only upon the mutual agreement of the Parties.

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2.1.4.                     Upfront License Fee.  Provided that this Agreement and the Product License have become effective and neither has not been terminated, Genzyme will pay to Isis the upfront license fee specified in the Product Term Sheet upon five (5) business days after the earlier of (a) expiration of the Diligence Period or (b) the Parties enter into the More Detailed Product Agreement.

2.1.5.                     Access.  Isis will afford to Genzyme and its representatives reasonable access to and copies of all information (including reasonable access to knowledgeable employees and representatives of Isis to discuss such information) within the possession or control of Isis or any of its Affiliates pertaining to the development of the Product and the Licensed IP, including all Regulatory Materials related to the Product.

2.1.6.                     Additional Rights after Effective Date.  After the Execution Date, Isis may wish to in-license or acquire rights to Know-How or Patents Controlled by Third Parties (such a Third Party in-license or acquisition agreement being an “Additional Third Party Agreement”) which, if so licensed or acquired, may be included in the Licensed IP licensed to Genzyme under Section 2.1.1.  In such event (and to the extent permitted by Isis’ confidentiality agreement with the applicable Third Party), Isis will notify Genzyme regarding the nature of the technology and status of negotiations related to the Additional Third Party Agreement through the JDC.  Once Isis has executed such Additional Third Party Agreement, Isis will offer such Third Party Patents or Know-How to Genzyme (which offer will include a description of the payments paid or potentially payable by Isis thereunder).  At such time, if Genzyme wishes to include such Third Party Patents or Know-How under the licenses granted under Section 2.1.1, Genzyme will notify Isis of its desire to do so and the Parties will fairly and in good faith allocate upfront payments or ongoing payment obligations between Products and compounds that are not Products and other Isis licensees, if appropriate.  As part of this allocation process, Isis will share with Genzyme, in reasonable detail, the assumptions and methodology Isis used to create the proposed allocation.  If Genzyme does not agree to reimburse Isis for the amount of any upfront or similar acquisition payments fairly allocated to Product, and to be responsible for the payment of its share of any upfront, milestone and royalty payments, then the Know-How or Patents acquired or in licensed by Isis under the Additional Third Party Agreement will not be considered Licensed IP licensed to Genzyme under the Product License.  When Genzyme pays its share of any upfront, milestone and royalty payments assumed by Genzyme under this Section 2.1.6, such payments will be considered Program Costs for the applicable Product.

2.2.                              Follow-On Product.  The Parties contemplate that after the Effective Date Genzyme, either on its own or in collaboration with Isis, may wish to research, develop and commercialize Follow-On Products.  The scope of the In-Licensed Third Party IP included in Licensed IP under the Product License with respect to such Follow-On Products will be determined in accordance with the procedures set forth in this Section 2.2.  At the time Genzyme intends to designate a Follow-On Product as a development candidate, Genzyme will notify Isis in writing of such intention and will describe in

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reasonable detail the applicable Follow-On Product.  Subject to Section 2.1.6 (Additional Rights after Effective Date), if a Follow-On Product utilizes any In-Licensed Third Party IP (an “Encumbered Follow-On Product”), such In-Licensed Third Party IP will be included in Licensed IP only to the extent set forth below:

2.2.1.                     If the applicable Third Party Agreement contains a contractual obligation that would preclude Isis from including such In-Licensed Third Party IP in Licensed IP  with respect to such Encumbered Follow-On Product, then the In-Licensed Third Party IP that is the subject of such Third Party Agreement will not be included in Licensed IP.

2.2.2.                     If the applicable Third Party Agreement contains any potential encumbrances known by Isis and related to the potential Follow-On Product, including field or territory restrictions, covenants, or milestones, royalty, sublicense revenue or other payments (“Follow-On Product Encumbrances”), Isis will fully disclose to Genzyme such Follow-On Product Encumbrances and, if Genzyme agrees in writing to assume the Follow-On Product Encumbrances (with any payments being included in Program Costs for such Encumbered Follow-On Product), then the In-Licensed Third Party IP that is the subject of such Third Party Agreement will be included in Licensed IP.

