Exhibit 10.1

    

     

    

    
      CONFIDENTIAL

      EXECUTION VERSION

    

     

    

    CERTAIN IDENTIFIED INFORMATION HAS BEEN EXCLUDED FROM THE EXHIBIT BECAUSE IT IS BOTH (I) NOT MATERIAL AND (II) WOULD BE COMPETITIVELY HARMFUL IF PUBLICLY DISCLOSED.  SUCH EXCLUDED INFORMATION HAS BEEN MARKED WITH
      “[***]”.

    

    

    Amended and Restated

     

    Neurology Drug Discovery and Development Collaboration, Option and License Agreement

     

    Between

     

    Ionis Pharmaceuticals, Inc.,

     

    And

     

    Biogen MA Inc.

     

    Dated July 12, 2021

     

    
      
        


      
        
          
            CONFIDENTIAL

            EXECUTION VERSION

          

        

         

      

    

    
    TABLE OF CONTENTS

     

    	 	 	 	
            Page

          
	
            ARTICLE 1 RESEARCH AND DEVELOPMENT

          	
            2

          
	 	
            1.1.

          	
            Collaboration Overview

          	
            2

          
	 	
            1.2.

          	
            Collaboration Programs

          	
            2

          
	 	
            1.3.

          	
            High Interest Targets

          	
            2

          
	 	
            1.4.

          	
            Collaboration Targets

          	
            3

          
	 	
            1.5.

          	
            Ionis’ Research and Development Responsibilities

          	
            4

          
	 	
            1.6.

          	
            Research and Development Costs and Expenses

          	
            9

          
	 	
            1.7.

          	
            Drug Discovery and Drug Development Terms

          	
            10

          
	 	
            1.8.

          	
            Additional Activities Requested by Biogen

          	
            11

          
	 	
            1.9.

          	
            Biogen’s Participation in Regulatory Meetings

          	
            13

          
	 	
            1.10.

          	
            Impact of [***] Development Path

          	
            14

          
	 	
            1.11.

          	
            Research and Development Management

          	
            14

          
	
            ARTICLE 2 EXCLUSIVITY COVENANTS

          	
            16

          
	 	
            2.1.

          	
            Exclusivity; Right of First Negotiation

          	
            16

          
	 	
            2.2.

          	
            Effect of Exclusivity on Indications

          	
            20

          
	 	
            2.3.

          	
            Consequences of Ionis-Discovered High Interest Target Development Candidate

          	
            20

          
	
            ARTICLE 3 EXCLUSIVE OPTION

          	
            21

          
	 	
            3.1.

          	
            Option

          	
            21

          
	 	
            3.2.

          	
            Restrictions on Ionis’ Right to Grant Diagnostic Rights; Right to Negotiate Diagnostic Rights

          	
            22

          
	
            ARTICLE 4 LICENSE GRANTS

          	
            23

          
	 	
            4.1.

          	
            License Grants to Biogen

          	
            23

          
	 	
            4.2.

          	
            Assignment of Ionis Product-Specific Patents; Grant Back to Ionis

          	
            25

          
	 	
            4.3.

          	
            Enabling Licenses

          	
            26

          
	 	
            4.4.

          	
            Licenses to Ionis for Biogen Results.

          	
            29

            

          
	 	
            4.5.

          	
            Right to Obtain Direct License from Biogen to Ionis Partner; Sublicensees of Ionis

          	
            30

          
	 	
            4.6.

          	
            Ownership of and Assistance with Regulatory Filings

          	
            30

          
	 	
            4.7.

          	
            Subcontracting

          	
            31

          
	 	
            4.8.

          	
            Technology Transfer after the License Effective Date

          	
            31

          
	
            ARTICLE 5 DEVELOPMENT, MANUFACTURING AND COMMERCIALIZATION

          	
            34

          
	 	
            5.1.

          	
            Biogen Diligence

          	
            34

          


    

    

    
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            5.2.

          	
            Global Safety Database; Pharmacovigilance Agreement

          	
            36

          
	 	
            5.3.

          	
            Research and Manufacturing Records

          	
            38

          
	
            ARTICLE 6 FINANCIAL PROVISIONS

          	
            38

          
	 	
            6.1.

          	
            Option Fee

          	
            38

          
	 	
            6.2.

          	
            Milestone Payments for Achievement of Pre-Licensing Milestone Events

          	
            38

          
	 	
            6.3.

          	
            License Fee

          	
            39

          
	 	
            6.4.

          	
            Milestone Payments for Achievement of Post-Licensing Milestone Events

          	
            39

          
	 	
            6.5.

          	
            Limitations on Milestone Payments; Exceptions; Notice

          	
            39

          
	 	
            6.6.

          	
            Royalty Payments to Ionis

          	
            40

          
	 	
            6.7.

          	
            Reverse Royalty Payments to Biogen for a Discontinued Product

          	
            43

          
	 	
            6.8.

          	
            Third Party Payment Obligations

          	
            43

          
	 	
            6.9.

          	
            Payments

          	
            45

          
	 	
            6.10.

          	
            Audits

          	
            46

          
	 	
            6.11.

          	
            Taxes

          	
            46

          
	 	
            6.12.

          	
            Interest

          	
            47

          
	
            ARTICLE 7 INTELLECTUAL PROPERTY

          	
            47

          
	 	
            7.1.

          	
            Ownership

          	
            47

          
	 	
            7.2.

          	
            Prosecution and Maintenance of Patents

          	
            51

          
	 	
            7.3.

          	
            Patent Costs

          	
            56

          
	 	
            7.4.

          	
            Defense of Claims Brought by Third Parties

          	
            56

          
	 	
            7.5.

          	
            Enforcement of Patents against Competitive Infringement

          	58
	 	
            7.6.

          	
            Other Infringement

          	
            60

          
	 	
            7.7.

          	
            Patent Listing

          	
            61

          
	 	
            7.8.

          	
            Joint Research Agreement under the Leahy-Smith America Invents Act

          	
            61

          
	 	
            7.9.

          	
            Obligations to Third Parties

          	
            62

          
	 	
            7.10.

          	
            Additional Right and Exceptions

          	
            62

          
	 	
            7.11.

          	
            Patent Term Extension

          	
            62

          
	
            ARTICLE 8 REPRESENTATIONS AND WARRANTIES

          	
            62

          
	 	
            8.1.

          	
            Representations and Warranties of Both Parties

          	
            62

          
	 	
            8.2.

          	
            Representations and Warranties of Ionis

          	
            63

          
	 	
            8.3.

          	
            Ionis Covenants

          	
            64

          
	 	
            8.4.

          	
            DISCLAIMER

          	
            65

          
	
            ARTICLE 9 INDEMNIFICATION; INSURANCE

          	
            66

          
	 	
            9.1.

          	
            Indemnification by Biogen

          	
            66

          


    

    

    
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            9.2.

          	
            Indemnification by Ionis

          	
            66

          
	 	
            9.3.

          	
            Procedure

          	
            67

          
	 	
            9.4.

          	
            Insurance

          	
            67

          
	 	
            9.5.

          	
            LIMITATION OF CONSEQUENTIAL DAMAGES

          	
            68

          
	
            ARTICLE 10 TERM; TERMINATION

          	
            68

          
	 	
            10.1.

          	
            Agreement Term; Expiration

          	
            68

          
	 	
            10.2.

          	
            Termination of the Agreement

          	
            68

          
	 	
            10.3.

          	
            Alternative Remedies to Termination Available to Biogen Prior to the License Effective Date

          	
            73

          
	 	
            10.4.

          	
            Consequences of Expiration or Termination of the Agreement

          	
            74

          
	
            ARTICLE 11 CONFIDENTIALITY

          	
            83

          
	 	
            11.1.

          	
            Confidentiality; Exceptions

          	
            83

          
	 	
            11.2.

          	
            Prior Confidentiality Agreement Superseded

          	
            83

          
	 	
            11.3.

          	
            Authorized Disclosure

          	
            83

          
	 	
            11.4.

          	
            Press Release; Publications; Disclosure of Agreement

          	
            84

          
	
            ARTICLE 12 MISCELLANEOUS

          	
            89

          
	 	
            12.1.

          	
            Dispute Resolution

          	
            89

          
	 	
            12.2.

          	
            Governing Law; Jurisdiction; Venue; Service of Process

          	
            89

          
	 	
            12.3.

          	
            Remedies

          	
            90

          
	 	
            12.4.

          	
            Assignment and Successors

          	
            90

          
	 	
            12.5.

          	
            Change of Control

          	
            91

          
	 	
            12.6.

          	
            Protective Provisions

          	
            93

          
	 	
            12.7.

          	
            Force Majeure

          	
            93

          
	 	
            12.8.

          	
            Notices

          	
            94

          
	 	
            12.9.

          	
            Export Clause

          	
            94

          
	 	
            12.10.

          	
            Waiver

          	
            95

          
	 	
            12.11.

          	
            Severability

          	
            95

          
	 	
            12.12.

          	
            Entire Agreement

          	
            95

          
	 	
            12.13.

          	
            Independent Contractors

          	
            95

          
	 	
            12.14.

          	
            Interpretation

          	
            95

          
	 	
            12.15.

          	
            Books and Records

          	
            96

          
	 	
            12.16.

          	
            Further Actions

          	
            96

          
	 	
            12.17.

          	
            Construction of Agreement

          	
            96

          
	 	
            12.18.

          	
            Supremacy

          	
            96

          
	 	
            12.19.

          	
            Counterparts

          	
            96

          
	 	
            12.20.

          	
            Compliance with Laws

          	
            96

          


    

    

    
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    AMENDED AND RESTATED NEUROLOGY DRUG DISCOVERY AND DEVELOPMENT COLLABORATION, OPTION AND LICENSE AGREEMENT

     

    This AMENDED AND RESTATED NEUROLOGY DRUG DISCOVERY AND DEVELOPMENT COLLABORATION, OPTION AND LICENSE AGREEMENT (the “Agreement”) is entered
      into as of the 12th day of July, 2021 (the “Amendment Date”) by and between Ionis Pharmaceuticals, Inc. (formerly known as
      Isis Pharmaceuticals, Inc.), a Delaware corporation, having its principal place of business at 2855 Gazelle Court, Carlsbad, CA 92010 (“Ionis”), and Biogen MA Inc. (formerly known as Biogen Idec MA Inc.), a Massachusetts corporation, having its principal place of business at 225 Binney Street, Cambridge, MA 02142 (“Biogen”). Biogen and Ionis each may be referred to herein individually as a “Party” or collectively as the “Parties.” 






      Capitalized terms used in this Agreement, whether used in the singular or the plural, have the meaning set forth in Appendix 1.  All attached appendices and schedules are a part of this
      Agreement.

     

    RECITALS

     

    WHEREAS, Ionis possesses certain Patent Rights, Know-How, technology and expertise with
        respect to antisense therapeutics, and has novel and valuable capabilities for the research, discovery, identification, synthesis and development of antisense therapeutics;

     

    WHEREAS, Biogen has expertise in developing and commercializing human therapeutics, and Biogen
        is interested in developing and commercializing antisense therapeutics for up to three gene targets;

     

    WHEREAS, Biogen desires Ionis to (a) identify a development candidate for each of the three
        gene targets, (b) develop the development candidates through completion of the first clinical trial designed to demonstrate proof of mechanism or proof of therapeutic benefit and (c) provide Biogen an option to obtain an exclusive license under
        this Agreement to develop, manufacture and commercialize Products in the Field;

     

    WHEREAS, Biogen and Ionis entered into that certain Neurology Drug Discovery and Development
        Collaboration, Option and License Agreement, as amended (the “Original Agreement”) dated December 10, 2012 (the “Effective Date”);






        and

     

    WHEREAS, Biogen and Ionis seek to amend and restate the Original Agreement in its entirety as
        set forth herein.

     

    NOW, THEREFORE, in consideration of the respective covenants, representations, warranties and
        agreements set forth herein, the Parties hereto agree as follows:

     

    
      
        


      
        
          
            CONFIDENTIAL

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    ARTICLE 1

    RESEARCH AND DEVELOPMENT

     

    	1.1.	
            Collaboration Overview.  The intent of the collaboration is for Ionis to (a) conduct Collaboration Programs for each of
                the three Collaboration Targets, (b) generate at least one Development Candidate for each Collaboration Program; (c) advance each Development Candidate through the completion of the first PoC Trial under the applicable Collaboration
                Program; and (d) allow Biogen the opportunity to exercise an Option to further Develop and ultimately Commercialize Compounds and Products under such Collaboration Program under an exclusive license from Ionis.  The purpose of this Section






                  1.1 is to provide a high-level overview of the roles, responsibilities, rights and obligations of each Party under this Agreement, and therefore this Section 1.1 is qualified in its entirety by the more detailed provisions of
                this Agreement set forth below.

          


     

    	1.2.	
            Collaboration Programs.  Subject to and in accordance with the terms of this Agreement, Ionis and Biogen will be
                responsible for conducting three programs to discover, Develop, Manufacture and Commercialize Products (each, a “Collaboration Program”), each to be focused on a different
                Collaboration Target, pursuant to which:

          


     

    	 	1.2.1.	
            Ionis will use its Commercially Reasonable Efforts to (a) conduct drug discovery activities including drug screening, identification, characterization, optimization and other necessary activities according to the applicable Collaboration
              Program Research Plans to achieve Target Sanction status, (b) identify a Development Candidate for the applicable Collaboration Program, and (c) conduct drug development activities for each Development Candidate through completion of the
              first PoC Trial under a Collaboration Program in accordance with the applicable Development Plan; provided that Ionis will not be required to commence work on more than [***]






              Collaboration Programs in any rolling [***] month period; and

          


     

    	 	1.2.2.	
            following the License Effective Date with respect to each Collaboration Program, Biogen will use its Commercially Reasonable Efforts to Develop, Manufacture and Commercialize at least one Product from each such Collaboration Program for
              which Biogen has exercised an Option in accordance with this Agreement.

          


     

    	1.3.	
            High Interest Targets.

          


     

    	 	1.3.1.	
            High Interest Target List.  Subject to the replacement rights set forth in Section 1.3.2 below, the Parties
                will maintain, through the Neurology JSC, a list of mutually-agreed gene targets that are of high interest as potential Collaboration Targets (each such target, a “High Interest Target”
                and such list the “High Interest Target List”) according to the following procedure:

          


     

    	

          	(a)	
            As of the Effective Date, the Parties have agreed upon a written list containing the initial [***] High Interest Targets;

          


     

    	

          	(b)	
            On [***], the number of High Interest Targets on the High Interest Target List will be reduced to [***] High Interest Targets.  By [***], Biogen will provide Ionis a written notice designating the [***] gene targets (from the [***] gene
              targets listed on the High Interest Target List) that will remain as High Interest Targets;

          


     

    	

          	(c)	
            Each time after the Effective Date that a Collaboration Target is designated under Section 1.4.1, Section 1.4.2 or Section 2.3, the number of High Interest Targets for purposes of the High Interest Target List will
              be reduced by [***], and the High Interest Target so designated as a Collaboration Target will no longer be a High Interest Target for purposes of the High Interest Target List; and

          


     

    
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          	(d)	
            Upon the earlier of the (i) [***]; and (ii) [***], the High Interest Target List will be dissolved and no gene target will thereafter be a High Interest Target.

          


     

    	 	1.3.2.	
            Replacement.  At any time prior to the [***], Biogen may, in accordance with the terms of this Agreement, propose a
                replacement of a High Interest Target on the High Interest Target List, in which case Ionis and Biogen will mutually agree to replace such High Interest Target with a different gene target for purposes of the High Interest Target List; provided, however, that Ionis may only choose not to agree to replace a High Interest Target on the High Interest Target List with a gene target proposed by
                Biogen if, at the time of such proposal, [***], a “Dispositive Disagreement Condition”).  If Ionis notifies Biogen within [***] days after receipt of Biogen’s request to add a gene
                target as a High Interest Target that a Dispositive Disagreement Condition exists with respect to such gene target, the members of the Neurology JSC will discuss such Dispositive Disagreement Condition and work together in good faith to
                promptly repeat a similar process as set forth in this Section 1.3.2 until Biogen and Ionis have selected a replacement target.  With respect to any replacement under this Section 1.3.2, (A) the gene target substituted-in
                will thereafter be a High Interest Target on the High Interest Target List; and (B) the gene target removed will no longer be a High Interest Target on the High Interest Target List. The Parties acknowledge and agree that, as of August 4,
                2014, [***] has been designated as a Collaboration Target (as such term is defined in the Neurology II Agreement) that is an ALS Target (as such term is defined in the Neurology II Agreement) under the Neurology II Agreement and is no
                longer a Collaboration Target under this Agreement or the subject of this Agreement.

