AMENDED AND RESTATED COLLABORATION AGREEMENT BY AND BETWEEN ALNYLAM PHARMACEUTICALS, INC. AND MEDTRONIC, INC

Collaboration Agreement

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Title: AMENDED AND RESTATED COLLABORATION AGREEMENT BY AND BETWEEN ALNYLAM PHARMACEUTICALS, INC. AND MEDTRONIC, INC
Governing Law: Delaware Date: 11/8/2007
Industry: BIOTRX Law Firm: Wilmer Cutler Pickering Hale and Dorr LLP Sector: Healthcare

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CONFIDENTIAL		EXECUTION COPY

Exhibit 10.4

Confidential Materials omitted and filed separately with the
Securities and Exchange Commission. Asterisks denote omissions.

AMENDED AND RESTATED

COLLABORATION AGREEMENT

BY AND BETWEEN

ALNYLAM PHARMACEUTICALS, INC.

AND

MEDTRONIC, INC.

Table of Contents


	Page
Article I Definitions		1
Section 1.1 “Affiliate”		1
Section 1.2 “Alnylam Intellectual Property”		2
Section 1.3 “Alnylam Know-How”		2
Section 1.4 “Alnylam Patent Rights”		2
Section 1.5 “Alnylam siRNA”		2
Section 1.6 “Blocking Third Party Intellectual Property”		2
Section 1.7 “[**]”		2
Section 1.8 “Collaboration Program”		3
Section 1.9 “Collaboration Term”		3
Section 1.10 “Commercialization” or “Commercialize”		3
Section 1.11 “Commercializing Party”		3
Section 1.12 “Commercially Reasonable Efforts”		3
Section 1.13 “Confidential Information”		3
Section 1.14 “Control” or “Controlled”		4
Section 1.15 “Cover”, “Covering” or “Covered”		4
Section 1.16 “CPI”		4
Section 1.17 “Develop” or “Development”		4
Section 1.18 “Development Candidate”		4
Section 1.19 “Development Costs”		4
Section 1.20 “Device”		5
Section 1.21 “Device-Related”		5
Section 1.22 “Discover” or “Discovery”		5
Section 1.23 “[**]”		5
Section 1.24 “Effective Date”		5
Section 1.25 “Exclusivity Field”		5
Section 1.26 “Executive Officers”		5
Section 1.27 “FDA”		5
Section 1.28 “Field”		5
Section 1.29 “First Commercial Sale”		5
Section 1.30 “FTE Cost”		5
Section 1.31 “GAAP”		6
Section 1.32 “Gene Target”		6
Section 1.33 “IND”		6
Section 1.34 “Initial PDP Workplan”		6
Section 1.35 “Initial Product Development Program”		6
Section 1.36 “JCC Representative”		6
Section 1.37 “JRDC Representative”		6
Section 1.38 “[**] Agreement”		6
Section 1.39 “Know-How”		6
Section 1.40 “Launch Costs”		6
Section 1.41 “Licensed Product”		7
Section 1.42 “Listed or Approved Third Party Agreement”		7


	Page
Section 1.43 “Major Market”		7
Section 1.44 “Manufacturing Cost”		7
Section 1.45 “Medtronic Device”		7
Section 1.46 “Medtronic Fiscal Quarter”		8
Section 1.47 “Medtronic Fiscal Year”		8
Section 1.48 “Medtronic Intellectual Property”		8
Section 1.49 “Medtronic Know-How”		8
Section 1.50 “Medtronic Patent Rights”		8
Section 1.51 “NDA”		8
Section 1.52 “Net Sales”		8
Section 1.53 “Neurodegenerative Disease”		9
Section 1.54 “Party”		9
Section 1.55 “Patent Rights”		9
Section 1.56 “Person”		9
Section 1.57 “Phase I Study”		9
Section 1.58 “Phase II(a) Study”		9
Section 1.59 “Phase II(b) Study”		10
Section 1.60 “Phase III Study”		10
Section 1.61 “[**] Opt Out”		10
Section 1.62 “[**] Opt Out”		10
Section 1.63 “[**] Opt Out”		10
Section 1.64 “[**] Opt Out”		10
Section 1.65 “Preliminary Success Criteria”		10
Section 1.66 “Primary Sequence or Chemical Modification Know-How”		10
Section 1.67 “Product”		10
Section 1.68 “Product Development Program”		10
Section 1.69 “Product Development Term”		11
Section 1.70 “Program Intellectual Property”		11
Section 1.71 “Program Know-How”		11
Section 1.72 “Program Patent Rights”		11
Section 1.73 “Regulatory Approval”		11
Section 1.74 “Regulatory Authority”		11
Section 1.75 “ROW Territory”		11
Section 1.76 “Royalty Term”		11
Section 1.77 “Section 2.5(d)(iii) [**] Agreement”		12
Section 1.78 “siRNA”		12
Section 1.79 “Target Indication”		12
Section 1.80 “Territory”		12
Section 1.81 “Third Party”		12
Section 1.82 “US Territory”		12
Section 1.83 “Valid Claim”		12
Section 1.84 “Workplan”		12
Section 1.85 Additional Definitions		12

Article II Collaboration Program; Commercialization		14
Section 2.1 General		14
Section 2.2 Governance; Decision-Making		14


	Page
Section 2.3 Conduct of the Collaboration Program		17
Section 2.4 Right to Opt Out		20
Section 2.5 Exclusivity, Diligence and RoFN Obligations		22
Section 2.6 Supply of Alnylam siRNAs		24
Section 2.7 SAB Observer Right		25