2.2.3.                     If the applicable Third Party Agreement does not contain the obligations or encumbrances described in Sections 2.2.1 and 2.2.2 above, the In-Licensed Third Party IP that is the subject of such Third Party Agreement will automatically be included in Licensed IP.

2.2.4.                     If the applicable Third Party Agreement is or was also applicable to Mipomersen, then the In-Licensed Third Party IP that is the subject of such Third Party Agreement will automatically be included in the Licensed IP to the extent that (a) the terms of such Third Party Agreement do not preclude Isis from including it and (b) Genzyme agrees in writing to assume any applicable Follow-On Product Encumbrances associated with such Third Party Agreement.

2.2.5.                     Each time the Parties complete the process set forth above, Isis will update the schedules relating to Licensed Patents and Third Party Agreements, and Schedule 2.1.1 as appropriate.

2.3.                              Research Option Agreement.  Isis and Genzyme hereby enter into a research agreement under which Isis will perform research on the terms and conditions set forth in the Research Term Sheet (the “Research Option Agreement”).  The Parties agree that the Research Term Sheet and this Agreement contain all material terms of the Research Option Agreement and will form a legally binding and enforceable research agreement, without need for execution of further documentation or any further action by any Party.  The Parties also recognize that it may be desirable to agree upon other more detailed customary terms and conditions with respect to the Research Option Agreement.  Accordingly, as quickly as practicable following the Effective Date, the Parties will negotiate and enter into a more detailed research agreement that will include the terms set

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forth in the Research Term Sheet and any additional terms and conditions that are customary and reasonable for agreements of this type that may be agreed to by the Parties, including provisions relating to intellectual property ownership, prosecution and enforcement, regulatory matters, term and termination, indemnification and confidentiality (the “More Detailed Research Agreement”).

ARTICLE 3.
NON-COMPETE

3.1.                              Product.  During the term of the Product License, Isis and its Affiliates will not, directly or indirectly, and will not collaborate with, license or otherwise authorize any Third Party to, research, develop or commercialize any [***] apoB, except pursuant to (a) the agreements identified on Schedule 2.1.1, as they exist on the Execution Date, (b) Permitted Licenses, or (c) this Agreement, including the Product License, and the More Detailed Product Agreement.

ARTICLE 4.
[RESERVED]

ARTICLE 5.
REPRESENTATIONS AND WARRANTIES

5.1.                              Representations and Warranties of Both Parties.  Each Party hereby represents and warrants to the other Party as of both the Execution Date and Effective Date (collectively, the “General Representations and Warranties”) that:

5.1.1.                     it is a duly organized and validly existing corporation under the laws of its jurisdiction of incorporation;

5.1.2.                     it has the power and authority and the legal right to enter into this Agreement and perform its obligations hereunder, and that it has taken all necessary action on its part required to authorize the execution and delivery of this Agreement and the performance of its obligations hereunder;

5.1.3.                     the execution and delivery of this Agreement, the Product License and the Research Option Agreement and the performance of such Party’s obligations hereunder do not conflict with or violate any requirement of applicable law or any provision of its articles of incorporation or similar organizational documents, its bylaws, or the terms or provisions of any agreement or other instrument to which it is a party or by which it is bound, or any order, award, judgment or decree to which it is a party or by which it is bound; and

5.1.4.                     this Agreement has been duly executed and delivered on behalf of such Party and constitutes a legal, valid and binding obligation of such Party and is enforceable against it in accordance with its terms subject to the effects of bankruptcy, insolvency or other laws of general application affecting the enforcement of creditor rights and judicial principles affecting the availability of specific performance and general principles of equity, whether enforceability is considered

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a proceeding at law or equity.

5.2.                              Product Representations and Warranties.  Isis represents and warrants to Genzyme that the statements contained in this Section 5.2 (the “Product Representations and Warranties”) are true and correct as of the Execution Date and will be true as of the Effective Date, as though made as of the Effective Date, with each such representation and warranty subject only to such exceptions, if any, as are set forth in the particular section in the Disclosure Schedule attached hereto as Exhibit D that corresponds to the particular section number in this Agreement:

5.2.1.                     Schedule 1.20, Schedule 1.22, and Schedule 1.37 set forth true, correct and complete lists of all Isis Core Technology Patents, Isis Manufacturing and Analytical Patents, and Product-Specific Patents, respectively, and all Licensed Patents used in the development or commercialization of Mipomersen and existing as of the Execution Date and indicates whether each such Patent is owned by Isis or licensed by Isis from a Third Party and if so, identifies the licensor or sublicensor from which the Patent is licensed.