          


     

    	 	1.3.3.	
            Replacement Limit.  Notwithstanding the foregoing, the Parties may not replace more than one High Interest Target in
                any rolling [***] month period, without Ionis’ written consent (the “Replacement Limit”); provided that replacing-in another gene target
                under Section 1.5.6 will not count for purposes of calculating the Replacement Limit.

          


     

    	1.4.	
            Collaboration Targets.

          


     

    	 	1.4.1.	
            Designation.  The maximum number of Collaboration Targets will be three.  Subject to the substitution rights set forth
                in Section 1.4.2 below, as of the Effective Date, the first Collaboration Target is [***].  At any time from [***] through [***], Biogen may designate the second Collaboration Target from the High Interest Target List, and at any
                time from [***] through the [***] anniversary of the Effective Date, Biogen may designate the third Collaboration Target from the High Interest Target List.

          


     

    
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    	 	1.4.2.	
            Substitution.  With respect to any Collaboration Target that [***], Biogen may substitute such Collaboration Target
                with a gene target from the High Interest Target List by providing written notice to Ionis designating the gene target it is removing as a Collaboration Target and the High Interest Target from the High Interest Target List it is now
                designating as a Collaboration Target.  Upon such substitution, (a) Ionis will begin a Collaboration Program on the High Interest Target so substituted-in as a Collaboration Target; and (b) Ionis’ obligations, and Biogen’s rights, under
                this Agreement with respect to the removed gene target will terminate, and the removed gene target will no longer be a Collaboration Target.  Notwithstanding the foregoing, Biogen may not substitute
                more than [***] Collaboration Target (the “Substitution Limit”), without Ionis’ written consent; provided that substituting-in an
                Accelerated Target under Section 2.3 or another High Interest Target under Section 1.5.6 or Section 10.2.4(a) will not count for purposes of calculating the Substitution Limit.

          


     

    	1.5.	
            Ionis’ Research and Development Responsibilities.

          


     

    	 	1.5.1.	
            Collaboration Program Research Plans.  Ionis will carry out its drug discovery efforts for each Collaboration Program
                pursuant to the applicable Collaboration Program Research Plan in a manner consistent with its internal practices for other gene targets with the goal of achieving Target Sanction and identifying a Development Candidate for the applicable
                Collaboration Program as soon as practicable.  Ionis will update each Collaboration Program Research Plan as needed and submit it to the Neurology JSC for its review and comment.  In addition, once a Collaboration Program achieves Target
                Sanction, the Neurology JSC will begin preliminary discussions regarding an appropriate development plan for the contemplated Development Candidate under such Collaboration Program.

          


     

    For each Collaboration Program, Ionis will provide the Neurology JSC:

     

    	

          	(a)	
            promptly (but no later than [***]) following the designation of a Collaboration Target, an initial research plan delineating the experiments that should be conducted to achieve Target Sanction for such Collaboration Target; and

          


     

    	

          	(b)	
            the initial plan approved by Ionis’ RMC in connection with a Target Sanction under a Collaboration Program to identify a Development Candidate, as may be modified from time to time to address the discovery, research and optimization
              activities Ionis will conduct under the applicable Collaboration Program (together, each such plan under Sections 1.5.1(a) and 1.5.1(b), a “Collaboration Program Research
                Plan”).

          


     

    Ionis will reasonably consider the comments provided by the Neurology JSC on each Collaboration Program Research Plan.

     

    
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    	1.5.2.	
            Development Candidates; Development Plans; Option Acceleration.

          


     

    	

          	(a)	
            Ionis will notify Biogen in writing within [***] days of designating a Development Candidate and will provide Biogen the applicable Development Candidate Data Package. For each Development Candidate under a Collaboration Program within
              [***] after designation of such Development Candidate, the Parties will mutually agree on an appropriate development plan for such Development Candidate through completion of the [***] (each, a “Development Plan”) and will update Schedule 5.1.1 to add Specific Performance Milestone Events related to Biogen’s Development and Commercialization of the Development
              Candidate following the License Effective Date for the applicable Collaboration Program, which Specific Performance Milestone Events will be generally consistent with Biogen’s development timelines for its other drug development programs of
              similar stage and market potential.  Prior to the License Effective Date with respect to a Collaboration Program, in the event the Parties are unable to agree upon the PoC Trial Design for a particular Collaboration Program, in lieu of
              mediation pursuant to Section 12.1.2, [***] will have final decision-making authority with respect to the PoC Trial Design. If the Parties are unable to agree upon the Specific Performance Milestone Events for a particular
              Collaboration Program, the matter will be resolved in accordance with Section 12.1, including, for the avoidance of doubt, mediation pursuant to Section 12.1.2, if necessary.  Ionis will update each Development Plan as needed,
              but at least once Annually, and submit it to the Neurology JSC for its review and comment; provided, however, that [***], must be unanimously agreed to by the
              Neurology JSC.  In addition, prior to the Initiation of the first Clinical Study under the Development Plan for a Collaboration Program, the Parties will endeavor to mutually agree on a communication plan regarding the public disclosure of
              data and results arising from such Collaboration Program; provided, that if the Parties cannot agree on such a communication plan, then [***] will have final decision-making authority regarding any
              such communications occurring prior to the License Effective Date with respect to a Collaboration Program.

          


     

    
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          	(b)	
            After designation of such Development Candidate, the Neurology JSC will agree on an initial estimate of the expected cost for Ionis to conduct the work [***] specified in the applicable Development Plan, including Ionis’ expected [***] and
              [***] costs (each, a “Cost Estimate”). The initial Cost Estimate [***] shall be agreed on by the Neurology JSC no later than [***] months prior to the anticipated [***]. Based on the
              Cost Estimates, the Neurology JSC will establish the [***] and [v] milestone payments for such Collaboration Program, which payments will be equal to (i) [***]; plus (ii) [***].  The Parties will promptly negotiate in good faith using the
              Ionis/Biogen Preexisting Development Agreements as a basis for Cost Estimates and, if the total milestone payment [***] is more than $[***], the Parties will apportion such total milestone payment into smaller milestone payments in accordance
              with Schedule 1.5.2(b); provided, however, that if [***], then the Neurology JSC shall determine whether and how to apportion such total
              milestone payment into smaller milestone payments. Each such smaller milestone payment shall be payable by Biogen within [***] days after receipt of the applicable invoice by Biogen
              following [***]. If the total milestone payment [***] is $[***] or less, then such milestone payment shall become due in its entirety upon [***], and shall be payable by Biogen within [***] days after receipt of the applicable invoice by
              Biogen following [***].  As part of this process, Ionis will provide the Neurology JSC with a good faith estimate of the cost to conduct the work necessary to develop such Development Candidates under the applicable Development Plan using a
              similar methodology as used under the Ionis/Biogen Preexisting Development Agreements.  [***] months prior to the [***], using the process set forth above, the Neurology JSC will re-assess the total cost of such [***] and, if the cost has
              changed from the initial Cost Estimate, the Neurology JSC will adjust the applicable milestone payment accordingly, with any such adjustment to be agreed in writing to no later than the date that is [***] months prior to the [***]. Once there
              is less than [***] months prior to the [***], or such [***], if there are any changes to such [***] in accordance with this Agreement that result in an increase to the cost of such [***], then (A) if such cost is increased by more than [***],
              such increased costs will constitute an additional milestone payment to be paid in accordance with the provisions of this Section 1.5.2(b), or (B) if such cost is increased by [***], such increase will not affect the milestone
              payments for such [***] established under this Section 1.5.2(b), but instead will be handled in accordance with Section 1.8.  For clarity, with respect to any increase in the cost of a [***] by more than [***]% under clause
              (A) of the preceding sentence, if such increased costs total $[***] or less and such [***], then such increased costs shall become due in their entirety immediately, and shall be payable by Biogen within [***] days after receipt of the
              applicable invoice by Biogen.  Once the Neurology JSC has agreed on a Cost Estimate and/or the [***] milestone payments for such Collaboration Program are established under this Section 1.5.2(b) or Section 1.8, such agreement
              will be documented in a written side letter, in the form and format attached hereto as Appendix 3, which shall be executed by both Parties.

          


     

    	

          	(c)	
            Ionis will not be required to conduct any Development activities for a Development Candidate if an initial Development Plan, Specific Performance Milestone Events and the corresponding Cost Estimates have not been agreed to pursuant to
              this Section 1.5.2. Prior to such time as the Parties mutually agree on such Cost Estimate and/or the applicable [***] milestone payments and have executed a written side letter with respect to the foregoing in accordance with Section






                1.5.2(b), Ionis may, in its discretion, commence Development activities for which it is responsible under this Agreement; provided, however, that Biogen will not be responsible for any costs of
              such Development activities if commenced by Ionis prior to the execution of any such side letter unless and until such a side letter has been executed by the Parties, and in no event will Biogen be responsible for any amounts incurred by
              Ionis for such Development activities in excess of amounts set forth in the side letter executed by the Parties with respect to such Development activities.

          


     

    
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          	(d)	
            If the PoC Trial for a Collaboration Program will be [***] or more, or require more than [***], then, if Ionis provides to Biogen the notice described in the following sentence, Ionis will not be required to conduct such PoC Trial for such
              Collaboration Program.  Ionis will notify Biogen within [***] after finalization of the initial PoC Trial Design (or each time there is a material change thereto) for a Collaboration Program pursuant to Section 1.5.2(a) if Ionis
              elects not to conduct such PoC Trial for such Collaboration Program (such notice, an “Option Acceleration Notice”).  If Ionis has delivered an Option Acceleration Notice as provided
              in this Section 1.5.2(d), Biogen will have [***] from its receipt of the data generated under the [***] for the first Phase 1 Trial for such Collaboration Program (an “Option
                Acceleration Deadline”) to exercise its Option for the applicable Collaboration Program.  If Biogen does not exercise its Option for the applicable Collaboration Program by the applicable Option Acceleration Deadline, Biogen’s Option
              under Section 3.1 with respect to such Collaboration Program will expire and such Collaboration Program will terminate. In addition, after Biogen’s receipt of an Option Acceleration Notice with respect to a particular Collaboration
              Program, [***] will have final decision-making authority with respect to [***] to the extent related to the PoC Trial for the applicable Collaboration Program.

          


     

    	

          	(e)	
            The Neurology JSC will attach each Development Plan and associated Cost Estimates to the minutes of the Neurology JSC for the first meeting following agreement regarding such Development Plan and Cost Estimates by the Parties.

          


     

    	 	1.5.3.	
            Drug Development.  Ionis will use Commercially Reasonable Efforts to conduct all activities under each Development Plan
                on the timeline set forth in the applicable Development Plan, including the following Development activities under this Agreement:

          


     

    	

          	(a)	
            Subject to Section 1.6 below, Develop each Development Candidate through [***]; provided, however, that Ionis may discontinue such Development if at any time after having consulted, and
              having given good faith consideration to the recommendations of the Neurology JSC and a mutually-agreed Third Party expert, Ionis in good faith believes that continuing such Development would (i) pose an unacceptable risk or threat of harm in
              humans, or (ii) violate any Applicable Law, ethical principles, or principles of scientific integrity. Prior to discontinuing Development of a Development Candidate, Ionis will provide Biogen with reasonable advance notice of such
              discontinuation, including the grounds for Ionis’ determination. If Ionis elects to discontinue Development of a Development Candidate pursuant to this Section 1.5.3(a), Biogen may, in its discretion, elect to continue Development of
              the Development Candidate by providing Ionis with written notice of Biogen’s exercise of the Option within [***] after Ionis’ written notice to Biogen of such discontinuation.  If Biogen timely exercises its Option under this Section
                1.5.3(a), then [***].

          


     

    
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          	(b)	
            Phase 1 Trials.  Each Phase 1 Trial will be conducted in
                accordance with the applicable Phase 1 Trial Design set forth in the applicable Development Plan. Ionis will keep Biogen informed of the progress and status of each Phase 1 Trial.  When [***] a Phase 1 Trial, Ionis will notify Biogen in
                writing within [***] days. Ionis will provide Biogen with the [***] as soon as practicable after such notice.

          


     

    	

          	(c)	
            PoC Trial.  Each PoC Trial will be conducted in accordance
                with the PoC Trial Design set forth in the applicable Development Plan. Ionis will keep Biogen informed of the progress and status of each PoC Trial. When Ionis [***] a PoC Trial under the applicable Development Plan, Ionis will notify
                Biogen in writing within [***] days after such [***]. Ionis will provide Biogen with the [***] as soon as practicable after such notice.  If Biogen exercises its Option prior to the Initiation of the first PoC Trial for a Collaboration
                Program, Biogen will keep Ionis informed of the progress and status of the PoC Trial for such Collaboration Program. When Biogen completes such PoC Trial, Biogen will notify Ionis in writing within [***] days after such completion, and will
                provide Ionis with [***] as soon as practicable after such notice.

          


     

    	 	1.5.4.	
            Briefing of the Neurology JSC; Conduct of Research and Development.  At each regularly scheduled meeting of the
                Neurology JSC, Ionis will provide to the Neurology JSC progress updates on (a) the status of each Collaboration Program generally; (b) Ionis’ research activities on the High Interest Targets conducted pursuant to Section 2.3; (c)
                activities conducted under each Collaboration Program Research Plan, including progress towards Target Sanction or Development Candidate, as applicable; and (d) activities conducted under the Development Plans for each Development
                Candidate, in each case, together with a summary of data associated with Ionis’ research and/or Development activities for each Collaboration Program.  Ionis will conduct its work under each Collaboration Program in a good scientific
                manner, and in compliance with all applicable good laboratory practices and cGMP, and all Applicable Laws.

          


     

    	 	1.5.5.	
            Clinical Supplies by Ionis.  Ionis, at its expense, will supply API (on its own or through a CMO approved by Biogen)
                and Clinical Supplies to support the Research and Development activities under each Collaboration Program Research Plan and each Development Plan through the License Effective Date for such Collaboration Program.  If Biogen exercises an
                Option at least [***] prior to the planned Initiation of the PoC Trial for the applicable Collaboration Program, Biogen may elect to either have (a) Ionis supply Clinical Supplies for such PoC Trial (on its own or through a CMO approved by
                Biogen), in which case Biogen will pay Ionis an amount equal to [***], or (b) a CMO supply Clinical Supplies for such PoC Trial in accordance with the Manufacturing Agreement entered into with such CMO. If Biogen exercises an Option prior
                to, but less than [***] before, the planned Initiation of the PoC Trial for the applicable Collaboration Program, Ionis will supply Clinical Supplies for such PoC Trial (on its own or through a CMO approved by Biogen) and Biogen will pay
                Ionis an amount equal to [***].

          


     

    
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    	 	1.5.6.	
            Collaboration with Third Parties.  Ionis may engage one or more academic or non-profit institutions to conduct work
                under any Collaboration Program Research Plan or Development Plan or to conduct drug discovery activities to identify a High Interest Target Development Candidate pursuant to Section 2.3; provided,
                however, that (a) with respect to any such academic or non-profit institution engaged to conduct such activities with respect to a Collaboration Target, where such engagement occurs after the date
                such Collaboration Target is designated, or (b) with respect to any such academic or non-profit institution engaged to conduct such activities with respect to one of the remaining High Interest Targets, where such engagement occurs after
                the later of [***] or the date such High Interest Target is designated, (i) prior to engaging such academic or non-profit institution to conduct such activities, Ionis will consult with Biogen in good faith with respect to the terms of any
                agreement or amendment to an existing agreement to be entered into with such institution and consider Biogen’s comments with respect thereto in good faith and (ii) if Ionis enters into any such agreement or amendment on terms objected to by
                Biogen in a written notice provided to Ionis prior to the execution thereof, it shall promptly so notify Biogen, which notice will include a copy of such agreement or amendment, and within [***] days following Biogen’s receipt of such
                notice, Biogen may elect to replace the applicable High Interest Target or Collaboration Target with a different gene target in accordance with the procedures set forth in Section 1.3.2 or Section 1.4.2, as applicable, and
                such replacement will not be counted for purposes of determining whether Biogen has exceeded the Replacement Limit or Substitution Limit, as applicable.

          


     

    	1.6.	
            Research and Development Costs and Expenses.

          


     

    	 	1.6.1.	
            Research and Development Costs Paid by Ionis.  Until the License Effective Date with respect to a Collaboration
                Program, Ionis will be responsible for all research and Development activities for each Development Candidate under the Collaboration Program Research Plan and Development Plan with respect to such Collaboration Program and, except as
                otherwise provided under Section 1.6.2(a), all costs and expenses associated therewith.

          


     

    	 	1.6.2.	
            Development Costs Paid by Biogen.

          


     

    	

          	(a)	
            Before the License Effective Date.  Prior to the License Effective Date with respect to a Collaboration Program, Biogen
                will be responsible for paying any Biogen-Approved Costs resulting from Biogen-Approved Changes using the payment mechanisms set forth in Section 1.8.