Article III Grant of Rights		25
Section 3.1 Alnylam Grants		25
Section 3.2 Medtronic Grants		27
Section 3.3 Retained Rights		29

Article IV Financial Provisions		29
Section 4.1 Development Cost and Launch Cost Sharing		29
Section 4.2 Milestone Payments for Product Development Programs		30
Section 4.3 Royalty Payments		31
Section 4.4 Duration of Royalty Payments		33
Section 4.5 Royalties Payable Only Once		33
Section 4.6 Credits Against Future Royalties		33

Section 4.7 Quarterly Reconciliation of Development Costs and Net Sales; Royalty Reports and Accounting		34
Section 4.8 Currency Exchange		35
Section 4.9 Tax Withholding		35
Section 4.10 Late Payments		35

Article V Intellectual Property Ownership, Protection and Related Matters		36
Section 5.1 Ownership of Inventions		36
Section 5.2 Prosecution and Maintenance of Patent Rights		37
Section 5.3 Third Party Infringement		38
Section 5.4 Claimed Infringement; Claimed Invalidity		40
Section 5.5 Patent Term Extensions		41
Section 5.6 Patent Marking		41
Section 5.7 Maintain Licenses in Force		41

Article VI Confidentiality		41
Section 6.1 Confidential Information		42
Section 6.2 Disclosures to Employees, Consultants and Advisors		42
Section 6.3 Term		42
Section 6.4 Publicity		42
Section 6.5 Publications		43

Article VII Representations and Warranties		43
Section 7.1 Representations of Authority		44
Section 7.2 Consents		44
Section 7.3 No Conflict		44
Section 7.4 Enforceability		44
Section 7.5 Employee Obligations		44
Section 7.6 Intellectual Property		44

iii


	Page
Section 7.7 No Warranties		45

Article VIII Term and Termination		45
Section 8.1 Term		45
Section 8.2 Termination For Material Breach		45
Section 8.3 Termination Upon No-Go Decision		46
Section 8.4 Effect of Termination		46
Section 8.5 Survival		49

Article IX Miscellaneous Provisions		50
Section 9.1 Indemnification		50
Section 9.2 Governing Law and Waiver of Jury Trial		51
Section 9.3 Assignment		52
Section 9.4 Entire Agreement; Amendments		52
Section 9.5 Notices		52
Section 9.6 Force Majeure		53
Section 9.7 Independent Contractors		53
Section 9.8 No Strict Construction		54
Section 9.9 Headings		54
Section 9.10 No Implied Waivers; Rights Cumulative		54
Section 9.11 Severability		54
Section 9.12 Execution in Counterparts; Facsimile Signatures		54
Section 9.13 No Consequential or Punitive Damages		54
Section 9.14 Interpretation		54


Schedules
Schedule 1.4		Alnylam Patent Rights
Schedule 1.42		Listed or Approved Third Party Agreements
Schedule 3.1(d)		Existing Third Party Contractual Obligations of Alnylam
Schedule 3.2(d)		Existing Third Party Contractual Obligations of Medtronic
Schedule 4.3(h)		Payments Under Listed or Approved Third Party Agreements

Exhibits
Exhibit A		siRNA Supply Agreement Principal Terms
Exhibit B		Press Release
Exhibit C		Permitted Disclosures
Exhibit D		Device Supply Agreement Principal Terms

AMENDED AND RESTATED COLLABORATION AGREEMENT

This Amended and Restated Collaboration Agreement (this “ Agreement ”) is entered into as of the 27th day of July, 2007 (the “ Restatement Date ”), by and between Alnylam Pharmaceuticals, Inc., a corporation organized and existing under the laws of the State of Delaware and having its principal office at 300 Third Street, Cambridge, Massachusetts 02142 (“ Alnylam ”), and Medtronic, Inc., a corporation organized and existing under the laws of the State of Minnesota and having its principal office at 710 Medtronic Parkway, Minneapolis, Minnesota 55432 (“ Medtronic ”).

INTRODUCTION

1. Alnylam is engaged in the business of discovering and developing siRNA-based therapeutics.

2. Medtronic is engaged in the business of developing and marketing medical devices.

3. On the Effective Date, Alnylam and Medtronic entered into a Collaboration Agreement (as amended prior to the Restatement Date, the “ Original Collaboration Agreement ”), pursuant to which Alnylam and Medtronic agreed to collaborate on the discovery, development, manufacture and commercialization of siRNA-based therapeutics for the treatment of certain diseases using implanted infusion devices for the direct delivery of siRNAs to the human nervous system.

4. Alnylam and Medtronic now desire to amend and restate the Original Collaboration Agreement to reflect their joint determination to commence and carry out the Initial Product Development Program and to otherwise modify the terms of their collaboration on the discovery, development, manufacture and commercialization of siRNA-based therapeutics as set forth herein.

NOW, THEREFORE, in consideration of the respective representations, warranties, covenants and agreements contained herein, and for other valuable consideration, the receipt and adequacy of which are hereby acknowledged, Alnylam and Medtronic hereby amend and restate the Original Collaboration Agreement in its entirety as follows:

Article I

Definitions

When used in this Agreement, each of the following terms shall have the meanings set forth in this Article I:

Section 1.1 “ Affiliate ”. Affiliate of a specified Person shall mean any Person that controls, is controlled by, or is under common control with such Person. For purposes of this Section 1.1 and Section 9.3, “control” shall mean (a) in the case of corporate entities, direct or indirect ownership of at least fifty percent (50%) of the stock or shares having the right to vote for the election of directors, and (b) in the case of non-corporate entities, direct or indirect

ownership of at least fifty percent (50%) of the equity interest with the power to direct the management and policies of such non-corporate entities.