5.2.2.                     A true, correct and complete list of any Third Party Agreements related to Mipomersen is set forth on Schedule 5.2.2.

5.2.3.                     With respect to all Product-Specific Patents, and all Licensed IP used in the development or commercialization of Mipomersen, Isis has the sufficient legal and/or beneficial title and ownership or rights to grant the Product License to Genzyme and the grant of the Product License to Genzyme does not violate the terms of any Third Party Agreement or any other agreement Isis has with a Third Party.

5.2.4.                     Each of the Product-Specific Patents, and each of the Licensed Patents used in the development or commercialization of Mipomersen properly identifies each and every inventor of the claims thereof as determined in accordance with the laws of the jurisdiction in which such Patent is issued or such application is pending.

5.2.5.                     With respect to all Product-Specific Patents owned by Isis, and all Licensed Patents owned by Isis and used in the development or commercialization of Mipomersen, (a) each person who has or has had any rights in or to each of such Patents has executed an agreement assigning his, her or its entire right, title and interest in and to such Patents to Isis and (b) to the best of Isis’ knowledge, each such inventor has complied in all material respects with all applicable duties of candor and good faith in dealing with any patent office, including the duty to disclose to any applicable patent office all information known to be material to patentability.

5.2.6.                     To the best of Isis’ knowledge, no circumstances or grounds exist that would invalidate, reduce or eliminate, in whole or in part, the enforceability, validity or scope of any Product-Specific Patent or any Licensed Patent used in the development or commercialization of Mipomersen.

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5.2.7.    Isis is not aware of any Patents owned or Controlled by a Third Party that would be infringed by Genzyme during the development or commercialization of Mipomersen in its current form.

5.2.8.    To the best of Isis’ knowledge, no actions, suits, claims, disputes or proceedings concerning the Licensed Patents are currently pending or are threatened, that if determined adversely to Isis would have a material adverse effect on or would impair Genzyme’s rights under the Product License.

5.2.9.    Isis is not subject to any agreement with any Third Party or to any outstanding order, judgment or decree of any court or administrative agency that restricts it in any way from granting to Genzyme the Product License.

5.2.10.            Isis has not granted, or permitted to be attached, and it will not grant or permit to be attached, any lien, security interest or other encumbrance with respect to any Product-Specific Patent, or any Licensed IP used in the development or commercialization of Mipomersen which would adversely affect the rights granted to Genzyme hereunder.

5.2.11.            Each Third Party Agreement related to Mipomersen is in full force and effect, and Isis, and to the best of Isis’ knowledge, each counterparty thereto, is in compliance in all material respects with all such Third Party Agreements and no circumstances or grounds exist that would reasonably be expected to give rise to a claim of material breach or right of rescission, termination, revision or amendment of such Third Party Agreements.

5.2.12.            Isis has not assigned, licensed, sublicensed, granted any interest in or options to, or entered into an agreement with respect to the Licensed IP with a Third Party that would adversely impair Genzyme’s exclusive rights under this Agreement, except for the agreements identified on Schedule 2.1.1.

5.2.13.            Isis has not received any claim alleging that Isis’ development of Mipomersen or use of any Product-Specific Patent or any Licensed IP used in the development or commercialization of Mipomersen interferes with, infringes, or misappropriates any intellectual property rights of any Third Party (including any claim that Isis must license or refrain from using any intellectual property rights of any Third Party in order to develop, make, use, sell or offer for sale any product or technology using or incorporating the Licensed IP), and to the best of Isis’ knowledge, the development and commercialization of Mipomersen and the use of any Product-Specific Patent or any Licensed IP used in the development or commercialization of Mipomersen will not interfere with, infringe or misappropriate the intellectual property rights of any Third Party.  To the best of Isis’ knowledge, no Third Party has interfered with, infringed upon or misappropriated the Licensed IP in the making, using or selling of a lipid lowering product.