          


     

    	

          	(b)	
            Additional Activities Approved by Biogen.  If, with respect to a particular Collaboration Program, Biogen desires that
                either Ionis or a Third Party [***] or conduct other work to support Approval of a Product, including [***], prior to the License Effective Date with respect to
                such Collaboration Program, and Ionis agrees to perform such work, Biogen will pay the costs of conducting such work using the payment mechanism set forth in Section 1.8.

          


     

    
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          	(c)	
            After the License Effective Date.  After the License Effective Date with respect to a Collaboration Program, Biogen
                will be solely responsible for the costs and expenses related to the Development, Manufacture and Commercialization of Products with respect to such Collaboration Program, including any work performed by Ionis at Biogen’s request, and all
                supply chain planning and decision-making.  All such work performed by Ionis at Biogen’s request will be conducted and reimbursed pursuant to a budget agreed upon by the Parties.

          


     

    	1.7.	
            Drug Discovery and Drug Development Terms.

          


     

    	 	1.7.1.	
            The term for the conduct of the Drug Discovery Program will begin on the Effective Date and will end upon the earlier of (a) designation of a Development Candidate for each Collaboration Program and (b) the [***] anniversary of the
              Effective Date (the “Drug Discovery Term”); provided, however, that if Ionis is still conducting
              work under a Collaboration Program Research Plan on the date of expiration of the Drug Discovery Term, the Drug Discovery Term will be automatically extended until the earlier of the (i) date on which Ionis completes all activities under each
              such Collaboration Program Research Plan and (ii) the [***] anniversary of the Effective Date; provided further that if, as a result of Ionis’ breach, Biogen has substituted a High Interest Target
              for a Collaboration Target pursuant to Section 10.2.4(a), and Ionis is conducting activities under the applicable Collaboration Program Research Plan on the date on which the Drug Discovery Term would otherwise expire, the Drug
              Discovery Term will be extended for a reasonable period of time (not to exceed the [***] anniversary of the date of such substitution) to allow Ionis to complete such activities.

          


     

    	 	1.7.2.	
            The term for the conduct of the Drug Development Program will begin on the designation of the first Development Candidate and will end upon the earlier of (a) [***] for a Development Candidate under each Collaboration Program, which the
              Parties estimate will be approximately [***] years after the Effective Date, (b) exercise by Biogen of each of its Options for each Collaboration Program; (c) the termination of the last Collaboration Program; and (d) mutual agreement of the
              Parties to terminate the Drug Development Program.

          


     

    	 	1.7.3.	
            Upon the end of the Drug Discovery Term, subject to Section 1.7.4, (a) Ionis will no longer have an obligation to perform any activities under Section 1.5; (b) any Collaboration Programs that have not reached the
              Development Candidate stage will no longer be Collaboration Programs and the applicable gene targets associated therewith will no longer be Collaboration Targets; (c) Ionis’ obligations and Biogen’s rights under this Agreement with respect to
              such gene target and any ASOs targeting such gene target will then terminate, and Ionis will be free to Develop and Commercialize on its own or with a Third Party such gene target and any Compounds targeting such gene target; and (d) Ionis
              will own any data generated under the Collaboration Program for such gene target and any Compounds targeting such gene target.  For clarity, except to the extent explicitly set forth in the foregoing, the expiration of the Drug Discovery Term
              will not affect Biogen’s rights or Ionis’ obligations with respect to Collaboration Programs under this Agreement that have reached the Development Candidate stage by the end of the Drug Discovery Term, including, but not limited to, Ionis’
              obligation under Section 1.5.3 to Develop each such Development Candidate under the remaining Collaboration Programs through the [***].

          


     

    
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    	 	1.7.4.	
            If, despite Ionis’ Commercially Reasonable Efforts, by the end of the Drug Discovery Term, Ionis has not designated a Development Candidate for a particular Collaboration Program, then if at any time during the [***] period after the end
              of the Drug Discovery Term Ionis’ RMC designates an ASO discovered by Ionis that is designed to bind to the RNA that encodes the Collaboration Target that was the subject of such Collaboration Program as a development candidate ready to start
              IND-Enabling Toxicology Studies (such ASO, a “Carryover Development Candidate”), then, Ionis will notify Biogen and will provide Biogen with the data package presented to Ionis’ RMC
              to approve such Carryover Development Candidate. Biogen will then have [***] days from its receipt of such package to elect to enter into an agreement (or amendment to this Agreement) for an option and license under the same terms as set
              forth in this Agreement (except that no additional upfront payment under Section 6.1 will be due). If, within [***] days after Biogen’s receipt of such notice from Ionis, Biogen provides Ionis with written notice that it accepts such
              offer from Ionis for such Carryover Development Candidate, the Parties will execute an agreement (or amendment to this Agreement) regarding such Carryover Development Candidate containing the same terms as those described herein. If Biogen
              either notifies Ionis that it declines the offer for such Carryover Development Candidate, or Biogen does not
              provide Ionis with written notice during such [***] day period that Biogen accepts such offer from Ionis for such Carryover Development Candidate, then Ionis will be free to research, develop, manufacture and commercialize such Carryover
              Development Candidate (and/or any other ASO designed to bind to the RNA that encodes the gene target targeted by such Carryover Development Candidate) by itself or with or for a Third Party.

          


     

    	1.8.	
            Additional Activities Requested by Biogen.  Biogen will pay Ionis (a) costs resulting from requests from Biogen that
                Ionis perform additional work under this Agreement, including, the cost of Ionis’ time incurred in performing such work at the then-applicable Ionis FTE Rate (“FTE Costs”), the
                cost of [***], and any [***] incurred by Ionis in performing such work, or (b) Additional Plan Costs resulting from Biogen-Approved Changes (such costs, collectively “Biogen-Approved Costs”).  For clarity, the Biogen-Approved Costs shall include Additional Plan Costs for a [***] that result from changes to such [***] made after the
                milestone payment with respect to such [***] is agreed upon in writing by the Parties pursuant to Section 1.5.2(b), if such cost is increased by [***] as described in Section 1.5.2(b)).  For the avoidance of doubt, if such
                cost is increased by [***] as described in Section 1.5.2(b)), such increased costs will constitute an additional milestone payment to be paid in accordance with the provisions of Section 1.5.2(b), and will not be handled
                under this Section 1.8.  Ionis will permit Biogen to review, negotiate (with Ionis) and approve (including through the Neurology JSC) all Biogen-Approved Costs; provided Biogen will provide
                a substantive, good faith response within [***] days of Ionis’ request for approval.  For clarity (1) this Section 1.8 will not be used to establish the initial milestone payments under Section 1.5.2(b), and (2) expenses
                paid under this Section 1.8 are not subject to reconciliation.  Once Biogen-Approved Costs are mutually agreed under this Section 1.8, such agreement will be documented in a written side letter, in the form and format
                attached hereto as Appendix 3, which shall be executed by both Parties. Prior to such time as the Parties mutually agree on such Biogen-Approved Costs and have executed a written side
                letter with respect to the foregoing, Ionis may, in its discretion, commence Development activities for which it is responsible under this Agreement; provided, however, that Biogen will not be
                responsible for any costs of such Development activities if commenced by Ionis prior to the execution of any such side letter unless and until such a side letter has been executed by the Parties, and in no event will Biogen be responsible
                for any amounts incurred by Ionis for such Development activities in excess of amounts set forth in the side letter executed by the Parties with respect to such Development activities.

          


     

    
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    	 	1.8.1.	
            For Biogen-Approved Costs resulting from [***], or from [***] that are made after the milestone payment with respect to such [***] is agreed upon in writing by the Parties pursuant to Section 1.5.2(b), Biogen will pay Ionis for
              such Biogen-Approved Costs [***] within [***] days after receipt of the applicable invoice by Biogen following [***], or the date that Biogen agrees to such changes to such [***], as applicable; provided,
                however, that if such Biogen-Approved Costs total more than $[***], the Parties will apportion such total Biogen-Approved Costs into smaller milestone payments in accordance with Schedule 1.5.2(b)
              (or, if such Biogen-Approved Costs result from changes to a [***], then the Neurology JSC shall determine whether and how to apportion such Biogen-Approved Costs into smaller milestone payments).  Each such smaller milestone payment shall be
              payable by Biogen within [***] days after receipt of the applicable invoice by Biogen following the event that triggered such milestone payment.  If such Biogen-Approved Costs total $[***] or less, then such Biogen-Approved Costs shall become
              due in their entirety upon [***] or the date that the Parties agree to such Biogen-Approved Costs, if such [***], and shall be payable by Biogen within [***] days after receipt of the applicable invoice by Biogen following [***] or the date
              of such agreement regarding the Biogen-Approved Costs, as applicable.

          


     

    	 	1.8.2.	
            For Biogen-Approved Costs resulting from [***], Biogen will pay Ionis, in accordance with any applicable [***] entered into by the Parties after the Effective Date, for [***]% of such Biogen-Approved Costs within [***] days after receipt
              of the applicable invoice by Biogen following Biogen’s request or approval for such [***], and the remaining [***]% within [***] days after receipt of the applicable invoice by Biogen following [***].

          


     

    	 	1.8.3.	
            For any Biogen-Approved Cost that (i) has an Estimated Biogen-Approved Cost of less than [***] and (ii) does not result from [***], from [***] that are made after the milestone payment with respect to such [***] is agreed upon in writing
              by the Parties pursuant to Section 1.5.2(b) or from [***], Ionis will invoice Biogen directly for such Biogen-Approved Cost in advance, on a [***] basis based upon the applicable Estimated Biogen-Approved Costs and Biogen will pay the
              invoices submitted pursuant to this Section 1.8.3 for such Biogen-Approved Costs within [***] days after receipt of the applicable invoice by Biogen.  For purposes of this Section 1.8.3, “Measurement Period” means each [***].

          


     

    	 	1.8.4.	
            For any Biogen-Approved Costs that (i) has an Estimated Biogen-Approved Cost of $[***] or more and (ii) does not result from [***], from [***] that are made after the milestone payment with respect to such [***] is agreed upon in writing
              by the Parties pursuant to Section 1.5.2(b) or from [***], Ionis will invoice Biogen directly for such Biogen-Approved Cost in advance on a [***] basis based upon the applicable Estimated Biogen-Approved Costs and Biogen will pay the
              invoices submitted pursuant to this Section 1.8.4 for such Biogen-Approved Costs within [***] days after receipt of the applicable invoice by Biogen.  For purposes of this Section 1.8.4, “Measurement Period” means each [***].

          


     

    
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    	 	1.8.5.	
            Within [***] days after the end of the applicable Measurement Period, Ionis will provide Biogen with a written statement (i) reconciling the [***] the Estimated Biogen-Approved Costs and the [***] within the
              Biogen-Approved Costs (the “Actual Biogen-Approved Costs”) incurred by Ionis during the just-ended Measurement Period and (ii) confirming that the FTE Costs portion of the Estimated
              Biogen-Approved Costs is a reasonable approximation of the actual FTE Costs incurred by Ionis during the just-ended Measurement Period. If the Estimated Biogen-Approved Costs exceed the Actual Biogen-Approved Costs for such period, Ionis will
              offset all such excess payments against any future invoices under this Agreement until Biogen has recouped all such overpayments.  If the Estimated Biogen-Approved Costs are less than the Actual Biogen-Approved Costs for such period, Ionis
              will invoice Biogen for the remaining amounts owed to Ionis, and Biogen will pay such invoices within [***] days of receipt of such invoice. In the case where additional activities under this Section 1.8 are performed by a Third
              Party, the Parties will arrange for the Third Party to directly bill Biogen and for Biogen to pay such Third Party directly.

          


     

    	1.9.	
            Biogen’s Participation in Regulatory Meetings.  Prior to the License Effective Date for each Collaboration Program:

          


     

    	

          	(a)	
            Ionis will not initiate discussions with a Regulatory Authority regarding the [***] for a Collaboration Program until Ionis and Biogen have mutually agreed upon such [***], as applicable.

          


     

    	

          	(b)	
            To the extent practical, prior to any scheduled meeting with a Regulatory Authority regarding the [***] for a Collaboration Program, (i) the Parties will discuss and mutually agree upon the timing and objectives for such meeting and (ii)
              Ionis will provide Biogen with (A) an invitation to attend at least one pre-meeting rehearsal with Ionis and (B) an opportunity to discuss the strategy for such meeting with Ionis.  In addition, Ionis will allow Biogen to participate in any
              such meeting under the direction of Ionis.

          


     

    	

          	(c)	
            In each case, to the extent regarding the [***] for a Collaboration Program, Ionis will promptly provide Biogen with (i) final copies of all material correspondence with and submission to any Regulatory Authority promptly following
              submission thereof, (ii) a copy of material communications received from a Regulatory Authority, and (iii) a copy of the minutes from each meeting with a Regulatory Authority.

          


     

    	

          	(d)	
            Ionis will provide Biogen with a draft of all correspondence with and submissions to any Regulatory Authority that materially impact the [***] for a Collaboration Program sufficiently in advance of providing such correspondence or
              submission to the applicable Regulatory Authority to enable Biogen to have a meaningful opportunity to provide comments on the contents thereof.  The contents of such correspondence or submission to any Regulatory Authority must reflect the
              Development Plan.  The Parties will mutually agree on the contents of all such correspondence or submissions; provided that if mutual agreement is not obtained prior to a Regulatory Authority’s
              requirement for a response, Ionis will consider in good faith including any comments provided by Biogen to such correspondence or submissions.

          


     

    
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    	1.10.	
            Impact of [***] Development Path.  If the Parties mutually agree to amend a Development Plan where such amended plan contemplates [***], then the Parties will make appropriate changes to the operational terms of this Agreement (e.g., [***])
                to reflect such [***] development plan, consistent with the comparable provisions necessary to support the development plan under the [***].

          


     

    	1.11.	
            Research and Development Management.

          


     

    	 	1.11.1.	
            Neurology JSC.  The Parties will establish a joint steering committee (the “Neurology JSC”) to provide advice and make recommendations on the conduct of activities under each Collaboration Program. The Neurology JSC will consist of two
                representatives appointed by Ionis and two representatives appointed by Biogen. Each Neurology JSC member will be a senior scientific staff leader or have other experience and expertise appropriate for the stage of development of the
                Collaboration Programs. Each Party will designate one of its two representatives who is empowered by such Party to make decisions related to the performance of such Party’s obligations under this Agreement to act as the co-chair of the
                Neurology JSC. The co-chairs will be responsible for overseeing the activities of the Neurology JSC consistent with the responsibilities set forth in Section 1.11.2. Schedule
                  1.11.1 sets forth certain Neurology JSC governance matters agreed to as of the Effective Date. The Neurology JSC will determine the Neurology JSC operating procedures at its first meeting, including the Neurology JSC’s policies for
                replacement of Neurology JSC members, policies for participation by additional representatives or consultants invited to attend Neurology JSC meetings, and the location of meetings, which will be codified in the written minutes of the first
                Neurology JSC meeting. Each Party will be responsible for the costs and expenses of its own employees or consultants attending Neurology JSC meetings. Ionis and Biogen will use reasonable efforts to schedule meetings of the Neurology JSC to
                take place at the same location and on the same dates as meetings of the joint development and steering committees under the Ionis/Biogen Additional Agreements, to maximize the use of each Party’s time, increase information sharing
                efficiencies and reduce the cost of additional travel, lodging and related expenses.  Once a Development Candidate is designated under a Collaboration Program, the Parties will consider in good faith creating a separate subcommittee of the
                Neurology JSC to govern the activities under this Agreement with respect to such Collaboration Program.

          


     

    	 	1.11.2.	
            Role of the Neurology JSC.  Without limiting any of the foregoing, subject to Section 1.11.3, the Neurology JSC
                will perform the following functions, some or all of which may be addressed directly at any given Neurology JSC meeting:

          


     

    	

          	(a)	
            maintain the list of Collaboration Targets and the High Interest Target List, as such lists may be updated from time to time in accordance with this Agreement, and attach such lists to the minutes of the next meeting of the Neurology JSC
              following any update to the High Interest Target List or Collaboration Targets;

          


     

    
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          	(b)	
            review and provide advice on the Collaboration Program Research Plan for each Collaboration Program, and the Development Plan for each Development Candidate;

          


     

    	

          	(c)	
            review the overall progress of Ionis’ efforts to achieve Target Sanction with respect to each Collaboration Program that has not achieved Target Sanction status;

          


     

    	

          	(d)	
            review the overall progress of Ionis’ efforts to discover, identify, optimize and select the Development Candidate for each Collaboration Program;

          


     

    	

          	(e)	
            amend each Collaboration Program Research Plan for each Collaboration Program, and the Development Plan for each Development Candidate upon unanimous agreement;

          


     

    	

          	(f)	
            agree on Cost Estimates and the [***] milestone payments under Section 1.5.2(b);

          


     

    	

          	(g)	
            approve Biogen-Approved Costs pursuant to Section 1.8;

          


     

    	

          	(h)	
            if the milestone payment agreed upon in writing by the Parties pursuant to Section 1.5.2(b) with respect to a [***] exceeds $[***], establishing whether and how such payment shall be apportioned into smaller milestone payments as
              described in Section 1.5.2(b);

          


     

    	

          	(i)	
            if any Biogen-Approved Costs that result from [***] exceed $[***], establishing whether and how such payments shall be apportioned into smaller milestone payments as described in Section 1.8.1;

          


     

    	

          	(j)	
            review and provide advice on the Phase 1 Trial Design and the PoC Trial Design for each Collaboration Program; and

          


     

    	

          	(k)	
            such other review and advisory responsibilities as may be assigned to the Neurology JSC pursuant to this Agreement.