Section 1.2 “ Alnylam Intellectual Property ”. Alnylam Intellectual Property shall mean Alnylam Know-How and Alnylam Patent Rights, collectively.

Section 1.3 “ Alnylam Know-How ”. Alnylam Know-How shall mean any Know-How, other than Know-How related to [**] and other than Program Know-How, that is (a) developed or acquired by Alnylam prior to or during the Collaboration Term, (b) used to Discover, Develop, manufacture or Commercialize Alnylam siRNAs, Medtronic Devices and/or Licensed Products, and (c) Controlled by Alnylam and (i) used by Alnylam in the Collaboration Program and/or (ii) identified during a Product Development Program as Know-How that will be used in the Commercialization of Licensed Products to be Developed in such Product Development Program.

Section 1.4 “ Alnylam Patent Rights ”. Alnylam Patent Rights shall mean any Patent Rights Controlled by Alnylam and Covering Alnylam Know-How, including those Patent Rights set forth on Schedule 1.4 , but excluding Alnylam’s interest in Program Patent Rights. The Parties acknowledge that Schedule 1.4 attached as of the Restatement Date is identical to Schedule 1.5 of the Original Collaboration Agreement and has not been modified since the Effective Date. Alnylam will provide Medtronic with an update to Schedule 1.4 within thirty (30) days after the Restatement Date.

Section 1.5 “ Alnylam siRNA ”. Alnylam siRNA shall mean any siRNA (a) the Discovery, Development, manufacture, Commercialization or other use of which uses Alnylam Know-How or Program Know-How or is Covered by Alnylam Patent Rights or Program Patent Rights and (b) that is made available or approved by Alnylam’s JRDC Representatives for Development in the Collaboration Program. Subject to Alnylam’s further development obligations pursuant to the siRNA Supply Agreement, if Alnylam opts out of a Product Development Program pursuant to Section 2.4(a), the Alnylam siRNAs with respect to the Licensed Product being developed in such Product Development Program shall be the Alnylam siRNAs made available by Alnylam’s JRDC Representatives for use in the Development of a Licensed Product in such Development Program prior to such opt-out.

Section 1.6 “ Blocking Third Party Intellectual Property ”. Blocking Third Party Intellectual Property shall mean, on a Licensed Product-by-Licensed Product and country-by-country basis, Valid Claims that (a) were not Controlled by Medtronic or by Alnylam as of the Restatement Date, (b) are not acquired or licensed by Medtronic or Alnylam, or any of their Affiliates, from a Third Party after the Restatement Date pursuant to a Section 2.5(d)(iii) [**] Agreement, and (c) Cover the manufacture or use of an siRNA or a Device contained in or used in such Licensed Product in such country. For the avoidance of doubt, Valid Claims Controlled by Alnylam or Medtronic under a [**] shall not constitute Blocking Third Party Intellectual Property.

Section 1.7 “[**] shall mean achievement of [**] criteria, determined pursuant to Section 2.3(a), for a Product Development Program as constituting reasonable evidence of [**].

Section 1.8 “ Collaboration Program ”. Collaboration Program shall mean the research and development program performed by the Parties pursuant to the Original Collaboration Agreement and to be performed by the Parties pursuant to this Agreement, to Develop Licensed Products.

Section 1.9 “ Collaboration Term ”. Collaboration Term shall mean the period commencing on the Effective Date and ending on the earliest of (a) the expiration or termination of all Product Development Terms, (b) the date (if any) on which the Collaboration Term is terminated by mutual written agreement of the Parties and (c) the date of termination of this Agreement in accordance with the provisions hereof.

Section 1.10 “ Commercialization” or “Commercialize ”. Commercialization or Commercialize shall mean any activities directed to marketing, promoting, distributing, importing, offering to sell, and/or selling a product, whether before or after Regulatory Approval for such product has been obtained.

Section 1.11 “ Commercializing Party ”. Commercializing Party shall mean, with respect to each Licensed Product and each country in the Territory, Medtronic, unless and until Alnylam becomes the Commercializing Party for such Licensed Product in such country due to (a) the exercise by Medtronic of its opt-out right pursuant to Section 2.4(b) or (b) Alnylam’s termination of Medtronic’s license rights relating to such Licensed Product in such country pursuant to Section 8.2.

Section 1.12 “ Commercially Reasonable Efforts ”. Commercially Reasonable Efforts shall mean the efforts, expertise and resources normally used by a Party to Discover, Develop, manufacture and Commercialize a product or compound owned by it or to which it has rights, which is of similar market potential at a similar stage in its development or product life, taking into account issues of safety and efficacy, product profile, difficulty in developing the product or compound, competitiveness of the marketplace for the product, the proprietary position of the compound or product, the regulatory structure involved, the availability and level of reimbursement for such treatment by Third Party payors or health insurance plans, the potential total profitability of the applicable product(s) marketed or to be marketed and other relevant factors affecting the cost, risk and timing of Development and the total potential reward to be obtained if a product is Commercialized. The Parties agree that Commercially Reasonable Efforts shall not require a Party to expend efforts, expertise and resources that such Party would not normally expend to Discover, Develop, manufacture and Commercialize a product or compound owned by it or to which it has rights, taking into account the foregoing factors.