5.2.14.            Isis holds, and is operating in material compliance with, such exceptions, permits,

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licenses, franchises, authorizations and clearances of any governmental entity required in connection with the current development of Mipomersen.  Isis has not received any warning letters or written correspondence from any governmental entity requiring the termination, suspension or modification of any clinical or pre-clinical studies or tests with respect to Mipomersen.  Isis has conducted and required its contractors to conduct all clinical studies related to Mipomersen in accordance with cGCP, cGLP and applicable law.

5.2.15.            As of the Execution Date, Isis has prepared, maintained and retained all Regulatory Materials required to be maintained or reported pursuant to and in accordance with applicable laws and the Regulatory Materials do not contain any materially false or misleading statements.

5.2.16.            Except for the agreements identified on Schedule 2.1.1, Isis has not granted to any Third Party rights under the Licensed Patents to research, develop or commercialize any nucleic acid that hybridizes to a nucleic acid molecule encoding apoB.

5.3.      Research Representations and Warranties.  Isis represents and warrants to Genzyme that the statements contained in this Section 5.3 are true and correct as of the Execution Date and will be true as of the Effective Date, as though made as of the Effective Date, with each such representation and warranty subject only to such exceptions, if any, as are set forth in the particular section in the Disclosure Schedule attached hereto as Exhibit D that corresponds to the particular section number in this Agreement:

5.3.1.    To the best of Isis’ knowledge, no actions, suits, claims, disputes or proceedings are currently pending or are threatened, that if determined adversely to Isis would have a material adverse effect on or impair Isis’ ability to perform its obligations under the Research Option Agreement.

5.3.2.    Isis is not subject to any agreement with any Third Party or to any outstanding order, judgment or decree of any court or administrative agency that materially restricts Isis from performing its obligations under the Research Option Agreement.

5.3.3.    Isis has sufficient resources to perform the activities contemplated under the Research Option Agreement and the Isis personnel or permitted contractors performing such activities will be skilled, appropriately credentialed, licensed and qualified to provide the specific research services they are providing.

5.4.      Right to Update Disclosure Schedule Prior to Effective Date.  On or before the Effective Date, Isis may deliver to Genzyme an updated Disclosure Schedule reflecting any exceptions to the representations and warranties made by Isis as of the Effective Date.

5.5.      Isis Covenants.

5.5.1.    Third Party Agreements.  Isis covenants that it will not, without Genzyme’s prior written consent, agree, consent or acquiesce to any amendment, supplement or

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other modification to any Third Party Agreement or take any action under such Third Party Agreement or with respect to the intellectual property licensed thereunder that would adversely affect the rights granted to Genzyme under this Agreement, including under the Product License.

5.5.2.    Sublicense Survival.  Isis covenants that it will use good faith and commercially reasonable efforts to enter into any necessary amendments or side agreements to its Third Party Agreements to ensure that (a) sublicenses under each Third Party Agreement will survive termination of such Third Party Agreement or (b) Genzyme will receive a direct license from the counterparty to each Third Party Agreement upon termination of such Third Party Agreement.

5.5.3.    Notice of Developments.  During the Diligence Period, Isis will give Genzyme prompt written notice upon becoming aware of any development, event or circumstance that could reasonably be expected to result in a breach of or inaccuracy in any of the General Representations and Warranties and Product Representations and Warranties.

ARTICLE 6.
DISPUTE RESOLUTION

6.1.      Escalation.

6.1.1.    In the event any dispute, controversy or claim arises under, out of, in connection with or in relation to this Agreement, or the breach, termination, validity or enforceability of any provision hereof (a “Dispute”), the Parties will discuss and negotiate in good faith a solution acceptable to the Parties and in the spirit of this Agreement.  If, after negotiating in good faith pursuant to the foregoing sentence, the Parties fail to reach agreement within sixty (60) days, then the Dispute may be referred to the Chief Executive Officer of Genzyme and the Chief Executive Officer of Isis (the “Executives”) for resolution at the request of either Party.