          


     

    	 	1.11.3.	
            Decision-Making.

          


     

    	

          	(a)	
            Decisions by the Neurology JSC will be made by unanimous consent, with each Party’s representatives having, collectively, one vote.  At any given meeting of the Neurology JSC, quorum will have deemed to be reached if a voting
              representative of each Party is present or participating in such meeting.  No action taken at any meeting of the Neurology JSC will be effective unless there is a quorum at such meeting.  Unless otherwise specified in this Agreement, no
              action will be taken with respect to a matter for which the Neurology JSC has not reached unanimous consensus.

          


     

    
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          	(b)	
            Ionis will give due consideration to, and consider in good faith, the recommendations and advice of the Neurology JSC regarding the conduct of the Collaboration Program. Subject to Section 1.5.1 and Section 1.5.2(a), prior
              to the License Effective Date for a particular Collaboration Program, Ionis will have the final decision-making authority regarding [***]. After the License Effective Date for a particular Collaboration Program, Biogen will have the final
              decision-making authority regarding [***] for such Collaboration Program, provided, however, that [***]. Except as otherwise permitted by Section 1.5.2(a) and Section 1.11.2(e), the
              Neurology JSC will have no decision-making authority and will act as a forum for sharing information about the activities conducted by the Parties hereunder and as an advisory body, in each case only on the matters described in, and to the
              extent set forth in, this Agreement.

          


     

    	 	1.11.4.	
            Term of the Neurology JSC.  Ionis’ obligation to participate in the Neurology JSC, or any of its subcommittees, will
                terminate upon Biogen’s exercise (or expiration) of the Option for the last Collaboration Program. Thereafter, Ionis will have the right, but not the obligation, to participate in Neurology JSC meetings upon Ionis’ request.

          


     

    	 	1.11.5.	
            Alliance Managers.  Each Party will appoint a representative to act as its alliance manager under this Agreement (each,
                an “Alliance Manager”). Each Alliance Manager will be responsible for supporting the Neurology JSC and performing the activities listed in Schedule
                  1.11.5.

          


     

    ARTICLE 2

    EXCLUSIVITY COVENANTS

     

    	2.1.	
            Exclusivity; Right of First Negotiation.

          


     

    	 	2.1.1.	
            Exclusivity Covenants.

          


     

    	

          	(a)	
            Ionis’ Exclusivity Covenants During the Drug Discovery Term for High Interest Targets.  On a High Interest
                Target-by-High Interest Target basis, Ionis agrees that, except in the performance of its obligations or exercise of its rights under this Agreement and except as set forth in Section 2.3, Section 2.1.2, Section 2.1.3,
                Section 10.4.2 or Section 10.4.3, it will not work for the benefit of any Third Party (including the grant of any license to any Third Party) with respect to the discovery, research, development, manufacture or
                commercialization of an ASO that is designed to bind to the RNA that encodes such High Interest Target in the Field from the Effective Date until the date on which the High Interest Target List is dissolved in
                accordance with Section 1.3.1(d).

          


     

    
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          	(b)	
            The Parties’ Exclusivity Covenants During the Option Period for Collaboration Targets.  On a Collaboration
                Target-by-Collaboration Target basis, each Party agrees that, except in the performance of its obligations or exercise of its rights under this Agreement and except as set forth in Section 2.1.2, Section 2.1.3, Section
                  10.4.2 or Section 10.4.3, it will not work independently or for or with any of its Affiliates or any Third Party (including the grant of any license to any Third Party) with respect to discovery, research, development,
                manufacture or commercialization of an ASO that is designed to bind to the RNA that encodes such Collaboration Target in the Field from the date such gene target was designated a Collaboration Target under
                this Agreement through the earlier of (i) the License Effective Date with respect to the Collaboration Program for such Collaboration Target and (ii) the expiration or earlier termination of the applicable Option Period.

          


     

    	

          	(c)	
            Ionis’ Exclusivity Covenant after the License Effective Date.  On a Collaboration Target-by-Collaboration Target basis,
                except as set forth in Section 2.1.2, Section 2.1.3, Section 10.4.2 or Section 10.4.3, after the License Effective Date for the Collaboration Program with respect to the applicable Collaboration Target, Ionis
                will not work independently or for or with any of its Affiliates or any Third Party (including the grant of any license to any Third Party) with respect to:

          


     

    	

          	(i)	
            discovery, research or development of an ASO that is designed to bind to the RNA that encodes such Collaboration Target in the Field until [***]; and

          


     

    	

          	(ii)	
            on a country-by-country basis, commercializing an ASO that is designed to bind to the RNA that encodes such Collaboration Target in the Field until [***].

          


     

    	

          	(d)	
            Biogen’s Exclusivity Covenant After the License Effective Date.  After the License Effective Date for a particular
                Collaboration Program, Biogen’s exclusivity obligations under Section 2.1.1(b) with respect to the Collaboration Target that is the subject of such Collaboration Program will be extended and will continue for so long as and to the
                extent of Ionis’ exclusivity obligations under Section 2.1.1(c).

          


     

    Except as expressly set forth in Section 2.1.2, Section 2.1.3, or Section 10.4.3, in no event will Ionis have the right to [***].

     

    	 	2.1.2.	
            Right of First Negotiation for Follow-On Compounds.  On a Collaboration Program-by-Collaboration Program basis, during
                the period commencing on the Effective Date and ending upon (i) if the applicable Option is not exercised in accordance with this Agreement, [***] or (ii) if the applicable Option is exercised in accordance with this Agreement, [***] (such period, the “ROFN Period”), Ionis hereby grants to Biogen a right of first negotiation to develop and commercialize any Follow-On Compound
                developed by or on behalf of Ionis, which right of first negotiation is granted on the following terms and conditions:

          


     

    
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          	(a)	
            Within [***], Biogen may provide Ionis with a non-binding, good faith written notice expressing Biogen’s desire for Ionis to identify a Follow-On Compound with respect to the Collaboration Target that is the subject of such Collaboration
              Program (a “Follow-On Interest Notice”). If (i) Biogen does not, within such [***] period, provide Ionis with a Follow-On Interest Notice, or (ii) Biogen does timely provide Ionis
              with a Follow-On Interest Notice but the Parties do not agree on a [***] related to such Follow-On Compound by 5:00 pm (Eastern Time) on the [***] following the License Effective Date for such Collaboration Program, then, Ionis may work
              independently or with any of its Affiliates or any Third Party with respect to the discovery, research, development and manufacture of a Follow-On Compound with respect to such Collaboration Target; provided, however, that during the ROFN Period, Ionis will not grant any license (or an option to obtain such a license) under any intellectual property owned, controlled or licensed by Ionis to make, use or sell
              any Follow-On Compound (a “Follow-On Agreement”) with respect to such Collaboration Target unless and until Ionis provides a written
              notice to Biogen (a “Follow-On Negotiation Notice”), which notice identifies [***].  Ionis will not initiate negotiations regarding or enter into such a Follow-On Agreement with any
              Third Party until [***] (each, a “ROFN Termination Event”).

          


     

    	

          	(b)	
            If Biogen or one of its Affiliates responds within [***] after its receipt of a Follow-On Negotiation Notice indicating that Biogen or one of its Affiliates desires to negotiate with Ionis regarding the proposed Follow-On Agreement, Ionis
              and Biogen or one of its Affiliates will negotiate in good faith with each other until the [***] after the date Ionis provided Biogen the Follow-On Negotiation Notice (or such other period as mutually agreed by the Parties) (the “Negotiation Period”) regarding a mutually satisfactory Follow-On Agreement (which may take the form of an amendment to this Agreement). During the Negotiation Period, Ionis will make at
              least [***] to Biogen or its Affiliate setting forth all material business and legal terms on which Ionis would be willing to enter into the proposed Follow-On Agreement with Ionis; provided that
              neither Party will have any obligation to enter into any such Follow-On Agreement. If the Negotiation Period expires before Biogen or its Affiliate and Ionis have entered into such a Follow-On Agreement, Ionis will have no further obligation
              to negotiate with Biogen or its Affiliates with respect to such Follow-On Agreement and Ionis will be free to negotiate and enter an agreement with a Third Party with respect to a Follow-On Agreement [***]; provided, however, that Ionis will not enter into any such Follow-On Agreement with any Third Party unless the terms and pricing of such Follow-On Agreement, [***] during the Negotiation Period. If, with respect to
              any Follow-On Compound that was the subject of the Follow-On Agreement previously discussed by the Parties, after the end of the Negotiation Period and prior to Ionis entering into a Follow-On Agreement with a Third Party, [***] regarding the
              Follow-On Compound, Ionis’ obligations and Biogen’s rights under Section 2.1.2(a) and this Section 2.1.2(b) will reset and Ionis will provide Biogen with a new Follow-On Negotiation Notice.

          


     

    
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          	(c)	
            Any Follow-On Agreement entered into by Ionis with a Third Party in accordance with Section 2.1.2(b) will be a Permitted License to the extent related to the Follow-On Compound.

          


     

    	

          	(d)	
            Notwithstanding anything to the contrary in this Agreement, until [***], Ionis will provide to Biogen a Follow-On Negotiation Notice for each [***]






                pursuant to this Section 2.1.2, unless Ionis enters into a Follow-On Agreement with a Third Party pursuant to this Section 2.1.2 and the terms of such agreement do not permit Ionis to grant Biogen rights with respect to the applicable Follow-On Compound.

          


     

    	 	2.1.3.	
            Limitations and Exceptions to Exclusivity Covenants.

          


     

    	

          	(a)	
            Notwithstanding anything to the contrary in this Agreement, Ionis’ practice of the following will not violate Section 2.1.1:

          


     

    	

          	(i)	
            The discovery, research, development, manufacture or commercialization of Gene-Editing Products or messenger RNA;

          


     

    	

          	(ii)	
            Any activities pursuant to the Prior Agreements as in effect on the Effective Date;

          


     

    	

          	(iii)	
            The granting of, or performance of obligations under, Permitted Licenses;

          


     

    	

          	(iv)	
            The discovery, research, development, manufacture or commercialization of one or more Pre-Existing Competitive Products in accordance with Section 12.5.1; and

          


     

    	

          	(v)	
            The limited continuation of discovery, research, development, manufacture or commercialization of Acquired Competitive Product(s) as permitted under Section 12.5.2(a) and in accordance with Section 12.5.2(a) and Section
                12.6.

          


     

    	

          	(b)	
            Notwithstanding anything to the contrary in this Agreement, Biogen’s practice of the following will not violate Section 2.1.1:

          


     

    	

          	(i)	
            The discovery, research, development, manufacture or commercialization of Gene-Editing Products or messenger RNA;

          


     

    	

          	(ii)	
            The discovery, research, development, manufacture or commercialization of one or more Pre-Existing Competitive Products in accordance with Section 12.5.1; and

          


     

    
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          	(iii)	
            The limited continuation of discovery, research, development, manufacture or commercialization of Acquired Competitive Product(s) as permitted under Section 12.5.2(a) and in accordance with Section 12.5.2(a) and Section
                12.6.

          


     

    	2.2.	
            Effect of Exclusivity on Indications.  The Compounds are
                designed to bind to the RNA that encodes a Collaboration Target in the Field with the intent of treating a neurological or neuromuscular disease. Ionis and Biogen are subject to exclusivity obligations under Section 2.1; however, the Parties acknowledge and agree that each Party (on its own or with a Third Party) may continue to discover, research, develop, manufacture and commercialize products that are designed to bind
                to the RNA that encodes a gene that is not a Collaboration Target (or with respect to Ionis, that is not a High Interest Target, to the extent
                Section 2.1.1(a) still applies) for any indication, even if such products are designed to treat a neurological or neuromuscular disease.

          


     

    	2.3.	
            Consequences of Ionis-Discovered High Interest Target Development Candidate.  Ionis may work for itself (but not for
                the benefit of a Third Party) to conduct drug discovery activities to identify a High Interest Target Development Candidate, including drug screening, identification, characterization, optimization, and, subject to Section 1.5.6,
                research collaborations with academic or non-profit institutions.  Ionis will notify the Neurology JSC of any such activities and keep the Neurology JSC reasonably apprised of the status thereof.  If Ionis designates a High Interest Target
                Development Candidate targeting a particular High Interest Target (such target, an “Accelerated Target”), Ionis may notify Biogen in writing regarding Ionis’ designation of such
                High Interest Target Development Candidate and will provide Biogen the applicable Development Candidate Data Package; provided, however, that unless
                otherwise agreed to by Biogen in writing, Ionis may not provide Biogen more than [***] in any rolling [***] month period.  Within [***] following Biogen’s receipt of the applicable Development
                Candidate Data Package, Biogen may (a) if Biogen has not designated all three Collaboration Targets, designate the Accelerated Target as a Collaboration Target, or (b) if Biogen has designated all three Collaboration Targets, substitute-out
                a Collaboration Target in exchange for substituting-in the Accelerated Target as a Collaboration Target (pursuant to the procedures set forth in Section 1.4.2).  If Biogen does not, within such [***] period, designate the
                Accelerated Target as a Collaboration Target pursuant to clause (a) or (b) of this Section 2.3, then, such Accelerated Target will no longer be a High Interest Target and Ionis may work independently or with any of its Affiliates or
                any Third Party with respect to the discovery, research, development, and commercialization of ASOs (or any other compounds) targeting such Accelerated Target.

          


     

    
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    ARTICLE 3

    EXCLUSIVE OPTION

     

    	3.1.	
            Option.

          


     

    	 	3.1.1.	
            Advance Data Disclosure.  On or about 90 days before the date on which Ionis estimates that the database will be locked
                for the first PoC Trial for a particular Collaboration Program that is being conducted by Ionis (each an “Estimated Lock Date”), Ionis will provide Biogen with a written notice of
                such Estimated Lock Date. If Biogen provides written notice to Ionis [***] after Biogen’s receipt of the notice regarding the Estimated Lock Date that Biogen has a good faith intention to exercise the Option for the applicable Collaboration
                Program under Section 3.1.3, then as soon as reasonably practicable after Ionis receives such notice from Biogen, Ionis will provide Biogen with an early preview of the information to be included in the [***] for the applicable
                Collaboration Program to the extent then in Ionis’ possession and not already provided to Biogen, to assist Biogen with its decision of whether to exercise the Option. Within 15 Business Days after Biogen’s receipt of such data, Biogen will
                provide Ionis with a [***] notice of whether Biogen still intends to exercise the Option for the applicable Collaboration Program; provided, however, that
                Biogen’s failure to do so will not be deemed a breach of this Agreement.

          


     

    	 	3.1.2.	
            PoC Trial Completion Notice.  On a Collaboration Program-by-Collaboration Program basis where Ionis conducts the first
                PoC Trial, Ionis will provide to Biogen or its designated Affiliate (a) a copy of the most recent Investigator’s Brochure for the applicable Product, (b) written notice from Ionis regarding completion of the first PoC Trial, and (c) the PoC
                Data Package for such Collaboration Program, to the extent not already provided to Biogen under Section 3.1.1 above (such notice and package, a “PoC Trial Completion Notice”)






                promptly, and in any event within [***] days after database lock for the PoC Trial for such Collaboration Program.  Within 15 days of receipt of the PoC Trial Completion Notice, Biogen or an Affiliate will notify Ionis of any omissions or
                deficiencies that Biogen or its Affiliate believes in good faith cause the PoC Trial Completion Notice to be incomplete (“Deficiency Notice”). Ionis will promptly, and in any event
                within 15 days of receipt of the Deficiency Notice, resubmit a complete PoC Trial Completion Notice to Biogen or its designated Affiliate, including any information required to be included in the PoC Data Package that Biogen identified in
                the Deficiency Notice. If the Parties do not agree as to whether the PoC Trial Completion Notice is complete, the matter will be referred to the Executives for resolution. The Executives will meet promptly and negotiate in good faith to
                resolve the dispute and agree upon a complete PoC Trial Completion Notice.