Section 1.13 “ Confidential Information ”. Confidential Information of a Party shall mean all Know-How or other information that is of a confidential and proprietary nature to such Party. Confidential Information includes Know-How or other information (whether or not patentable) regarding a Party’s technology, products, business information or objectives and reports and audits under Section 4.7, and all biological materials of a Party. Notwithstanding the foregoing, Confidential Information shall not include Know-How or other information that:

(a) was known or used by the receiving Party or its Affiliates prior to its date of disclosure to the receiving Party as demonstrated by contemporaneous written records; or

(b) either before or after the date of the disclosure to the receiving Party is lawfully disclosed to the receiving Party or its Affiliates by sources other than the disclosing Party rightfully in possession of such Know-How or other information and not bound by confidentiality obligations to the disclosing Party; or

(c) either before or after the date of the disclosure to the receiving Party or its Affiliates is or becomes published or otherwise is or becomes part of the public domain through no breach hereof on the part of the receiving Party or its Affiliates; or

(d) is independently developed by or for the receiving Party or its Affiliates without reference to or reliance upon the Confidential Information of the disclosing Party as demonstrated by contemporaneous written records.

Section 1.14 “ Control” or “Controlled ”. Control or Controlled, with respect to any (a) Know-How or other information or materials or (b) intellectual property right, shall mean the possession (whether by license or ownership) by a Party of the ability to grant to the other Party access and/or a license as provided herein without violating the terms of any agreement with any Third Party existing as of the Effective Date or thereafter during the term of the Original Collaboration Agreement or this Agreement.

Section 1.15 “ Cover ”, “ Covering ” or “ Covered ”. Cover, Covering or Covered, with respect to a product or technology, shall mean that, but for a license granted to a Person under a Valid Claim included in the Patent Rights under which such license is granted, the Discovery, Development, manufacture, Commercialization and/or other use of such product or practice of such technology by such Person would infringe such Valid Claim.

Section 1.16 “ CPI ”. CPI shall mean the Consumer Price Index – Urban Wage Earners and Clerical Workers, U.S. City Average, All Items, 1982-84 = 100, published by the United States Department of Labor, Bureau of Labor Statistics (or its successor equivalent index) in the United States.

Section 1.17 “ Develop” or “Development ”. Develop or Development shall mean preclinical and clinical siRNA and/or Device development activities, including test method development and stability testing, Device design, siRNA-Device compatibility testing, toxicology, animal efficacy studies, formulation, quality assurance/quality control development, statistical analysis, clinical studies, regulatory affairs, product approval and registration.

Section 1.18 “ Development Candidate ”. Development Candidate shall mean an Alnylam siRNA that is designated as a Development Candidate by mutual agreement of the Parties.

Section 1.19 “ Development Costs ”. Development Costs shall mean FTE Costs incurred and costs and expenses paid to Third Parties (or payable to Third Parties and accrued in accordance with GAAP) by either Party after the Restatement Date, in the performance of Development responsibilities assigned to such Party under a Workplan in accordance with a budget under such Workplan that has been approved by the JRDC.

Section 1.20 “ Device ”. Device shall mean any implanted infusion device for delivery of siRNAs to the human nervous system.

Section 1.21 “ Device-Related ”. Device-Related, with respect to Know-How or Patent Rights, shall mean relating specifically to the design or physical features of a Device, any [**] a Device (excluding [**]), any hardware component of a Device, any software that controls a Device and/or any associated medical devices or accessories, such as [**], and any use or implantation of any of the foregoing, but not relating specifically to an siRNA ([**]) to be delivered by such Device.

Section 1.22 “ Discover” or “Discovery ”. Discover or Discovery shall mean any activities conducted to discover and characterize siRNAs as potential therapeutics in the Field and to support the designation of the same as Development Candidates in connection with any Product Development Program.

Section 1.23 “[**] shall mean an [**] produced [**].

Section 1.24 “ Effective Date ”. Effective Date shall mean February 8, 2005.

Section 1.25 “ Exclusivity Field ”. Exclusivity Field, with respect to a [**], shall mean the treatment of Target Indications for which a Licensed Product is to be Commercialized, using Devices for the direct delivery of siRNAs to the human nervous system [**]. Notwithstanding the foregoing, (a) the Exclusivity Field shall not include [**] and (b) the term ‘direct delivery to the human nervous system’ does not encompass [**].

Section 1.26 “ Executive Officers ”. Executive Officers shall mean Medtronic’s Senior Vice President of Medicine and Technology, Medtronic’s Vice President Corporate Technologies and New Ventures, or the President of Medtronic’s Neurological division (or an officer or employee of Medtronic then serving in a substantially equivalent capacity) and Alnylam’s Chief Operating Officer (or the officer or employee of Alnylam then serving in a substantially equivalent capacity).

Section 1.27 “ FDA ”. FDA shall mean the United States Food and Drug Administration.

Section 1.28 “ Field ”. Field shall mean the treatment of Neurodegenerative Diseases using Devices for the direct delivery of siRNAs to the human nervous system [**], it being understood that “direct delivery to the human nervous system” does not encompass [**]. For the avoidance of doubt, the Parties agree that treatment of a Neurodegenerative Disease does not include [**]. Notwithstanding the foregoing, the Field shall not include [**].

Section 1.29 “ First Commercial Sale ”. First Commercial Sale, with respect to a Licensed Product, shall mean the first commercial sale of such Licensed Product by the Commercializing Party, its Affiliates, distributors and/or agents. Sales for test marketing or clinical trial purposes shall not constitute a First Commercial Sale.