6.1.2.    If the Executives fail, after good faith discussions, to reach an amicable agreement on the Dispute within ten (10) business days of submission to the Executives, then:

(a)       if the Dispute relates to the Parties’ failure to reach agreement with respect to the interpretation of this Agreement, the Product Term Sheet or Research Term Sheet or with respect to any term or condition to be included in the More Detailed Product Agreement or More Detailed Research Agreement, then either Party’s sole recourse is to submit such Dispute to binding arbitration pursuant to Section 6.2 (Binding Arbitration with Respect to Agreement Terms) after providing written notice to the other Party; and

(b)       if the Dispute relates to any other matter, either Party may pursue a legal remedy in accordance with Section 6.3 (Jurisdiction, Venue, Service of Process).

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6.2.      Binding Arbitration With Respect to Agreement Terms.

6.2.1.    If the Parties fail to reach agreement with respect to the interpretation of this Agreement, the Product Term Sheet or Research Term Sheet or with respect to any term or condition to be included in the More Detailed Product Agreement or More Detailed Research Agreement and the Dispute is not resolved informally through negotiation between the Parties or the Executives, then the Dispute will be submitted to binding arbitration.  The Parties will select a mutually agreeable arbitrator experienced in matters regarding contracts of a similar nature who (a) is a lawyer with at least fifteen (15) years experience who has extensive experience negotiating and drafting license, research and collaboration agreements among biotechnology and pharmaceutical companies and (b) has no affiliation or pre-existing relationship with either Genzyme or Isis or their respective Affiliates.  If the Parties are unable to agree on an arbitrator within a thirty (30) day period, then each Party will select an arbitrator satisfying the criteria described in the immediately preceding sentence within five (5) business days, the two (2) designated arbitrators will select a mutually agreeable third arbitrator satisfying the criteria described in the immediately preceding sentence within five (5) business days and all three (3) arbitrators will hear the Dispute as a panel and render a decision upon the determination of the majority of the panel.  In each case, the arbitrator(s) will render their decision by supplying the term or condition upon which the Parties failed to agree.

6.2.2.    The arbitration will be conducted in accordance with the rules of, and under the auspices of, the American Arbitration Association (the “AAA”).  The decisions rendered by the arbitrators will be final and binding, and the Parties will not have any right of appeal to any court on the merits of the Dispute.  Judgment upon the award rendered in any such arbitration may be entered in any court having jurisdiction thereof.  The location of the arbitration will be Chicago, Illinois.  This Agreement and the Product License and Research Option Agreement will remain in effect pending completion of the proceedings brought under this Section 6.2.  Each Party will bear its own costs and expenses with respect to any such arbitration, including one-half of the fees and expenses of the arbitrator.

6.3.      Jurisdiction; Venue; Service of Process.

6.3.1.    Jurisdiction.  Each Party by its execution hereof, (a) hereby irrevocably submits to the exclusive jurisdiction of the United States District Court located in Chicago, Illinois for the purpose of any Dispute arising between the Parties in connection with this Agreement, other than those Disputes that must be resolved by binding arbitration pursuant to Section 6.2 (Binding Arbitration With Respect to Agreement Terms) (each, an “Action”), and (b) hereby waives to the extent not prohibited by applicable law, and agrees not to assert, by way of motion, as a defense or otherwise, in any such Action, any claim that it is not subject personally to the jurisdiction of the above-named court, that its property is exempt or immune from attachment or execution, that any such Action brought in the above-named court should be dismissed on grounds of forum non conveniens,

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should be transferred or removed to any court other than the above-named court, or should be stayed by reason of the pendency of some other proceeding in any other court other than the above-named court, or that this Agreement or the subject matter hereof may not be enforced in or by such court and (c) hereby agrees not to commence any such Action other than before the above-named court.  Notwithstanding the previous sentence a Party may commence any Action in a court other than the above-named court solely for the purpose of enforcing an order or judgment issued by the above-named court.

6.3.2.    Venue.  Each Party agrees that for any Action between the Parties arising in whole or in part under or in connection with this Agreement, such Party bring Actions only in the federal courts of the United States of America located in Chicago, Illinois and any appellate court having jurisdiction over appeals from such courts.  Each Party further waives any claim and will not assert that venue should properly lie in any other location within the selected jurisdiction.

6.3.3.    Service of Process.  Each Party hereby agrees that service of process made by registered or certified mail, return receipt requested, at its address specified pursuant to Section 8.5 (Notices), will constitute good and valid service of process in any such Action and (c) waives and agrees not to assert (by way of motion, as a defense, or otherwise) in any such Action any claim that service of process made in accordance with clause (a) or (b) does not constitute good and valid service of process.