          


     

    	 	3.1.3.	
            Option and Option Deadline.  On a Collaboration Program-by-Collaboration Program basis, Ionis hereby grants to Biogen
                and its Affiliates an exclusive option to obtain the license set forth in Section 4.1.1 with respect to such Collaboration Program (each an “Option”). Each Option will be
                available to Biogen and its Affiliates until 5:00 pm (Eastern Time) on the [***] following Biogen’s receipt of a complete PoC Trial Completion Notice for the applicable Collaboration Program (the “Option Deadline”); provided, however, that if Biogen determines that an HSR Filing is required to be made under the HSR Act to exercise the
                Option and notifies Ionis of such determination within [***] after Biogen’s receipt of the complete PoC Trial Completion Notice, the Parties will promptly file an HSR Filing in accordance with Section 3.1.4 and the Option Deadline
                will be extended until 5:00 pm (Eastern Time) on the fifth Business Day after the HSR Clearance Date. If, by the Option Deadline, Biogen or its designated Affiliate (a) notifies Ionis in writing that it wishes to exercise the applicable
                Option, and (b) pays to Ionis the license fee set forth in Section 6.3, Ionis will, and hereby does, grant to Biogen or its designated Affiliate the license set forth in Section 4.1.1. If, by the Option Deadline, Biogen or
                its designated Affiliate has not both (y) provided Ionis a written notice stating that Biogen is exercising its Option, and (z) paid Ionis the license fee in accordance with Section 6.3, then Biogen’s Option for the applicable
                Collaboration Program will expire and Sections 10.4.2(a), 10.4.2(b), 10.4.2(c) and 10.4.2(e) will apply.

          


     

    
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    	3.1.4.	
            HSR Compliance.

          


     

    	

          	(a)	
            HSR Filing.  If Biogen notifies Ionis pursuant to Section 3.1.3 that an HSR Filing is required to exercise an
                Option under this Agreement, then each of Biogen and Ionis will, within five Business Days after such notice from Biogen (or such later time as may be agreed to in writing by the Parties), file with the United States Federal Trade
                Commission (“FTC”) and the Antitrust Division of the United States Department of Justice (“DOJ”), any HSR Filing
                required with respect to the transactions contemplated hereby. The Parties will cooperate with one another to the extent necessary in the preparation of any such HSR Filing. Each Party will be responsible for its own costs and expenses
                (other than filing fees, which Biogen will pay) associated with any HSR Filing.

          


     

    	

          	(b)	
            HSR Clearance.  In furtherance of obtaining HSR Clearance for an HSR Filing filed under Section 3.1.4(a), Ionis
                and Biogen will use their respective commercially reasonable efforts to resolve as promptly as practicable any objections that may be asserted with respect to this Agreement or the transactions contemplated by this Agreement under any
                antitrust, competition or trade regulatory law. In connection with obtaining such HSR Clearance from the FTC, the DOJ or any other governmental authority, Biogen and its Affiliates will not be required to (i) sell, divest (including through
                a license or a reversion of licensed or assigned rights), hold separate, transfer or dispose of any assets, operations, rights, product lines, businesses or interest therein of Biogen or any of its Affiliates (or consent to any of the
                foregoing actions); or (ii) litigate or otherwise formally oppose any determination (whether judicial or administrative in nature) by a governmental authority seeking to impose any of the restrictions referenced in clause (i) above.

          


     

    	3.2.	
            Restrictions on Ionis’ Right to Grant Diagnostic Rights; Right to Negotiate Diagnostic Rights.

          


     

    	 	3.2.1.	
            On a Product-by-Product basis, Ionis hereby grants to Biogen and its Affiliates an option (the “Diagnostic Option”) to negotiate during the Full Royalty Period the terms of an agreement under which [***]. The Diagnostic Option will be
              available to Biogen and its Affiliates until the expiration of the [***].

          


     

    	 	3.2.2.	
            During the [***], Ionis (a) has the right to [***], and (b) will not [***].

          


     

    	 	3.2.3.	
            If, during the [***], Ionis grants any Third Party a [***], then Ionis will promptly notify Biogen of such [***] and will offer Biogen a [***].

          


     

    
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    ARTICLE 4

    LICENSE GRANTS

     

    	4.1.	
            License Grants to Biogen.

          


     

    	 	4.1.1.	
            Development and Commercialization Licenses.  Subject to the terms and conditions of this Agreement, on a Collaboration
                Program-by-Collaboration Program basis, effective upon the License Effective Date for a particular Collaboration Program in accordance with this Agreement, Ionis grants to Biogen a worldwide, exclusive, royalty-bearing, sublicensable (in
                accordance with Section 4.1.2 below) license under the Licensed Technology to research, Develop, Manufacture, have Manufactured (in accordance with Section 4.1.2 below), register, market and Commercialize Products under such
                Collaboration Program in the Field.

          


     

    	 	4.1.2.	
            Sublicense Rights; CMO Licenses.

          


     

    	

          	(a)	
            Subject to the terms and conditions of this Agreement, and on a Collaboration Program-by-Collaboration Program basis, Biogen will have the right to grant sublicenses under the licenses granted under Section 4.1.1 above and Section






                4.3.1(b) below:

          


     

    	

          	(i)	
            under the Ionis Core Technology Patents, Ionis Product-Specific Patents and Ionis Know-How, to an Affiliate of Biogen or a Third Party; and

          


     

    	

          	(ii)	
            under the Ionis Manufacturing and Analytical Patents and Ionis Manufacturing and Analytical Know-How, solely to (A) [***] or (B) [***];

          


     

    provided that each such sublicense will be subject to, and consistent with, the terms and
        conditions of this Agreement. If, within [***] days of first learning of any breach of such sublicense terms, Biogen fails to take any action to enforce the sublicense terms of a sublicense granted pursuant to this Section 4.1.2, which
        failure would cause an adverse effect on Ionis, then Biogen hereby grants Ionis the right to enforce such sublicense terms on Biogen’s behalf and will cooperate with Ionis (which cooperation will be at Biogen’s sole expense and will include, Biogen
        joining any action before a court or administrative body filed by Ionis against such Sublicensee if and to the extent necessary for Ionis to have legal standing before such court or administrative body) in
        connection with enforcing such terms. Biogen will provide Ionis with a true and complete copy of any sublicense granted pursuant to this Section 4.1.2 within [***] days after the execution thereof.

     

    	

          	(b)	
            In connection with Biogen’s selecting and engaging one or more CMOs to supply Clinical Supplies under Section 4.3.1(b) or after the License Effective Date with respect to a Collaboration Program, or supply API and Finished Drug
              Product for Commercialization, Ionis will, at Biogen’s option, either (i) grant a license from Ionis to [***] under the [***] to the extent necessary for [***], which Ionis agrees it will grant to [***], or, (ii) permit Biogen to grant a
              sublicense from Biogen to [***].  Each such manufacturing agreement between Biogen and a CMO will contain [***]. Biogen will provide Ionis with a true and complete copy of any manufacturing agreement entered into with a CMO within [***] days
              after the execution thereof.  Notwithstanding the foregoing, if Ionis fails to comply with the terms of this Section 4.1.2(b) and does not cure such failure within 90 days after written notice from Biogen specifying the details of any
              such failure, then Biogen will have the right to [***].

          


     

    
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          	(c)	
            Effect of Termination on Sublicenses.

          


     

    	

          	(i)	
            If this Agreement terminates for any reason, then any Sublicensee of Biogen will, from the effective date of such termination, automatically become a direct licensee of Ionis with respect to the rights sublicensed to the Sublicensee by
              Biogen; so long as (i) such Sublicensee is not in breach of its sublicense agreement, (ii) such Sublicensee agrees in writing to comply with all of the terms of this Agreement to the extent applicable
              to the rights originally sublicensed to it by Biogen, and (iii) such Sublicensee agrees to pay directly to Ionis such Sublicensee’s payments under this Agreement to the extent applicable to the rights sublicensed to it by Biogen.  Biogen
              agrees that it will confirm clause (i) of the foregoing in writing at the request and for the benefit of Ionis and if requested, the Sublicensee.

          


     

    	

          	(ii)	
            If this Agreement terminates for any reason, then any Sublicensee of Biogen under Section 4.3.1(c) and any Sublicensee of Ionis under Section 4.5.2 will, from the effective date of such termination, automatically become a
              direct licensee of the applicable Party with respect to the rights sublicensed to the Sublicensee by the other Party hereunder; so long as (A) such Sublicensee is not in breach of its sublicense
              agreement, (B) such Sublicensee agrees in writing to comply with all of the terms of this Agreement to the extent applicable to the rights originally sublicensed to such Sublicensee, and (C) with respect to Sublicensees of Ionis, such
              Sublicensee agrees to pay directly to Biogen such Sublicensee’s payments under Section 4.4.2 to the extent applicable to the rights sublicensed to it by Ionis.  Each Party agrees that it will confirm clause (A) of this Section
                4.1.2(c)(ii) in writing at the request and for the benefit of the other Party and if requested, the Sublicensee.

          


     

    	 	4.1.3.	
            No Implied Licenses.  All rights in and to the Licensed Technology not expressly licensed to Biogen under this
                Agreement are hereby retained by Ionis or its Affiliates. All rights in and to Biogen Technology not expressly licensed or assigned to Ionis under this Agreement, are hereby retained by Biogen or its Affiliates.  Except as expressly
                provided in this Agreement, no Party will be deemed by estoppel or implication to have granted the other Party any license or other right with respect to any intellectual property.

          


     

    
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    	 	4.1.4.	
            License Conditions; Limitations.  Subject to Section 6.8, any license granted under Section 4.1.1 and
                the sublicense rights under Section 4.1.2 are subject to and limited by (a) any applicable Third Party Obligations, (b) the Prior Agreements, and (c) the Ionis In-License Agreements, in each case to the extent the provisions of such
                obligations or agreements are specifically disclosed to Biogen in writing (or via electronic data room) prior to Biogen’s exercise of the applicable Option. Ionis will disclose to Biogen any Third Party Obligations Ionis believes apply to
                applicable Products each time Ionis provides Biogen with (x) the [***]; and (z) the [***], and Biogen will have the right to elect to exclude any Third Party Patent Rights and Know-How to which such Third Party Obligations
                apply by providing Ionis written notice prior to the License Effective Date for a particular Collaboration Program. If, prior to the License Effective Date with respect to a Collaboration Program, Biogen provides Ionis with such a written
                notice to exclude certain Third Party Patent Rights and Know-How, such Third Party Patent Rights and Know-How will not be included in the Licensed Technology licensed with respect to the applicable Products under this Agreement. If Biogen
                does not provide Ionis with such a written notice to exclude such Third Party Patent Rights and Know-How prior to the License Effective Date for such Collaboration Program, then such Third Party Patent Rights and Know-How (and any Third
                Party Obligations to the extent applicable to Products) will be included in the Licensed Technology licensed with respect to the applicable Products under this Agreement.

          


     

    	 	4.1.5.	
            Trademarks for Products.  If Biogen exercises an Option for a Collaboration Program hereunder, to the extent that (a)
                Ionis owns any trademark(s) specific to a Product under such Collaboration Program, which trademark(s) Ionis used prior to the License Effective Date for such Collaboration Program, and (b) Biogen reasonably believes such trademark(s) would
                be necessary or useful for the marketing and sale of the applicable Product, then upon Biogen’s request and at Biogen’s sole cost and expense relating to such assignment, Ionis will assign its rights and title to such trademark(s) to Biogen
                or one or more designated Affiliates sufficiently in advance of the First Commercial Sale of the Product to enable Biogen or its Affiliates to offer such Product for sale under such trademark(s). Other






                than trademarks owned by Ionis prior to such License Effective Date, Biogen or its designated Affiliate will be solely responsible for developing, selecting, searching, registering and maintaining, and, subject to Section 10.4, will
                be the exclusive owner of, all trademarks, trade dress, logos, slogans, designs, copyrights and domain names used on or in connection with Products.

          


     

    	4.2.	
            Assignment of Ionis Product-Specific Patents; Grant Back to Ionis.

          


     

    	 	4.2.1.	
            After Biogen has obtained the license for a particular Collaboration Program under Section 4.1.1 and following review and consideration by the Joint Patent Committee, Ionis will assign to Biogen or one or more of its designated
              Affiliates, Ionis’ ownership interest in (a) all Ionis Product-Specific Patents related to such Collaboration Program in the Field that are owned by Ionis (whether solely owned or jointly owned with one or more Third Parties), and (b) any
              Jointly-Owned Program Patents Covering Products related to such Collaboration Program, and thereafter, subject to Section 7.2.4, Ionis will have no further right to control any aspect of the Prosecution and Maintenance of such Ionis
              Product-Specific Patents and such Jointly-Owned Program Patents. The assignment of Patent Rights assigned in this Section 4.2.1 will occur within [***] days of Biogen obtaining the applicable license under Section 4.1.1.

          


     

    
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    	 	4.2.2.	
            Subject to the terms and conditions of this Agreement (including Ionis’ exclusivity covenants under Section 2.1.1), Biogen grants to Ionis a worldwide, sublicensable license under any Ionis Product-Specific Patents and
              Jointly-Owned Program Patents assigned to Biogen under Section 4.2.1 [***], (b) to conduct activities under other Collaboration Program Research Plans and (c) to [***] to the extent permitted by this Agreement.

          


     

    	4.3.	
            Enabling Licenses.

          


     

    	 	4.3.1.	
            Licenses During the Option Period.

          


     

    	

          	(a)	
            Subject to the terms and conditions of this Agreement, Ionis hereby grants Biogen a worldwide, non-exclusive, sublicensable (but only as permitted in Section 4.3.1(c) below), royalty-free license under the Ionis Manufacturing and
              Analytical Know-How and Ionis Manufacturing and Analytical Patents solely to conduct Manufacturing and drug substance process and formulation development activities with respect to any Compound or Product under any Collaboration Program
              during the Option Period for such Collaboration Program; provided that the grant of rights pursuant to this Section 4.3.1(a) shall not include the right to Manufacture any Compound or Product
              for Commercialization purposes.

          


     

    	

          	(b)	
            Subject to the terms and conditions of this Agreement (including Biogen’s exclusivity covenants under Section 2.1.1), [***] for Biogen to conduct (i) Manufacturing of Compounds or Products under any Collaboration Program or (ii)
              any Biogen Activities that are Development activities with respect to any Collaboration Program in accordance with this Agreement, in each case ((i) and (ii) during the Option Period), Ionis hereby grants Biogen a worldwide, non-exclusive,
              sublicensable (but only as permitted in Section 4.1.2 above), royalty-free license under the Licensed Technology. Biogen will [***] arising under any Third Party agreement as a result of granting Biogen the license under this Section






                4.3.1(b) within [***] days after Biogen’s receipt of the applicable invoice. For clarity, the grant of rights pursuant to this Section 4.3.1(b) shall not include the right to Commercialize any such Product or to Manufacture any
              such Product for Commercialization.

          


     

    
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          	(c)	
            Biogen’s Right to Sublicense.  Biogen will have the right to grant sublicenses under the license granted under Section






                  4.3.1(a) above (i) in the case of a sublicense of Biogen’s right to conduct Manufacturing of Compounds or Products, other than any sublicense to conduct manufacturing in support of drug substance process and formulation development
                activities, solely to (A) [***] or (B) [***] and (ii) in the case of a sublicense of Biogen’s right to conduct drug substance process and formulation development activities, including manufacturing in support thereof, to any [***].  If,
                within [***] days after first learning of any breach of such sublicense terms by any such Sublicensee, Biogen fails to take any action to enforce the sublicense terms of a sublicense granted pursuant to this Section 4.3.1(c), which
                failure would cause an adverse effect on Ionis, then Biogen hereby grants Ionis the right to enforce such sublicense terms on Biogen’s behalf and will cooperate with Ionis (which cooperation will be at Biogen’s sole expense and will include
                Biogen joining any action before a court or administrative body filed by Ionis against such Sublicensee if and to the extent necessary to have legal standing before such court or administrative body) in connection with enforcing such
                terms.  Biogen will provide Ionis with a true and complete copy of any sublicense granted to a Third Party pursuant to this Section 4.3.1(c) within [***] days after the execution thereof.  For the avoidance of doubt, Section
                  4.1.2(c)(ii) shall apply to sublicenses granted under this Section 4.3.1(c).