Section 1.30 “ FTE Cost ”. FTE Cost shall mean the product obtained by multiplying (a) the number of full-time-equivalent person-years (each consisting of a total of [**] hours) of

scientific, technical or managerial work by each Party’s personnel on or directly related to any Product Development Program by (b) $[**], increased or decreased annually by the percentage increase or decrease in the CPI as of December 31 of the then most recently ended calendar year over the level of the CPI on December 31, 2006 ( i.e. , the first such increase or decrease would occur on January 1, 2008).

Section 1.31 “ GAAP ”. GAAP shall mean then current United States generally accepted accounting principles, consistently applied.

Section 1.32 “ Gene Target ”. Gene Target shall mean [**].

Section 1.33 “ IND ”. IND shall mean an application submitted to a Regulatory Authority to initiate human clinical trials, including (a) an Investigational New Drug application or any successor application or procedure filed with the FDA, (b) except where otherwise specifically provided in this Agreement, any foreign equivalent of a U.S. Investigational New Drug application, and (c) all supplements and amendments that may be filed with respect to the foregoing.

Section 1.34 “ Initial PDP Workplan ”. Initial PDP Workplan shall mean the Workplan for the Initial Product Development Program agreed by the Parties as of the Restatement Date, as amended by the JRDC from time to time.

Section 1.35 “ Initial Product Development Program ”. Initial Product Development Program shall mean the Discovery and Development activities to be performed by the Parties hereunder with respect to Licensed Product(s) for the treatment of Huntington’s disease.

Section 1.36 “ JCC Representative ”. JCC Representative shall mean a Party’s representative designated by such Party to serve on the JCC pursuant to Section 2.2(b).

Section 1.37 “ JRDC Representative ”. JRDC Representative shall mean a Party’s representative designated by such Party to serve on the JRDC pursuant to Section 2.2(a).

Section 1.38 “[**] Agreement ”. [**] Agreement shall mean that certain [**] Research Agreement, signed in [**], by and between Medtronic and [**].

Section 1.39 “ Know-How ”. Know-How shall mean any tangible or intangible know-how, expertise, discoveries, inventions, information, data or materials, including ideas, concepts, formulas, methods, procedures, designs, technologies, compositions, plans, applications, technical data, samples, chemical compounds and biological materials and all derivatives, modifications and improvements thereof.

Section 1.40 “ Launch Costs ”. Launch Costs shall mean, with respect to a Licensed Product in the US Territory, the incremental portion of FTE Costs and costs and expenses paid to Third Parties (or payable to Third Parties and accrued in accordance with GAAP) in connection with pre-launch [**] market development, and the pre-launch [**] promotion, marketing, selling and product support, of such Licensed Product (excluding cost of goods sold) in the US Territory, in accordance with the budget for such Launch Costs that has been approved by the JCC, that represents the amount of such FTE Costs and costs and expenses paid to Third Parties

that is in excess of levels of similar Commercialization expenses that are incurred in periods [**] following First Commercial Sale. Launch Costs shall include the incremental portion described above for the following expenses related to (or the portion thereof reasonably allocable to) the promotion, marketing, selling and product support of such Licensed Product in the US Territory: (i) Third Party marketing expenses (training materials etc.) as well as internal cost for preparation of materials; (ii) medical education events; (iii) convention expenses; (iv) sales calls, (v) market research costs, (vi) sales rep training, (vii) physician training and education, (viii) referral or local marketing events, and (ix) senior product manager.

Section 1.41 “ Licensed Product ”. Licensed Product shall mean a Product within the Field that includes, as an active pharmaceutical ingredient, an Alnylam siRNA for delivery via a Medtronic Device, together with such Medtronic Device, associated delivery hardware, and disposables, in each case whether or not uniquely developed for exclusive delivery of Alnylam siRNA(s).

Section 1.42 “ Listed or Approved Third Party Agreement ”. Listed or Approved Third Party Agreement shall mean any agreement listed on Schedule 1.42 or approved by the JRDC following the Effective Date pursuant to which Alnylam and/or Medtronic acquire or license from a Third Party Valid Claims that Cover an Alnylam siRNA or a Medtronic Device contained or used, alone or in combination, in a Licensed Product. In addition, any agreement between Alnylam and [**] under which Patent Rights are sublicensed to Medtronic pursuant to Section 3.1(e) shall be deemed to be a Listed or Approved Third Party Agreement.

Section 1.43 “ Major Market ”. Major Market shall mean any of the United States, France, Germany, Italy, Spain, the United Kingdom or Japan.

Section 1.44 “ Manufacturing Cost ”. Manufacturing Cost, with respect to the manufacture and/or supply of Alnylam siRNAs or Medtronic Devices for incorporation into Licensed Products, shall mean (a) if either Party or an Affiliate of either Party manufactures such Alnylam siRNAs or Medtronic Devices, such Party’s and/or its Affiliates’ aggregate manufacturing costs, which aggregate costs shall consist of (i) internal and out-of-pocket costs of raw materials, labor and other variable costs directly incurred in the manufacture of such Alnylam siRNAs or Medtronic Devices and (ii) reasonable and appropriate allocations (excluding [**]) pursuant to GAAP of Alnylam siRNA or Medtronic Device manufacturing overhead costs, as applicable, or (b) [**] to a Third Party, such Party’s aggregate internal and out-of-pocket costs of procuring such [**] from the Third Party, testing such [**] and putting such [**].