ARTICLE 7.
CONDITIONS PRECEDENT AND TERMINATION

7.1.      Conditions Precedent.

7.1.1.    HSR Compliance.

(a)       Each Party will use commercially reasonable efforts to satisfy any applicable requirements under the HSR, and the regulations promulgated thereunder, including by making an initial HSR filing no later than five (5) days after the Execution Date or upon such other timing as mutually agreed by the Parties.

(b)       Each Party will cooperate with the other Party in the prompt preparation, execution and filing of all documents that are required or permitted to be filed pursuant to HSR, and to notify the other Party upon receipt of any formal or informal requests for information from any government agency in connection with any filings under HSR.  Each Party will bear its own costs with respect thereto (except the filing fees for HSR, which will be paid by Genzyme).

7.1.2.    Effective Date.  This Agreement will not be effective until the date (the “Effective Date”) the requirements described in Section 7.1.1 have been satisfied and all applicable waiting periods (including any extensions thereof) under HSR have

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expired or been terminated.  All obligations, rights, duties and liabilities under this Agreement (except those contained in this Section 7.1 (Conditions Precedent), Article 3 (Non-Compete), Article 5 (Representations and Warranties) and Article 8 (Miscellaneous) of this Agreement) are subject to such date.

7.1.3.    Party’s Termination Right.  If the Effective Date has not occurred within ninety (90) days after the Execution Date, notwithstanding that each Party has fulfilled its obligations under this Section 7.1, either Party has the right to terminate this Agreement without liability to the other Party by notice in writing with immediate effect; provided, however, that if the Parties receive a request for more information from a government agency in connection with the HSR filing, the Parties will mutually agree to extend the ninety (90) day period for a reasonable period of time.

7.2.      Isis’ Right to Terminate.  If either (a) after the satisfaction or waiver of the closing conditions set forth in Section 5.2 of the Stock Purchase Agreement, Genzyme has not paid Isis the Purchase Price for the Shares by the Closing Date (as required by and defined in the Stock Purchase Agreement) or (b) Genzyme fails to pay the upfront license fee when due under Section 2.1.4 (Upfront License Fee), Isis has the right to terminate this Agreement without liability to Genzyme by notice in writing with immediate effect if Genzyme has failed to cure such non-payment within a reasonable period of time after receiving written notice from Isis of such failure to pay.

7.3.      Termination by Genzyme.  The Parties have negotiated and entered into this Agreement (but not the Stock Purchase Agreement) on an abbreviated schedule that has not permitted Genzyme to complete a customary due diligence review and analysis of the Product’s clinical data, regulatory history, relevant Isis and Third Party intellectual property, and relevant Third Party Agreements, and intend for Genzyme to conduct and complete such a due diligence review and analysis during the Diligence Period.  Therefore, Genzyme may terminate the Product License with immediate effect by providing written notice to Isis at any time during the Diligence Period if, based on its due diligence review and analysis, Genzyme concludes in good faith that the value of the Product License is significantly reduced.  For purposes of clarification, this Section 7.3 does not give Genzyme the right to terminate the Stock Purchase Agreement.

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ARTICLE 8.
MISCELLANEOUS

8.1.      Confidentiality.

8.1.1.    Non-Disclosure.  Genzyme and Isis agree that all information relating to the Licensed IP, the terms and conditions of this Agreement (including the Product Term Sheet and Research Term Sheet), or any activities conducted in connection with or pursuant to this Agreement and disclosed by either Party in accordance with this Agreement (“Confidential Information”) will be used and disclosed by the receiving Party only to perform its obligations and exercise its rights under this Agreement.  Information relating to the development of the Product, the Licensed IP and the terms and conditions of this Agreement will be considered the Confidential Information of both Parties under the Agreement, as if both Parties were receiving Parties.  Notwithstanding the foregoing, “Confidential Information” will not include information that the receiving Party can establish:

(a)       was already known by the receiving Party (other than under an obligation of confidentiality) at the time of disclosure by the disclosing Party;

(b)       was generally available to the public or otherwise part of the public domain at the time of its disclosure to the receiving Party;

(c)       became generally available to the public or otherwise part of the public domain after its disclosure or development, as the case may be, other than through any act or omission of the receiving Party or any of its Affiliates;

(d)       was disclosed to the receiving Party, other than under an obligation of confidentiality, by a Third Party who had no obligation to the disclosing Party not to disclose such information to others; or

(e)       was independently discovered or developed by or on behalf of the receiving Party without the use of any Confidential Information belonging to the disclosing Party.