          


     

    	 	4.3.2.	
            Enabling Licenses to Biogen.

          


     

    	

          	(a)	
            Subject to the terms and conditions of this Agreement (including Biogen’s exclusivity covenants under Section 2.1.1), Ionis hereby grants Biogen an irrevocable, perpetual, worldwide, non-exclusive, sublicensable (subject to the
              restrictions set forth in Section 4.3.2(c)) license under any Ionis Program Technology Controlled by Ionis or its Affiliates at any time during the Agreement Term, to research, develop, manufacture, have manufactured and commercialize
              (i) a product that is being developed or commercialized by Biogen, its Affiliates or its Sublicensee under any Ionis/Biogen Additional Agreement or this Agreement, (ii) products that do not include an Oligonucleotide as an active
              pharmaceutical ingredient, and (iii) Gene-Editing Products. The licenses in clause (ii) and clause (iii) of this Section 4.3.2(a) and in Section 4.3.2(b) are royalty-free; except that
              if a product that is not a Product being sold by Biogen, its Affiliates or Sublicensees is Covered by a Target Related Ionis Program Claim in a country, then on a country-by-country basis Biogen will pay to Ionis a royalty equal to [***]% of
              Net Sales of such product sold by Biogen, its Affiliates or Sublicensees so long as such product is Covered by such Target Related Ionis Program Claim in such country. A “Target Related
                Ionis Program Claim” means a Valid Claim that (A) is within an Ionis Program Patent that is solely owned by Ionis, (B) Covers a product being sold by Biogen, its Affiliates or Sublicensee and (C) claims a gene target, or a method of
              modulating such gene target to achieve a prophylactic or therapeutic effect/benefit.

          


     

    	

          	(b)	
            Subject to the terms and conditions of this Agreement (including Biogen’s exclusivity covenants under Section 2.1.1), Ionis hereby grants Biogen an irrevocable, perpetual, worldwide, non-exclusive, sublicensable (subject to the
              restrictions set forth in Section 4.3.2(c)) license under any Ionis Program Know-How and any Enabled Core Program Patents, in each case, Controlled by Ionis or its Affiliates at any time during the Agreement Term, to research,
              develop, manufacture, have manufactured and commercialize any product, including products that include an Oligonucleotide as an active pharmaceutical ingredient.

          


     

    
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          	(c)	
            Biogen may share any raw data included in the Ionis Program Know-How licensed to Biogen under Sections 4.3.2(a) and 4.3.2(b) for use in connection with the performance of its obligations or exercise of its rights under this
              Agreement or any Ionis/Biogen Additional Agreement, and Biogen may share the conclusions drawn from or based on the review of such raw data with any Third Party. Other than in accordance with the foregoing sentence, Biogen shall not share
              with any Third Party that is not an academic or non-profit institution or a contractor acting on Biogen’s behalf any raw data included in such Ionis Program Know-How or any tangible embodiments thereof to the extent such raw data and tangible
              embodiments constitute Confidential Information of Ionis.

          


     

    	 	4.3.3.	
            Enabling Licenses to Ionis.

          


     

    	

          	(a)	
            Subject to the terms and conditions of this Agreement (including Ionis’ exclusivity covenants under Section 2.1.1), Biogen hereby grants Ionis an irrevocable, perpetual, worldwide, non-exclusive, sublicensable (subject to the
              restrictions set forth in Section 4.3.3(c)) license under any Biogen Program Technology Controlled by Biogen or its Affiliates at any time during the Agreement Term other than any Biogen Results licensed to Ionis under Section
                4.4.1, to research, develop, manufacture, have manufactured and commercialize (a) products that include an Oligonucleotide as an active pharmaceutical ingredient (other than products that include an Oligonucleotide that is designed to
              bind to the RNA that encodes the same target as a product that is being developed or commercialized by Biogen, its Affiliates or Sublicensee pursuant to an Option or exclusive license granted from Ionis under this Agreement or any
              Ionis/Biogen Additional Agreement) and (b) Gene-Editing Products. The licenses set forth in this Section 4.3.3(a) and in Section 4.3.3(b) are royalty-free; except that if a product
              that is not a Discontinued Product being sold by Ionis, its Affiliates or Sublicensee is Covered by a Target Related Biogen Program Claim in a country, then on a country-by-country basis Ionis will pay to Biogen a royalty equal to [***]% of
              net sales of such product sold by Ionis, its Affiliates or Sublicensees, for so long as such product is Covered by such Target Related Biogen Program Claim in such country. For the purpose of the foregoing royalty calculation, “net sales”
              will be calculated [***]. The provisions of Sections 6.9, 6.10, 6.11 and 6.12 shall apply, mutatis mutandis, to any royalty payments by Ionis to Biogen under this Section






                4.3.3(a). A “Target Related Biogen Program Claim” means a Valid Claim that (i) is within a Biogen Program Patent that is solely owned by Biogen, (ii) Covers a product being
              sold by Ionis, its Affiliates or Sublicensee and (iii) claims a gene target, or a method of modulating such gene target to achieve a prophylactic or therapeutic effect/benefit.

          


     

    
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          	(b)	
            Subject to the terms and conditions of this Agreement (including Ionis’ exclusivity covenants under Section 2.1.1), Biogen hereby grants Ionis an irrevocable, perpetual, worldwide, non-exclusive, sublicensable (subject to the
              restrictions set forth in Section 4.3.3(c)) license under any Biogen Program Know-How and any Enabled Core Program Patents, in each case, Controlled by Biogen or its Affiliates at any time during the Agreement Term, to research,
              develop, manufacture, have manufactured and commercialize any product, including products that do not include an Oligonucleotide as an active pharmaceutical ingredient.

          


     

    	

          	(c)	
            Ionis may share any raw data included in the Biogen Program Know-How licensed to Ionis under Sections 4.3.3(a) and 4.3.3(b) for use in the performance of its obligations or exercise of its rights under this Agreement or any
              Ionis/Biogen Additional Agreement, and Ionis may share the conclusions drawn from or based on the review of such raw data with any Third Party. Other than in accordance with the foregoing sentence, Ionis shall not share with any Third Party
              that is not an academic or non-profit institution or a contractor acting on Biogen’s behalf any raw data included in such Biogen Program Know-How or any tangible embodiments thereof to the extent such raw data and tangible embodiments
              constitute Confidential Information of Biogen.

          


     

    	4.4.	
            Licenses to Ionis for Biogen Results.

          


     

    	 	4.4.1.	
            Subject to the terms and conditions of this Agreement, Biogen hereby grants Ionis an irrevocable, worldwide, non-exclusive, sublicensable license under the Biogen Results Controlled by Biogen or its Affiliate at any time during the
              Agreement Term, to research, develop, make, have made, import, export, use and sell (a) products that include an Oligonucleotide as an active pharmaceutical ingredient (other than products that include an
              Oligonucleotide that is designed to bind to the RNA that encodes the same target as a product that is being developed or commercialized by the Parties pursuant to an Option or exclusive license granted from Ionis under this Agreement or the
              Ionis/Biogen Additional Agreements) and (b) Gene-Editing Products.

          


     

    	

          	4.4.2.	
            The license granted in Section 4.4.1 shall be [***] with respect to any [***].  Such license will be [***] with respect to any [***] as follows: on a country-by-country, product-by-product and Biogen Manufacturing Program Patent-by-Biogen
              Manufacturing Program Patent basis, Ionis will pay to Biogen [***].  If one or more Biogen Manufacturing Program Patents expires, is invalidated or otherwise ceases to Cover a product bearing royalties as set forth above, the applicable
              royalty rate under this Section 4.4.2 shall be recalculated to reflect the number of Biogen Manufacturing Program Patents then-Covering such product.  For the purpose of the foregoing royalty calculation, [***] will be calculated as follows: 
              [***].  If Ionis grants a sublicense under this Section 4.4 to an entity that is an Ionis Affiliate at the time Ionis grants such sublicense, such applicable sublicense will [***].  The provisions of Section 6.9, Section 6.10, Section 6.11
              and Section 6.12 shall apply, mutatis mutandis, to any royalty payments by Ionis to Biogen under this Section 4.4.2.

          


     

    
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    	4.5.	
            Right to Obtain Direct License from Biogen to Ionis Partner; Sublicensees of Ionis.

          


     

    	

          	4.5.1.	
            If requested by Ionis, Biogen shall grant a direct, [***] license under the Biogen Results to [***] on the same terms as set forth in Section 4.4 with respect to sublicenses of Ionis.  Biogen shall endeavor in good faith to grant such
              license within [***] days of any such request by Ionis.

          


     

    	

          	4.5.2.	
            Ionis will have the right to grant sublicenses under the licenses granted under Section 4.4, provided that each such sublicense will be subject to, and consistent with, the terms and conditions of this Agreement.  If, within [***] days
              after first learning of any breach of such sublicense terms, Ionis fails to take any action to enforce the sublicense terms of a sublicense granted pursuant to this Section 4.5.2, which failure would cause an adverse effect on Biogen, Ionis
              hereby grants Biogen the right to enforce such sublicense terms on Ionis’ behalf and will cooperate with Biogen (which cooperation will be at Ionis’ sole expense and will include, Ionis joining any action before a court or administrative body
              filed by Biogen against such Sublicensee if and to the extent necessary for Biogen to have legal standing before such court or administrative body) in connection with enforcing such terms.  Ionis will provide Biogen with a true and complete
              copy of any sublicense granted pursuant to this Section 4.5.2 within [***] days after the execution thereof.

          


     

    	4.6.	
            Ownership of and Assistance with Regulatory Filings.  If requested by Biogen, Ionis’ and Biogen’s regulatory teams will
                meet and begin to prepare a plan, which plan will be complete no later than [***] prior to such anticipated filing date, for drafting and reviewing the sections of the NDA and MAA for the applicable Product (including establishing
                responsibilities for drafting and reviewing common technical document (“CTD”) modules, authorship, plan activity timelines and associated costs and expenses) to ensure a smooth
                transition to Biogen, accelerate CTD completion and facilitate rapid NDA and MAA filing. The Parties will act in good faith and mutually agree upon each such plan; provided, however, that after exercising an Option for the applicable Collaboration Program, Biogen will have final decision-making authority with respect to the [***]. Once such plan is complete, each Party will use Commercially
                Reasonable Efforts to execute their respective tasks and responsibilities under such plan in the time frames set forth in such plan. After the License Effective Date for a particular Collaboration Program, if Biogen requests, Ionis will
                assist Biogen in preparing regulatory filings for the Product, under terms negotiated in good faith between Ionis and Biogen, including payment for Ionis’ time at Ionis’ then applicable FTE Rate plus any reasonable out of pocket expenses
                incurred by Ionis in providing such assistance.

          


     

    
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    	4.7.	
            Subcontracting.

          


     

    	

          	4.7.1.	
            Subject to the terms of this Section 4.7, each Party will have the right to engage Third Party subcontractors to perform certain of its obligations under this Agreement. Any subcontractor to be engaged by a Party to perform a
              Party’s obligations set forth in the Agreement will meet the qualifications typically required by such Party for the performance of work similar in scope and complexity to the subcontracted activity and will enter into such Party’s standard
              nondisclosure agreement consistent with such Party’s standard practices. Any Party engaging a subcontractor hereunder will remain responsible and obligated for such activities and will not grant rights to such subcontractor that interfere
              with the rights of the other Party under this Agreement.  Each Party will be responsible for any income or non-income taxes that arise as a result of such Party’s use of any Third Party subcontractors hereunder, including payroll, income,
              withholding (including from subsequent payments) sales and use, VAT, customs, duties excise or property taxes, and such taxes will not be reimbursable expenditures.

          


     

    	

          	4.7.2.	
            Ionis agrees that, where Biogen wishes to (sub)contract with a Third Party with respect to any of the rights granted under Section 4.3.1(a), Ionis shall, within [***] days of any request by Biogen, provide Biogen with a letter of
              authorization as necessary for Biogen to be able to contract with such Third Party in accordance with the terms of this Agreement.  Biogen will ensure that any Third Party (sub)contractors Biogen uses to conduct the process development or
              manufacturing activities contemplated by Section 4.3.1(a) will be obligated to assign to Biogen all right, title and interest in and to any inventions developed by such (sub)contractors in the performance of such activities.    Biogen will not enter into any new agreement or other obligation with any Third Party, or amend an existing agreement with a Third Party, in each case that restricts, limits, diminishes or encumbers the rights
              granted to Ionis under the Manufacturing Process Development Terms.  In addition, after the Amendment Date, Biogen will use reasonable efforts to include, in any agreement with a (sub)contractor that has substantial material obligations
              related to the Development, Manufacture or Commercialization of a Product, provisions requiring that, in the event the applicable Option with respect to a Collaboration Program of which such Products are the subject is terminated, expires
              unexercised or this Agreement is terminated, such (sub)contractor would enter into an agreement with Ionis with respect to such Product that is substantially similar to such (sub)contractor’s agreement with Biogen and would reasonably
              cooperate with Ionis to facilitate the transition of such Product to Ionis following such termination or expiration of such Option, including the transfer to Ionis of data and information in such (sub)contractor’s possession related to the
              Product.

          


     

    	4.8.	
            Technology Transfer after the License Effective Date.  On a Collaboration Program-by-Collaboration Program basis, Ionis
                will promptly, but no later than [***] days after the License Effective Date for a Collaboration Program hereunder, deliver to Biogen or one or more designated Affiliates:

          


     

    
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          	4.8.1.	
            Ionis Know-How.  All Ionis Know-How in Ionis’ possession that has not previously been provided hereunder, for use
                solely in accordance with the licenses granted under Section 4.1.1 and Section 10.4.1(b), and Ionis will and does hereby assign to Biogen all of Ionis’ right, title and interest in and to the IND for the applicable
                Development Candidate, together with all Regulatory Materials (including drafts) that relate to the applicable Development Candidate and any orphan drug designations with respect to such Development Candidate, to the extent applicable; provided that, (x) notwithstanding the foregoing, and subject to the provisions of Section 2.1, the Parties acknowledge that Ionis shall be permitted to use excerpts or portions of any such
                assigned Regulatory Materials in any other regulatory submissions, notifications, registrations, approvals and/or other filings and correspondence made to or with a Regulatory Authority in any country or jurisdiction related to products
                other than the Development Candidate, provided, further that such excerpts or portions shall not include (i) any non-public data or information, in each case, related solely to the applicable
                Development Candidate, or (ii) any Confidential Information of Biogen, and (y) for clarity, such assignment of Ionis’ right, title and interest in and to such Regulatory Materials shall not include the assignment of any Know-How (including
                any data) contained therein. If Ionis intends to use any excerpt or portion of any such assigned Regulatory Materials in accordance with clause (x) of the preceding sentence that are not in the public domain and do not relate to Ionis’
                antisense oligonucleotide chemistry platform, Ionis shall, at least [***] days in advance of the anticipated submission of such excerpt or portion to a Regulatory Authority, notify Biogen of such intent and provide to Biogen a copy of such
                proposed excerpt or portion for review and comment. The Parties shall discuss in good faith any comments of Biogen with respect to such proposed excerpt or portion prior to submission thereof. To assist with the transfer of such Ionis
                Know-How, Ionis will make its personnel reasonably available to Biogen during normal business hours for up to [***] ([***]) of Ionis’ time for each Collaboration Program to transfer such Ionis Know-How under this Section 4.8.1.
                Thereafter, if requested by Biogen, Ionis will provide Biogen with a reasonable level of assistance in connection with such transfer, which Biogen will reimburse Ionis for its time incurred in providing such assistance at the
                then-applicable Ionis FTE Rate, plus any reasonable out-of-pocket expenses incurred by Ionis in providing such assistance.

          


     

    	

          	4.8.2.	
            Ionis Manufacturing and Analytical Know-How.  Solely for use by Biogen, its Affiliates or a Third Party acting on
                Biogen’s behalf to Manufacture API in Biogen’s own or an Affiliate’s manufacturing facility, all Ionis Manufacturing and Analytical Know-How in Ionis’ Control relating to applicable Products, that is necessary for the exercise by Biogen,
                its Affiliates or a Third Party of the Manufacturing rights granted under Section 4.1.1. Upon Biogen’s request, subject to Section 4.1.2, Ionis will provide up to [***] for [***] ([***]) of its time for each Collaboration
                Program to transfer such Ionis Manufacturing and Analytical Know-How under this Section 4.8.2 to any Third Party Manufacturing API, Clinical Supplies or Finished Drug Product on Biogen’s behalf solely to Manufacture API, Clinical
                Supplies or Finished Drug Product in accordance with the terms of this Agreement. Thereafter, if requested by Biogen, Ionis will provide Biogen with a reasonable level of assistance in connection with such transfer, for which assistance
                Biogen will reimburse Ionis for its time incurred in providing such assistance at the then-applicable Ionis FTE Rate, plus any reasonable out-of-pocket expenses incurred by Ionis in providing such assistance.

          


     

    
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          	4.8.3.	
            API and Product.  Upon Biogen’s written request, Ionis will sell to Biogen any bulk API, Clinical Supplies and Finished
                Drug Product, and any intermediates, impurity markers and reference standards relating to a Product in Ionis’ possession at the time of the License Effective Date for the applicable Collaboration Program, at a price equal to [***].