Section 1.45 “ Medtronic Device ”. Medtronic Device shall mean, with respect to a particular Product Development Program, any Device that is made available or approved by Medtronic’s JRDC Representatives for use in the Development of a Licensed Product in such Product Development Program. Subject to Medtronic’s further development obligations pursuant to the Device Supply Agreement, if Medtronic opts out of a Product Development Program pursuant to Section 2.4(b), the Medtronic Device with respect to the Licensed Product being developed in such Product Development Program shall be the Medtronic Device made available by Medtronic’s JRDC Representatives for use in the Development of a Licensed Product in such Development Program prior to such opt-out.

Section 1.46 “ Medtronic Fiscal Quarter ”. Medtronic Fiscal Quarter shall mean Medtronic’s fiscal quarters used for financial reporting purposes which, as of the Effective Date are the 13-week periods ending on the last Friday in July, October, January and April.

Section 1.47 “ Medtronic Fiscal Year ”. Medtronic Fiscal Year shall mean Medtronic’s fiscal year used for financial reporting purposes, which, as of the Effective Date, is a period consisting of four consecutive Medtronic Fiscal Quarters, and ending on the last Friday in April of the applicable year.

Section 1.48 “ Medtronic Intellectual Property ”. Medtronic Intellectual Property shall mean Medtronic Know-How and Medtronic Patent Rights, collectively.

Section 1.49 “ Medtronic Know-How ”. Medtronic Know-How shall mean any Know-How, other than Know-How related to [**] and other than Program Know-How, that is (a) developed or acquired by Medtronic prior to or during the Collaboration Term, (b) used to Discover, Develop, manufacture or Commercialize Alnylam siRNAs, Medtronic Devices and/or Licensed Products, and (c) Controlled by Medtronic and (i) used by Medtronic in the Collaboration Program and/or (ii) identified during a Product Development Program as Know-How that will be used in the Commercialization of Licensed Products to be Developed in such Product Development Program.

Section 1.50 “ Medtronic Patent Rights ”. Medtronic Patent Rights shall mean any Patent Rights Controlled by Medtronic and Covering Medtronic Know-How, excluding Medtronic’s interest in Program Patent Rights.

Section 1.51 “ NDA ”. NDA shall mean an application submitted to a Regulatory Authority for marketing approval of a product, including (a) a New Drug Application, Product License Application or Biologics License Application filed with FDA or any successor applications or procedures, (b) a foreign equivalent of a U.S. New Drug Application, Product License Application or Biologics License Application or any successor applications or procedures, and (c) all supplements and amendments that may be filed with respect to the foregoing.

Section 1.52 “ Net Sales ”. Net Sales, with respect to a particular Licensed Product in a particular period, shall mean the gross amount invoiced by the Commercializing Party, its Affiliates and/or its sublicensees on sales or other dispositions (excluding sales or dispositions for use in clinical trials or other scientific testing, in either case for which Commercializing Party receives no revenue) of the Licensed Product to unrelated Third Parties during such period, less the following deductions:

(a) Trade, cash and quantity discounts actually allowed and taken directly with respect to such sales or other dispositions;

(b) Tariffs, duties, excises, sales taxes or other taxes imposed upon and paid directly with respect to the delivery, sale or use of the Licensed Product and included and separately stated in the applicable invoice (excluding national, state or local taxes based on income);

(c) Amounts repaid or credited by reason of rejections, defects, recalls or returns or because of reasonable and customary chargebacks, refunds, rebates or retroactive price reductions;

(d) Amounts previously included in Net Sales of Licensed Products that are written-off by the Commercializing Party as uncollectible in accordance with the Commercializing Party standard practices for writing off uncollectible amounts consistently applied; provided that if any such written-off amounts are subsequently collected, such collected amounts shall be included in Net Sales in the period in which they are subsequently collected; and

(e) Freight, insurance and other transportation charges incurred in shipping a Licensed Product to Third Parties, included and separately stated in the applicable invoice.

Such amounts shall, subject to the provisions of Sections 4.7 and 4.8, be determined from the books and records of the Commercializing Party, its Affiliates and/or its sublicensees, maintained in accordance with GAAP, consistently applied.

Section 1.53 “ Neurodegenerative Disease ”. Neurodegenerative Disease shall mean a disease of the brain and/or spinal cord in humans that is characterized by the chronic and progressive death of neurons which leads to the loss of normal neural function. Such diseases include, but are not limited to, Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis. For the avoidance of doubt, Neurodegenerative Disease shall not include [**].

Section 1.54 “ Party ”. Party shall mean Alnylam or Medtronic; “Parties” shall mean Alnylam and Medtronic. As used in this Agreement, references to “Third Parties” do not include a Party or its Affiliates.

Section 1.55 “ Patent Rights ”. Patent Rights shall mean United States and foreign patents, patent applications and/or provisional patent applications, utility models and utility model applications, design patents or registered industrial designs and design applications or applications for registration of industrial designs, and all substitutions, divisionals, continuations, continuation-in-part applications, continued prosecution applications, reissues, reexaminations and extensions thereof.

Section 1.56 “ Person ”. Person shall mean any corporation, limited or general partnership, limited liability company, joint venture, trust, unincorporated association, governmental body, authority, bureau or agency, any other entity or body, or an individual.

Section 1.57 “ Phase I Study ”. Phase I Study shall mean a study of an siRNA or Product in human volunteers or patients the purpose of which is preliminary determination of safety and tolerability of a dosing regime and for which there are no primary endpoints (as recognized by FDA or other Regulatory Authorities) in the protocol relating to efficacy.

Section 1.58 “ Phase II(a) Study ”. Phase II(a) Study shall mean a preliminary efficacy and safety study of an siRNA or Product in the target patient population designed to demonstrate Clinical Proof of Concept.