8.1.2.    Authorized Disclosure and Use.  Notwithstanding the foregoing provisions of Section 8.1.1, each Party may disclose Confidential Information belonging to the other Party to the extent such disclosure is reasonably necessary to:

(a)       prosecute or defend litigation,

(b)       comply with applicable governmental laws and regulations (including the rules and regulations of the SEC); or

(c)       make filings and submissions to, or correspond or communicate with, any government authority.

In the event a Party deems it reasonably necessary to disclose Confidential

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Information belonging to the other Party pursuant to clauses (a), (b) and (c) of this Section 8.1.2, the disclosing Party will to the extent possible give reasonable advance notice of such disclosure to the other Party and take reasonable measures to ensure confidential treatment of such information.

8.2.      Specific Performance.  Each Party acknowledges and agrees that, in the event of any breach of this Agreement by such Party or any of its Affiliates, the non-breaching Party may be irreparably and immediately harmed and may not be able to be made whole by monetary damages.  Without prejudice to any rights and remedies otherwise available, the non-breaching Party will be entitled to seek equitable relief by way of injunction, specific performance or otherwise if the breaching Party or any of its Affiliates breaches any provision of this Agreement.

8.3.      Governing Law.  This Agreement will be governed by and interpreted in accordance with the laws of the State of New York without reference to its choice of laws or conflicts of laws provisions.

8.4.      Waiver.  The failure by either Party to take any action or assert any right hereunder will in no way be construed to be a waiver of such right, nor in any way be deemed to affect the validity of this Agreement or any part hereof, or the right of a Party to thereafter enforce each and every provision of this Agreement.

8.5.      Notices.  Any consent or notice required or permitted to be given or made under this Agreement by one of the Parties hereto to the other will be in writing and delivered by hand or sent by nationally recognized overnight delivery service, prepaid registered or certified air mail, or by facsimile confirmed by prepaid, registered or certified mail letter, and will be deemed to have been properly served to the addressee upon receipt of such written communication, in any event to the following addresses (or any updated address provided to the notifying Party in writing in accordance with this Section 8.5):

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8.6.      Entire Agreement.  This Agreement and all Exhibits and Schedules attached hereto (the terms of which are incorporated herein by reference) sets forth all the covenants, promises, agreements, warranties, representations, conditions and understandings between the Parties hereto with respect to the subject matter hereof and supersedes and terminates all prior agreements (including the Confidential Disclosure and Standstill Agreement dated September 19, 2007 between the Parties) and understandings between the Parties and constitutes the entire agreement between the Parties with respect to the subject matter hereof.  All Exhibits and Schedules referred to herein and other attachments hereto are intended to be, and hereby are, specifically incorporated herein and made a part of this Agreement.  No subsequent alteration, amendment or modification to this Agreement will be binding upon the Parties unless in writing and duly executed by authorized representatives of both Parties.

8.7.      Binding Effect; Assignment.  This Agreement will inure to the benefit of and be binding upon the Parties and their respective successors and permitted assigns.  Neither Party will assign this Agreement or any of its rights or obligations hereunder without the prior written consent of the other Party; provided, however, that Genzyme  may assign this Agreement or its rights or obligations hereunder to any of its Affiliates.

8.8.      Press Releases.  Except as required by applicable law, neither Party will give notice to any Third Party or otherwise make any public statement or releases concerning this Agreement or the transactions contemplated hereby without obtaining the prior written consent of the other Party to this Agreement as to the contents and manner of presentation and publication thereof, which consent will not be unreasonably withheld, delayed or conditioned.