          


     

    	

          	4.8.4.	
            Trial Master File.  Upon Biogen’s written request, Ionis will provide to Biogen or its designated Affiliate a copy of
                Ionis’ trial master file for such Collaboration Program (such trial master file, the “Trial Master File”) promptly, and in any event within [***] days after Ionis’ receipt of such
                written request. Within [***] days after receipt of the Trial Master File, Biogen or an Affiliate may notify Ionis of any omissions or deficiencies that Biogen or its Affiliate believes in good faith cause the Trial Master File to be
                incomplete (such notice, a “Trial Master File Deficiency Notice”). Ionis will promptly, and in any event within [***] days after receipt of the Trial Master File Deficiency Notice,
                resubmit a complete Trial Master File to Biogen or its designated Affiliate, including any information required to be included in a Trial Master File that Biogen requests be included in the Trial Master File. If the Parties do not agree as
                to whether the Trial Master File is complete, the matter will be referred to the Executives for resolution. The Executives will meet promptly and negotiate in good faith to resolve the dispute and agree upon a complete Trial Master File. If
                Ionis is the Commercializing Party of a Discontinued Product, this Section 4.8.4 will apply to such Discontinued Product mutatis mutandis such that Biogen will transfer to Ionis Biogen’s
                trial master file for such Discontinued Product.

          


     

    	

          	4.8.5.	
            Results.

          


     

    	

          	(a)	
            Each Party shall share with the other Party on an Annual basis (preferably at in-person meetings) the results of such Party’s manufacturing process development activities, including all data, the identity and location of vendors,
              information and results received from vendors, and planned additional work, (i) in the case of Biogen, to the extent arising under the Manufacturing Process Development Terms (all Know-How and Patent Rights within the foregoing, the “Biogen Results”) and (ii) in the case of Ionis, to the extent arising under or otherwise subject to a disclosure obligation of Ionis under this Agreement (all Know-How and Patent Rights
              within the foregoing, the “Ionis Results” and, collectively with the Biogen Results, the “Results”).  All intellectual
              property matters with respect to the Results, including any Patent Rights therein, will be governed by the intellectual property provisions of this Agreement, and the Know-How and Patent Rights included in the Ionis Results shall constitute
              Ionis Manufacturing and Analytical Know-How and Ionis Manufacturing and Analytical Patent Rights, respectively, under this Agreement.  If requested by either Party, Biogen and Ionis will establish a manufacturing committee to facilitate the
              exchange of Results between the Parties.  For clarity, Biogen shall have the right, in its sole discretion, to determine whether to seek patent protection for any Biogen Results that are not jointly owned with Ionis, and Biogen shall control
              and be responsible for all aspects of the Prosecution and Maintenance of any Patent Right within such Biogen Results (each, a “Biogen Manufacturing Program Patent”) in accordance
              with Section 7.2.2(c) of this Agreement.  Biogen shall notify Ionis within [***] days if Biogen files a patent application Controlled by Biogen or its Affiliates that claims any Biogen Results and shall provide Ionis with a copy of
              such patent application.  Ionis will have no obligation to incorporate any Biogen Results into Ionis’ manufacturing process.

          


     

    
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          	(b)	
            For clarity, the Manufacturing Process Development Terms, and not the enabling licenses set forth in Section 4.3.2 and Section 4.3.3, shall govern with respect to all Results.

          


     

    ARTICLE 5

    DEVELOPMENT, MANUFACTURING AND COMMERCIALIZATION

     

    	5.1.	
            Biogen Diligence.  Following the License Effective Date with respect to a Collaboration Program, Biogen will be solely
                responsible for all Development, Manufacturing and Commercialization activities, and for all costs and expenses associated therewith, with respect to the Development, Manufacture and Commercialization of the applicable Products; and Biogen
                will use Commercially Reasonable Efforts to Develop, Manufacture and Commercialize at least one Product from each Collaboration Program for which an Option has been exercised.  If Biogen exercises an Option for a Product involving a
                Collaboration Target added in accordance with Section 1.3.2 that is associated with [***], Biogen will use Commercially Reasonable Efforts to Develop such Product for use in a [***].

          


     

    	

          	5.1.1.	
            Specific Performance Milestone Events.  Without limiting any of the foregoing, following the License Effective Date for
                a Collaboration Program, Biogen will use Commercially Reasonable Efforts to achieve the specific performance milestone events set forth in Schedule 5.1.1, as such schedule may be
                updated from time to time in accordance with Section 1.5.2(a) (“Specific Performance Milestone Events”) for a Product under such Collaboration Program on the timeline set
                forth in Schedule 5.1.1; provided, however, [***].

          


     

    	

          	5.1.2.	
            Integrated Development Plan.  On a Product-by-Product basis, Biogen will prepare a Development and global integrated
                Product plan outlining key aspects of the Development of each Product through Approval as well as key aspects of worldwide regulatory strategy, market launch, and Commercialization, including Product sales and forecasts (each, an “Integrated Development Plan” or “IDP”).  Biogen will prepare the IDP no later than [***] after the License Effective Date
                for a Collaboration Program, and the IDP will contain information consistent in scope and content with the information Biogen’s senior management uses for internal decision-making for such Product. Once Biogen
                has prepared such plans, Biogen will update the IDP consistent with Biogen’s standard practice and provide such updates to Ionis [***]. Biogen and Ionis will meet [***] basis to discuss the draft of the IDP and Biogen will consider, in good
                faith, any proposals and comments made by Ionis for incorporation in the final IDP.  Notwithstanding the foregoing, Biogen’s obligations to provide Ionis with information or reports with respect to a Product under this Section 5.1.2
                will terminate if [***].

          


     

    
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          	5.1.3.	
            Investigator’s Brochure.  After the License Effective Date with respect to a Collaboration Program, Ionis will provide
                to Biogen an up-to-date version of the Investigator’s Brochure for the applicable Product. After the License Effective Date with respect to a Collaboration Program, Biogen will keep Ionis reasonably informed with respect to the status,
                activities and progress of Development of Products by providing updated versions of the Investigator’s Brochure for each Product to Ionis [***] and when Development of such Product results in any substantive change to the safety or risk to
                the Product. Biogen’s obligations under this Section 5.1.3 will terminate with respect to a Product if [***].

          


     

    	

          	5.1.4.	
            Regulatory Matters.

          


     

    	

          	(a)	
            IND-Holder. Subject to this Section 5.1.4, Ionis will be the IND-holder and will be responsible for all
                communications with Regulatory Authorities regarding the Collaboration Programs prior to the applicable License Effective Date.  Biogen will be the IND-holder and holder of any orphan drug designation after the
                applicable License Effective Date for each Collaboration Program in accordance with Section 3.1.3, and, except as otherwise provided in this Section 5.1.4, shall thereafter have sole decision-making authority with respect to
                the matters set forth in this Section 5.1.4.

          


     

    	

          	(b)	
            Participation in Regulatory Meetings.  With respect to a Collaboration Program, each Party will promptly provide the
                other Party with as much advance written notice as practicable of any meetings that such first Party has or plans to have with a Regulatory Authority regarding pre-approval or Approval matters for a Product under such Collaboration Program
                or that directly relate to Ionis’ antisense oligonucleotide chemistry platform, and will allow two representatives of the other Party to participate in any such meetings under the direction of such first Party; provided, however, that, if such first Party is Ionis, Ionis may exclude Biogen from any portion of such meeting that does not pertain to such Product; and provided, further, that, if such first Party is Biogen, Biogen may exclude Ionis from any portion of such meeting that does not pertain to such Product or to Ionis’ antisense oligonucleotide chemistry platform.

          


     

    	

          	(c)	
            Regulatory Communications.  With respect to a Collaboration Program, each Party will provide the other Party with
                copies of documents and communications submitted to (including drafts thereof) and received from Regulatory Authorities [***] that materially impact the Development or Commercialization of Products under such Collaboration Program for such
                other Party’s review and comment, and such first Party will consider in good faith including any comments provided by such other Party to such documents and communications. Each Party will promptly notify the other Party upon receipt of any
                such documents or communications from any Regulatory Authority [***].

          


     

    
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          	(d)	
            Class Generic Claims.  To the extent Biogen intends to make any claims in a Product label or regulatory filing that are
                class generic to ASOs, Biogen will provide such claims and regulatory filings to Ionis in advance and will consider in good faith any proposals and comments made by Ionis; provided, however, that Biogen is not obligated to incorporate such proposals and comments in any such claims and regulatory filings.

          


     

    	

          	5.1.5.	
            Applicable Laws.  Biogen will perform its activities pursuant to this Agreement in compliance with good laboratory and
                clinical practices and cGMP, in each case as applicable under the Laws and regulations of the country and the state and local government wherein such activities are conducted.

          


     

    	5.2.	
            Global Safety Database; Pharmacovigilance Agreement.

          


     

    	

          	5.2.1.	
            Pharmacovigilance Agreement.  As soon as reasonably practicable following designation of a particular Development
                Candidate, and in any event no later than [***] prior to the date on which Ionis anticipates filing an IND for the associated Product with a Regulatory Authority, the Parties will enter into a Safety Data Exchange Agreement relating to the
                collection, review, assessment, tracking, exchange and filing of information related to adverse events associated with such Product occurring prior to the First Commercial Sale in any country on terms substantially the same as the terms of
                the Safety Data Exchange Agreement to be entered into by the Parties with respect to adverse events associated with products developed under the Ionis/Biogen Additional Agreements.  No later than [***] prior to the date on which Biogen
                reasonably anticipates that it will exercise an Option, Biogen will so notify Ionis and the pharmacovigilance departments of each of Ionis and Biogen will meet and determine the approach to be taken for the collection, review, assessment,
                tracking, exchange and filing of information related to adverse events associated with the applicable Product occurring after such First Commercial Sale, consistent with the provisions of this Section 5.2. Such approach will be
                documented in a separate and appropriate written pharmacovigilance agreement between the Parties which will control with respect to the subject matter covered therein (the “Pharmacovigilance






                  Agreement”). Such agreement will specify that the owner of the IND for a Product will be the global commercial safety database owner for such Product with primary responsibility for maintaining such database, and that Ionis will be
                and remain the owner of the Ionis Internal ASO Safety Database with primary responsibility for maintaining such database. Such agreement will also specify that, prior to Biogen’s exercise of the applicable Option, Ionis will communicate
                updates on safety data regarding a Product to Biogen through monthly telephone calls between the drug safety representatives of Biogen and Ionis.  Biogen and Ionis will jointly review and discuss safety issues arising under any
                Collaboration Program that may have implications on any Development Plan for such Collaboration Program.  Biogen may suggest actions to address Product safety data or audit findings, and Ionis will consider all such suggestions in good
                faith. The Pharmacovigilance Agreement will be in accordance with, and will enable the Parties and their Affiliates or licensees or Sublicensees, as applicable, to fulfill, local and international regulatory reporting obligations to
                Regulatory Authorities and other Applicable Law.

          


     

    
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          	5.2.2.	
            Ionis’ Antisense Safety Database.

          


     

    	

          	(a)	
            Ionis maintains an internal database that includes information regarding the tolerability of its drug compounds, individually and as a class, including information discovered during pre-clinical and clinical development (the “Ionis Internal ASO Safety Database”). In an effort to maximize understanding of the safety profile and pharmacokinetics of Ionis compounds, after the License Effective Date with respect
              to a Collaboration Program, Biogen will cooperate in connection with populating the Ionis Internal ASO Safety Database. To the extent collected by Biogen and in the form in which Biogen uses/stores such information for its own purposes,
              Biogen will provide Ionis with information concerning toxicology, pharmacokinetics, safety pharmacology study(ies), serious adverse events and other safety information related to Products as soon as practicable following the date such
              information is available to Biogen (but not later than [***] days after Biogen’s receipt of such information). In connection with any reported serious adverse event, Biogen will provide Ionis all serious adverse event reports, including
              initial, interim, follow-up, amended, and final reports. In addition, with respect to Products, Biogen will provide Ionis with copies of Annual safety updates filed with each IND and the safety sections of any final Clinical Study reports
              within [***] days following the date such information is filed or is available to Biogen, as applicable. Furthermore, Biogen will promptly provide Ionis with any supporting data and answer any follow-up questions reasonably requested by
              Ionis. All such information disclosed by Biogen to Ionis will be Biogen Confidential Information; provided, however, that Ionis may disclose any such Biogen
              Confidential Information to (i) Ionis’ other partners pursuant to Section 5.2.2(b) below if such information is regarding class generic properties of ASOs, or (ii) any Third Party, in each case, so long as Ionis does not disclose the
              identity of a Product or Biogen. Biogen will deliver all such information to Ionis for the Ionis Internal ASO Safety Database to Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, California 92010, Attention: Chief Medical Officer (or
              to such other address/contact designated in writing by Ionis). Biogen will also cause its Affiliates and Sublicensees to comply with this Section 5.2.2(a).

          


     

    	

          	(b)	
            From time to time, Ionis utilizes the information in the Ionis Internal ASO Safety Database to conduct analyses to keep Ionis and its partners informed regarding class generic properties of ASOs, including with respect to safety. As such,
              if and when Ionis identifies safety or other related issues that may be relevant to a Product (including any potential class-related toxicity), Ionis will promptly (and in no event later than 5 Business Days following identification by Ionis)
              inform Biogen of such issues and, if requested, provide the data supporting Ionis’ conclusions.

          


     

    
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    	5.3.	
            Research and Manufacturing Records.  Each Party shall maintain, consistent with its then-current internal policies and
                practices, and cause its employees and subcontractors to maintain, consistent with its internal policies and Applicable Law, for at least ten years, records and laboratory notebooks, inventory, purchase and invoice
                records and Manufacturing records in each case with respect to the Products in sufficient detail and in a good scientific manner appropriate for (i) inclusion in filings with Regulatory Authorities for such
                Products, and (ii) obtaining and maintaining intellectual property rights and protections, including Patent Rights for such Products. Such records and laboratory notebooks shall be complete and
                accurate in all material respects and shall fully and properly reflect all work done, data and developments made, and results achieved.  Each Party shall allow the other Party, to the extent necessary for such regulatory or intellectual
                property protection purposes, to inspect or copy such records, subject to redaction by such Party.

          


     

    ARTICLE 6

    FINANCIAL PROVISIONS

     

    	6.1.	
            Option Fee.  In partial consideration for Biogen’s Options hereunder, within five Business Days following the Effective
                Date, Biogen will pay Ionis an Option fee equal to $10,000,000 for each of the three Collaboration Programs for an aggregate payment of $30,000,000.

          


     

    	6.2.	
            Milestone Payments for Achievement of Pre-Licensing Milestone Events.  As further consideration for Biogen’s Options,
                on a Collaboration Program-by-Collaboration Program basis, Biogen will pay to Ionis the milestone payments as set forth in Table 1 below when a milestone event (each, a “Pre-Licensing Milestone Event”) listed in Table






                    1 is first achieved by a Product under such Collaboration Program:

          


     

    	 	
            Table 1

          
	 	
            Pre-Licensing Milestone Event

          	
            Milestone Event Payment

          
	 	
            [***]

          	
            $[***]

          
	 	
            [***]

          	
            [***]

          
	 	
            [***]

          	
            [***]

          


    

    

    On a Collaboration Program-by-Collaboration Program basis, Biogen will pay to Ionis the Milestone Event payments as set forth in Table 1 after the applicable Milestone Event is first achieved by a Product under such Collaboration Program, even if Biogen has exercised the applicable Option prior to achievement of the Milestone Event; provided, however, that if Biogen exercises the Option prior to achievement of the [***] Milestone Event, then the milestone payment for achievement of the [***] Milestone
      Event will be [***].

     

    
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    	6.3.	
            License Fee.  On an Option-by-Option basis, together with Biogen’s written notice to Ionis stating that Biogen is
                exercising such Option in accordance with this Agreement, Biogen will pay to Ionis a license fee of $[***]; provided, however, that if Biogen exercises the Option prior to the [***], the license fee for such Option will be [***].

          


     

    	6.4.	
            Milestone Payments for Achievement of Post-Licensing Milestone Events.  On a Collaboration Program-by-Collaboration
                Program basis, Biogen will pay to Ionis the milestone payments as set forth in Table 2 below when a milestone event (each, a “Post-Licensing Milestone Event”) listed in Table 2 is first achieved by a Product under such
                Collaboration Program:

          


     

    	 	
            Table 2

          
	 	
            Post-Licensing Milestone Event

          	
            Milestone Event Payment

          
	 	
            [***]

          	
            $[***]

          
	 	
            [***]

          	
            $[***]

          
	 	
            [***]

          	
            $[***]

          
	 	
            [***]

          	
            $[***]

          


     

    On a Collaboration Program-by-Collaboration Program basis, if Biogen exercises an Option prior to the [***], Biogen will pay to Ionis [***] upon the earlier of (a) [***]. For the avoidance of doubt,
      if such $[***] payment is paid pursuant to clause (b) of the preceding sentence, such payment will be in addition to the amount due upon the occurrence of the corresponding Post-Licensing Milestone Event under Table






          2 above.