Section 1.59 “ Phase II(b) Study ”. Phase II(b) Study shall mean a study of an siRNA or Product to evaluate further any preliminary efficacy observed for, and the safety of, the siRNA or Product in the target patient population and/or to provide data that may be useful in the design of subsequent studies of the siRNA or Product such as Phase III Studies or Pivotal Studies.

Section 1.60 “ Phase III Study ”. Phase III Study shall mean a controlled study to confirm with statistical significance the efficacy and safety of an siRNA or Product performed to obtain marketing and/or manufacturing approval for the product in any country.

Section 1.61 “[**] Opt Out ”. [**] Opt Out shall mean, with respect to a Product Development Program, that a Party exercised its option to opt out of such Product Development Program pursuant to Section 2.4 any time after a [**] for the Initial Product Development Program or after the Restatement Date for any Additional Product Development Program but prior to the [**] with respect to any Alnylam siRNA included in such Product Development Program.

Section 1.62 “[**] Opt Out ”. [**] Opt Out shall mean, with respect to a Product Development Program, that a Party exercised its option to opt out of such Product Development Program pursuant to Section 2.4 any time after the [**] but prior to the achievement of [**] with respect to any Alnylam siRNA included in such Product Development Program.

Section 1.63 “[**] Opt Out ”. [**] Opt Out shall mean, with respect to a Product Development Program, that a Party exercised its option to opt out of such Product Development Program pursuant to Section 2.4 any time after the achievement of [**] but prior to the end of the Product Development Term.

Section 1.64 “[**] Opt Out ”. [**] Opt Out shall mean, with respect to a Product Development Program, that a Party exercised its option to opt out of such Product Development Program pursuant to Section 2.4 at any time after the [**] but prior to the [**] with respect to any Alnylam siRNA included in such Product Development Program.

Section 1.65 “ Preliminary Success Criteria ”. Preliminary Success Criteria shall mean the suppression, distribution and therapeutic criteria with respect to an Alnylam siRNA under the Initial Product Development Program as shall be agreed by the Parties or as shall be [**] pursuant to Section 2.3(a).

Section 1.66 “ Primary Sequence or Chemical Modification Know-How ”. Primary Sequence or Chemical Modifications Know-How shall mean information about the primary sequence of any siRNA or chemical modifications incorporated into any siRNA.

Section 1.67 “ Product ”. Product shall mean a human therapeutic product that includes siRNA(s) as active pharmaceutical ingredient(s) delivered or approved for delivery via a Device, together with any Device, associated delivery hardware, and disposables whether or not uniquely developed for exclusive delivery of such siRNA(s).

Section 1.68 “ Product Development Program ”. Product Development Program shall mean the Initial Product Development Program and/or any Additional Product Development Program(s).

Section 1.69 “ Product Development Term ”. Product Development Term, with respect to each Product Development Program, shall mean the period commencing on (a) with respect to the Initial Product Development Program, the Restatement Date, and (b) with respect to any Additional Product Development Program, the date on which the Parties mutually agree to commence such Additional Product Development Program in accordance with Section 2.3(e), and, subject to [**], ending on the earliest date on which a First Commercial Sale of Licensed Product(s) for the treatment of each of the Target Indication(s) designated for such Product Development Program has occurred.

Section 1.70 “ Program Intellectual Property ”. Program Intellectual Property shall mean Program Know-How and Program Patent Rights, collectively.

Section 1.71 “ Program Know-How ”. Program Know-How shall mean any Know-How or interest therein, other than Know-How related to [**], that is developed or acquired, either solely by a Party and/or its Affiliate(s) or jointly by both Parties and/or their Affiliate(s), in the conduct of the Collaboration Program. For the avoidance of doubt, any Know-How, including any Know-How that is Covered by Patent Rights Controlled by Medtronic, that is sublicensed by Medtronic to Alnylam (or, in the case of Know-How assigned to Medtronic under the [**] Agreement, that is licensed by Medtronic to Alnylam) under the letter agreement dated [**] between the Parties concerning the [**] Agreement shall be deemed Program Know-How hereunder.

Section 1.72 “ Program Patent Rights ”. Program Patent Rights shall mean any Patent Rights or interest therein Controlled by either Party or Controlled jointly by the Parties that Cover Program Know-How.

Section 1.73 “ Regulatory Approval ”. Regulatory Approval shall mean the approval of the applicable Regulatory Authority necessary for the marketing and sale of a Licensed Product for a particular indication in a country, excluding separate pricing and/or reimbursement approvals that may be required.

Section 1.74 “ Regulatory Authority ”. Regulatory Authority shall mean a federal, national, multinational, state, provincial or local regulatory agency, department, bureau or other governmental entity with authority over the testing, manufacture, use, storage, import, promotion, marketing or sale of a Product in a country or territory.

Section 1.75 “ ROW Territory ”. ROW Territory shall mean all countries in the world other than the US Territory.

Section 1.76 “ Royalty Term ”. Royalty Term, with respect to each Licensed Product in each country of the Territory, shall mean the period of time commencing with the First Commercial Sale of such Licensed Product in such country and ending on the later of (a) the latest date on which the use, offer for sale, sale or importation of such Licensed Product in such country or the manufacture of such Licensed Product in the country of manufacture is Covered by a Valid Claim of Alnylam Patent Rights, Medtronic Patent Rights or Program Patent Rights, or (b) a specified number of years after First Commercial Sale of such Licensed Product in such

country, which number shall be fifteen (15) years with respect to any Licensed Product resulting from the Initial Product Development Program.