8.9.      Severability.  If any term, covenant or condition of this Agreement or the application thereof to any Party or circumstance, to any extent, is invalid or unenforceable, then (a) the remainder of this Agreement, or the application of such term, covenant or condition to Parties or circumstances other than those as to which it is invalid or unenforceable, will not be affected thereby and each term, covenant or condition of this Agreement will be valid and be enforced to the fullest extent permitted by law; and (b) the Parties hereto covenant and agree to renegotiate any such term, covenant or application thereof in good faith in order to provide a reasonably acceptable alternative to the term, covenant or condition of this Agreement or the application thereof that is invalid or unenforceable, it being the intent of the Parties that the basic purposes of this Agreement are to be effectuated.

8.10.     Further Assurances.  Each Party will execute such other instruments, give such further

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assurances and perform such acts which are or may become necessary or appropriate to effectuate and carry out the provisions and intent of this Agreement.

8.11.     Independent Contractors.  The status of the Parties under this Agreement will be that of independent contractors.  No Party will have the right to enter into any agreements on behalf of the other Party, nor will it represent to any Third Party that it has any such right or authority.  Nothing in this Agreement will be construed as establishing a partnership or joint venture relationship between the Parties hereto.

8.12.     Interpretation.  The article and section headings herein are for reference purposes only and will not affect the meaning or interpretation hereof.  The term “including” (or any variation thereof such as “include”) will be without limitation.

8.13.     Counterparts.  This Agreement may be executed in one or more counterpart copies, and by facsimile signature, each of which will be deemed an original and all of which taken together will be deemed to constitute one and the same instrument.

8.14.     Rights in Bankruptcy.  All rights and licenses now or hereafter granted under or pursuant to this Agreement, the Product Term Sheet and the Research Term Sheet, including Section 2.1 of this Agreement, are rights to “intellectual property” (as defined in Section 101(35A) of Title 11 of the United States Code, as amended (such Title 11, the “Bankruptcy Code”)).  Isis hereby grants to Genzyme and all Affiliates of Genzyme a right of access and to obtain possession of and to benefit from (a) copies of research data, (b) laboratory samples, (c)  samples of Product, (d) formulas, (e) laboratory notes and notebooks, (f) data and results related to clinical trials, (g) regulatory filings and approvals, (h) rights of reference in respect of regulatory filings and approvals, (i) pre-clinical research data and results, and (j) marketing, advertising and promotional materials, all of which constitute “embodiments” of intellectual property pursuant to Section 365(n) of the Bankruptcy Code, and (k) all other embodiments of such intellectual property, in each case, solely in connection with Genzyme’s rights under the Product License and the Research Option Agreement, whether any of the foregoing are in Isis’ possession or control or in the possession and control of Third Parties.  Isis agrees not to interfere with Genzyme’s and its Affiliates’ exercise of rights and licenses to intellectual property licensed hereunder and embodiments thereof in accordance with this Agreement and agrees to use commercially reasonable efforts to assist Genzyme and its Affiliates to obtain such intellectual property and embodiments thereof in the possession or control of Third Parties as reasonably necessary or desirable for Genzyme or its Affiliates to exercise such rights and licenses in accordance with this Agreement.  The Parties hereto acknowledge and agree that all payments by Genzyme to Isis in the Product Term Sheet, other than the Profit Sharing and Sales Milestones referred to in the Product Term Sheet, do not constitute “royalties” within the meaning of Bankruptcy Code §365(n) or relate to licenses of intellectual property hereunder.

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IN WITNESS WHEREOF, the Parties have caused this License and Research Agreement to be executed by their officers thereunto duly authorized as of the date first written above.

SCHEDULE 1.20

ISIS CORE TECHNOLOGY PATENTS

[***]

SCHEDULE 1.22

ISIS MANUFACTURING & ANALYTICAL PATENTS

[***]

SCHEDULE 1.37

PRODUCT-SPECIFIC PATENTS

[***]

Schedule 2.1.1

Licenses to Third Parties

[***]

2

Schedule 5.2.2

Third Party Agreements

[***]

Exhibit A

Stock Purchase Agreement

Execution Version

STOCK PURCHASE AGREEMENT

THIS STOCK PURCHASE AGREEMENT (“Agreement”) is entered into as of January 7, 2008, by and between GENZYME CORPORATION, a Massachusetts corporation ( “Genzyme”), and ISIS PHARMACEUTICALS, INC., a Delaware corporation (“Isis”).