Section 1.77 “ Section 2.5(d)(iii) [**] Agreement ”. Section 2.5(d)(iii) [**] Agreement shall mean an agreement entered into by a [**] with a Third Party, as described in Section 2.5(d)(iii), that was not approved by the JRDC.

Section 1.78 “ siRNA ”. siRNA shall mean a composition designed to act primarily through an RNAi mechanism which consists of either (a) two separate oligomers of native or chemically modified RNA that are hybridized to one another along a substantial portion of their lengths, or (b) a single oligomer of native or chemically modified RNA that is hybridized to itself by self-complementary base-pairing along a substantial portion of its length to form a hairpin.

Section 1.79 “ Target Indication ”. Target Indication shall mean, with respect to an Alnylam siRNA Developed in the Initial Product Development Program, Huntington’s disease, and, with respect to an Alnylam siRNA Developed in any Additional Product Development Program, each human disease or condition that is designated by the Parties as a Target Indication with respect to such Alnylam siRNA in accordance with Section 2.3(e).

Section 1.80 “ Territory ”. Territory shall mean, subject to Section 8.2(b), the US Territory and/or the ROW Territory.

Section 1.81 “ Third Party ”. Third Party shall mean any Person other than Alnylam or Medtronic and their respective Affiliates.

Section 1.82 “ US Territory ”. US Territory shall mean the United States of America, including its territories, possessions and Puerto Rico.

Section 1.83 “ Valid Claim ”. Valid Claim shall mean (a) a claim of any issued, unexpired patent that has not been revoked or held unenforceable or invalid by a decision of a court or governmental agency of competent jurisdiction from which no appeal can be taken, or with respect to which an appeal is not taken within the time allowed for appeal, and that has not been disclaimed or admitted to be invalid or unenforceable through reissue, disclaimer or otherwise, or (b) a claim of any published patent application filed by a Party in good faith that has not been cancelled, withdrawn or abandoned, nor been pending for more than [**] years from the filing date of the earliest patent application from which such patent application claims priority.

Section 1.84 “ Workplan ”. Workplan shall mean the Initial PDP Workplan or any other work plan describing the activities to be undertaken during the applicable Product Development Program, as adopted, updated or amended pursuant to Section 2.3.

Section 1.85 Additional Definitions . Each of the following definitions is set forth in the section of this Agreement indicated below:


Definition	Section
“Additional Product Development Program”		2.3(e)
“Agreement”		Preamble
“Alnylam”		Preamble
“Alnylam Discontinuation Notice”		2.4(a)
“Alnylam Indemnified Parties”		9.1(a)
“[**] Agreement”		Schedule 1.42
“[**] Licensors”		3.2(e)
“Breaching Party”		8.2(a) or 8.2(c)
“[**]”		2.5(d)
“[**]”		9.3
“[**]”		3.1(e)
“Device Inventions”		5.1(b)
“Device Supply Agreement”		8.4(a)(vii)
“Electing Party”		5.2(c)
“Enjoined Period”		4.6
“Exclusive Negotiation Period”		2.5(c)(ii)
“GI”		Schedule 1.42
“GI Agreements”		Schedule 1.42
“Go Decision”		2.3(c)(i)
“Indemnified Party”		9.1(d)
“Indemnifying Party”		9.1(d)
“Initial Commitment”		4.1(a)
“Invalidity Claim”		5.4(c)
“Isis Agreement”		Schedule 1.42
“JCC”		2.1
“Jointly Developed Inventions”		5.1(c)
“JRDC”		2.2(a)
“[**]”		2.3(d)
“Losses”		9.1(a)
“[**]”		2.5(a)
“Medtronic”		Preamble
“Medtronic Discontinuation Notice”		2.4(b)
“Medtronic Indemnified Parties”		9.1(b)
“[**] Agreement”		Schedule 1.42
“[**] Agreement”		Schedule 1.42
“No-Go Decision”		2.3(c)(i)
“Non-Breaching Party”		8.2(a) or 8.2(c)
“Non-Electing Party”		5.2(c)
“Non-Performing Party”		2.3(f)
“Original Collaboration Agreement”		Introduction
“Performing Party”		2.3(f)
“[**]”		Schedule 1.42
“Program Data”		5.1(e)
“Quarterly Reports”		4.6(a)
“[**]”		2.5(d)
“Reimbursable Launch Costs”		4.3(f)


Definition	Section
“Restatement Date”		Preamble
“Right of Access”		5.1(e)
“RoFN Notice”		2.5(c)(i)
“RoFN Offer”		2.5(c)(iii)
“RoFN Opportunity”		2.5(c)
“RoFN Response Notice”		2.5(c)(i)
“RoFN Response Period”		2.5(c)(i)
“RoFN Term”		2.5(c)
“SEC”		6.1
“Severed Clause”		9.11
“siRNA Supply Agreement”		2.6(b)
“Sole Inventions”		5.1(c)
“Stanford Agreement”		Schedule 1.42
“Third Party Infringement Claim”		5.4(a)
“[**]”		2.5(a)

Article II

Collaboration Program; Commercialization

Section 2.1 General . Prior to the Restatement Date, the Parties conducted the Technology Development Program (as defined in the Original Collaboration Agreement). Pursuant to the terms of this Agreement, the Parties have agreed to terminate the Technology Development Program and to transition their collaboration on the Discovery, Development, manufacture and Commercialization of Licensed Products to the Initial Product Development Program commencing