     

    Notwithstanding anything to the contrary in this Section 6.4, if Biogen exercises an Option for a Product involving a Collaboration Target added in accordance with Section 1.3.2, and
      [***], then Biogen will pay to Ionis (i) [***] of the applicable amount set forth in Table 2 above when such Product achieves a Post-Licensing Milestone Event for the first time and (ii) [***] of
      the applicable amount set forth in Table 2 above when such Product achieves a Post-Licensing Milestone Event for the second time.

     

    	6.5.	
            Limitations on Milestone Payments; Exceptions; Notice.

          


     

    	

          	6.5.1.	
            On a Product-by-Product basis, the $[***] milestone payment is creditable against the first Milestone Event payment for [***]. For example, if the [***] Milestone Event is achieved by a Product in the [***], then the milestone payment for
              such Milestone Event is [***] the first to occur of the (a) [***] (b) [***] or (c) [***] milestone payments for such Product.

          


     

    	

          	6.5.2.	
            On a Collaboration Program-by-Collaboration Program basis, except as set forth in the second paragraph under Table 2 above, each milestone payment set forth in Table 1 and Table 2 above will be paid only once upon the first achievement of the Milestone Event regardless of how many Products under
              such Collaboration Program achieve such Milestone Event.

          


     

    
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          	6.5.3.	
            If a particular Milestone Event is not achieved because Development activities transpired such that achievement of such earlier Milestone Event was unnecessary or did not otherwise occur, then upon achievement of a later Milestone Event
              the Milestone Event payment applicable to such earlier Milestone Event will also be due. For example, if a Party proceeds directly to [***] without achieving the [***] then upon achieving the [***] Milestone Event, both the [***] and [***]
              Milestone Event payments are due.

          


     

    	

          	6.5.4.	
            Each time a Milestone Event is achieved under this ARTICLE 6, Biogen will send Ionis, or Ionis will send Biogen, as the case may be, a written notice thereof promptly (but no later than [***]) following the date of achievement of
              such Milestone Event and such payment will be due within [***] of the date such notice was delivered.

          


     

    	

          	6.5.5.	
            For clarity, the provisions of this Agreement (including the milestone payments and license fees set forth in Section 6.2, Section 6.3 and Section 6.4) shall not apply with respect to the Collaboration Program (as
              such term is defined in the Neurology II Agreement) for [***]; instead, royalties, milestone payments and license fees with respect to the [***] will be due in accordance with the Neurology II Agreement.

          


     

    	

          	6.6.	
            Royalty Payments to Ionis.

          


     

    	

          	6.6.1.	
            Biogen Full Royalty.  As partial consideration for the rights granted to Biogen hereunder, subject to the provisions of
                this Section 6.6.1 and Section 6.6.2, Biogen will pay to Ionis royalties on a Collaboration Program-by-Collaboration Program basis, on Annual worldwide Net Sales of Products included in the applicable Collaboration Program
                sold by Biogen, its Affiliates or Sublicensees, on a country-by-country basis, in each case in the amounts as follows in Table 3 below (the “Biogen Full Royalty”):

          


     

    	
            Table 3

          
	
            Royalty

            Tier

          	 	
            Annual Worldwide Net Sales of Products

          	
            Royalty

            Rate

          
	
            1

          	 	
            For the portion of Annual worldwide Net Sales        < $[***]

          	
            [***]%

          
	
            2

          	 	
            For the portion of Annual worldwide Net Sales        > $[***] but < $[***]

          	
            [***]%

          
	
            3

          	 	
            For the portion of Annual worldwide Net Sales        > $[***] but < $[***]

          	
            [***]%

          
	
            4

          	 	
            For the portion of Annual worldwide Net Sales        > $[***]

          	
            [***]%

          


    

    

    
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    Annual worldwide Net Sales will be calculated by [***].

     

    	

          	(a)	
            Biogen will pay Ionis royalties on Net Sales of Products arising from named patient and other similar programs under Applicable Laws, and Biogen will provide reports and payments to Ionis consistent with Section 6.9. No royalties
              are due on Net Sales of Products arising from compassionate use and other programs providing for the delivery of Product at no cost. The sales of Products arising from named patient, compassionate use, or other similar programs will not be
              considered a First Commercial Sale for purposes of calculating the Full Royalty Period.

          


     

    	

          	(b)	
            For purposes of clarification, any Ionis Product-Specific Patents assigned to Biogen as set forth in Section 4.2.1 will still be considered Ionis Product-Specific Patents for determining the royalty term and applicable royalty
              rates under this ARTICLE 6.

          


     

    	

          	(c)	
            For clarity, the provisions of this Agreement (including Section 6.6) shall not apply to Net Sales of Products under the Collaboration Program (as such term is defined in the Neurology II Agreement) for [***]; instead, royalties,
              milestone payments and license fees with respect to the [***] will be due in accordance with the Neurology II Agreement.

          


     

    	

          	6.6.2.	
            Application of Royalty Rates.  All royalties set forth under Section 6.6.1 are subject to the provisions of
                this Section 6.6.2, and are payable as follows:

          


     

    	

          	(a)	
            Full Royalty Period.  Biogen’s obligation to pay Ionis the Biogen Full Royalty above with respect to a Product will
                continue on a country-by-country and Product-by-Product basis from the date of First Commercial Sale of such Product until the later of the date of expiration of (i) the last Valid Claim within the Licensed Patents Covering such Product in
                the country in which such Product is made, used or sold, (ii) the data exclusivity period conferred by the applicable Regulatory Authority in such country with respect to such Product (e.g., such as in the case of an orphan drug), or
                (iii) the [***] anniversary of the First Commercial Sale of such Product in such country (such royalty period, the “Full Royalty Period”).

          


     

    	

          	(b)	
            Competition from Generic Products.  Subject to Section 6.6.2(d), on a country-by-country and Product-by-Product
                basis, if, within the [***], a Generic Product is sold in a country, then the Biogen Full Royalty rate used to pay Ionis royalties on such Product in such country will be reduced to [***]% of the otherwise applicable Biogen Full Royalty
                rate. For the purpose of determining the [***] for a particular Product under this Section 6.6.2(b), if requested by Biogen, Ionis and Biogen will meet and confer and mutually agree upon the Parties’ best estimate of when the Full
                Royalty Period [***] in each country where Products are being sold.

          


     

    
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          	(c)	
            Reduced Royalty Period.  Subject to Section 6.6.2(d), on a country-by-country and Product-by-Product basis,
                after the expiration of the Full Royalty Period and until the end of the Reduced Royalty Period, in lieu of the royalty rates set forth in Table 3 of Section 6.6.1, Biogen will
                pay Ionis royalty rates (the “Biogen Reduced Royalty”) on Net Sales of Products calculated on a Calendar Year-by-Calendar Year basis by [***]; provided, however, that the Biogen Reduced Royalty rate in each country will in no event exceed the [***].

          


     

    	

          	(d)	
            Limitation on Aggregate Reduction for Biogen Royalties.

          


     

    	

          	(i)	
            In no event will the aggregate royalty reductions under Section 6.6.2(b) and Section 6.6.2(c) reduce the royalties payable to Ionis on Net Sales of a Product in any given period to an amount that is less than [***] for such
              Product.

          


     

    	

          	(ii)	
            In no event will the aggregate royalty offsets under Section 6.8.3(b) and Section 6.8.3(d) reduce the royalties payable to Ionis on Net Sales of a Product in any given period to an amount that is less than the greater of
              [***].

          


     

    For example, if the Royalty Quotient during a given Calendar Year in the Reduced Royalty Period is less than [***]%, then the offsets under Section 6.8.3(b) and Section 6.8.3(d) will
      not apply during such Calendar Year but the full Royalty Quotient reduction pursuant to Section 6.6.2(c) will apply.

     

    As an additional example, if the Royalty Quotient during a given Calendar Year in the Reduced Royalty Period is [***], and the [***] in such Calendar Year are [***] of the applicable royalty rates
      in Table 3 of Section 6.6.1, then Biogen may apply the offsets under Section 6.8.3(b) and Section 6.8.3(d) until the actual royalty payment made to Ionis in such Calendar
      Year is equal to [***]% of the applicable royalty rates in Table 3 of Section 6.6.1.

     

    	

          	(e)	
            End of Royalty Obligation.  On a country-by-country and Product-by-Product basis, other than [***], Biogen’s obligation
                to make royalty payments hereunder for such Product in such country will end on the expiration of the Reduced Royalty Period in such country. “Reduced Royalty Period” means, on a
                country by country basis, the period commencing upon the expiration of the [***] for such Product in such country and ending when the [***].

          


     

    
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          	(f)	
            Royalty Examples.  Schedule 6.6.2(f) attached hereto
                contains examples of how royalties will be calculated under this Section 6.6.

          


     

    	

          	(g)	
            Allocation of Net Sales.  If, by reason of one or more royalty rate adjustments under this Section 6.6.2,
                different royalty rates apply to Net Sales of Products from different countries, Biogen will [***] such Net Sales [***]. Schedule 6.6.2(g)
                attached hereto contains examples of how Net Sales of Products from different countries at different royalty rates will be [***].

          


     

    	6.7.	
            Reverse Royalty Payments to Biogen for a Discontinued Product.

          


     

    	

          	6.7.1.	
            Reverse Royalty for a Discontinued Product.  If Ionis or any of its Affiliates or Sublicensees Commercializes a
                Discontinued Product for which Biogen has paid Ionis the license fee under Section 6.3, then following the First Commercial Sale of such Discontinued Product by Ionis or its Affiliates or Sublicensees, Ionis will pay Biogen or its
                designated Affiliate a royalty of [***]% of Annual worldwide Net Sales of such Discontinued Product (“Reverse Royalties”). Ionis’ obligation to pay Biogen Reverse Royalties will [***].

          


     

    	

          	6.7.2.	
            Applicable Royalty Provisions.  In addition to this Section 6.7, the definition of Net Sales in Appendix 1 and the other provisions contained in this ARTICLE 6 governing payment of royalties from Biogen to Ionis will govern the payment of Reverse Royalties from Ionis to
                Biogen under this Section 6.7, mutatis mutandis, including the provisions of Sections 6.6.2, 6.8, 6.9, 6.10, 6.11, and 6.12.

          


     

    	6.8.	
            Third Party Payment Obligations.

          


     

    	

          	6.8.1.	
            Existing Ionis In-License Agreements.

          


     

    	

          	(a)	
            Certain of the Licensed Technology Controlled by Ionis as of the Effective Date licensed to Biogen under Section 4.1.1 were in-licensed or were acquired by Ionis under the agreements with Third Party licensors or sellers listed on
              Schedule 6.8.1 or in a separate written agreement between the Parties (all such license or purchase agreements being the “Ionis
                In-License Agreements”), and certain milestone or royalty payments and license maintenance fees may become payable by Ionis to such Third Parties under the Ionis In-License Agreements based on the Development and Commercialization of
              a Product by Biogen under this Agreement.

          


     

    	

          	(b)	
            Any payment obligations arising under the Ionis In-License Agreements as existing on the Effective Date as they apply to Products will be paid by [***] as [***].

          


     

    
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          	6.8.2.	
            New In-Licensed Ionis Product-Specific Patents; Ionis Manufacturing and Analytical Patents.  If after the Effective
                Date, Ionis obtains Third Party Patent Rights necessary or useful to Develop, Manufacture or Commercialize a Product that would have been considered an Ionis Product-Specific Patent had Ionis Controlled such Patent Rights on the Effective
                Date, to the extent Controlled by Ionis, Ionis will include such Third Party Patent Rights in the license granted to Biogen under Section 4.1.1 if Biogen agrees in writing to pay Ionis as [***].

          


     

    	 	6.8.3.	
            Additional Core IP In-License Agreements.

          


     

    	

          	(a)	
            Biogen will promptly provide Ionis written notice of any Additional Core IP Biogen believes it has identified and Ionis will have the first right, but not the obligation, to negotiate with, and obtain a license from the Third Party
              Controlling such Additional Core IP. If Ionis obtains such a Third Party license, Ionis will include such Additional Core IP in the license granted to Biogen under Section 4.1.1, and any financial obligations under such Third Party
              agreement will be paid solely by [***] as [***].

          


     

    	

          	(b)	
            If, however, Ionis elects not to obtain such a license to such Third Party intellectual property, Ionis will so notify Biogen, and Biogen may obtain such a Third Party license and, subject to Section 6.6.2(d)(ii), Biogen may offset
              an amount equal to [***]% of any [***] paid by Biogen under such Third Party license against any [***] of this Agreement in such country for [***].

          


     

    	

          	(c)	
            If it is unclear whether certain intellectual property identified by Biogen pursuant to Section 6.8.3(a) is Additional Core IP under Section 6.8.3(b), Ionis will send written notice to such effect to Biogen, and the Parties
              will engage a mutually agreed upon independent Third Party intellectual property lawyer with expertise in the patenting of ASOs, and appropriate professional credentials in the relevant jurisdiction, to
              determine the question of whether or not such Third Party intellectual property is Additional Core IP. The determination of the Third Party expert engaged under the preceding sentence will be binding on the Parties solely for purposes of
              determining whether Biogen is permitted to [***].  The costs of any Third Party expert engaged under this Section 6.8.3(c) will be paid by the Party against whose position the Third Party lawyer’s determination is made.

          


     

    	

          	(d)	
            Notwithstanding the determination of the Third Party lawyer under Section 6.8.3(c), if a Third Party Controlling Additional Core IP is awarded a judgment from a court of competent jurisdiction arising from its claim against Biogen
              asserting that [***], Biogen will be permitted to [***].

          


     

    	6.8.4.	
            Other Third Party Payments.

          


     

    	

          	(a)	
            Ionis’ Third Party Agreements.  Except as otherwise expressly agreed to by Biogen under clause (c) of Section 1.3.2
                or Section 6.8.2, after the License Effective Date for a particular Collaboration Program, Biogen will be responsible for paying [***]% of the [***] arising under any Third Party agreements entered into by Ionis where either [***].

          


     

    
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          	(b)	
            Biogen’s Third Party Agreements.  Without limiting any applicable [***] under Section 6.8.3(b), Biogen will be
                responsible for paying [***]% of the [***] arising under any Third Party agreements entered into by Biogen as they apply to Products.

          


     

    	6.9.	
            Payments.

          


     

    	

          	6.9.1.	
            Commencement.  Beginning with the Calendar Quarter in which the First Commercial Sale for a Product is made and for
                each Calendar Quarter thereafter, Biogen will make royalty payments to Ionis under this Agreement within [***] following the end of each such Calendar Quarter. Each royalty payment will be accompanied by a report, summarizing Net Sales for
                Products during the relevant Calendar Quarter and the calculation of royalties due thereon, including country, units, sales price and the exchange rate used and the aggregate reduction to gross sales to arrive at Net Sales.  Following the
                end of the first full Calendar Quarter subsequent to the First Commercial Sale in a Major Market of any Product (but not in any subsequent Calendar Quarter unless there is a material change in the amount of any reduction to gross sales or
                the methodology used by Biogen to calculate any such reduction), Biogen will also include in such report a description of the reductions to gross sales to arrive at Net Sales, broken down by each category of reduction listed in clauses (a)
                through (d) of the definition of “Net Sales” and a non-binding qualitative analysis describing how Biogen anticipates such reductions may fluctuate over time. If no royalties are payable in respect of a given Calendar Quarter, then Biogen
                will submit a written royalty report to Ionis so indicating together with an explanation as to why no such royalties are payable. In addition, beginning with the Calendar Quarter in which the First Commercial Sale for a Product is made and
                for each Calendar Quarter thereafter, within [***] following the end of each such Calendar Quarter, Biogen will provide Ionis a [***] report estimating the total Net Sales of, and royalties payable to Ionis for Products projected for such
                Calendar Quarter.

          


     

    	

          	6.9.2.	
            Mode of Payment.  All payments under this Agreement will be (a) payable in full in U.S. dollars, regardless of the
                country(ies) in which sales are made, (b) made by wire transfer of immediately available funds to an account designated by Ionis in writing, and (c) non-creditable [***], irrevocable and non-refundable. Whenever for the purposes of
                calculating the royalties payable under this Agreement conversion from any foreign currency will be required, all amounts will first be calculated in the currency of sale and then converted into United States dollars by applying the monthly
                average rate of exchange calculated by using the foreign exchange rates published in Bloomberg during the applicable month starting two Business Days before the beginning of such month and ending two Business Days before the end of such
                month as utilized by Biogen, in accordance with generally accepted accounting principles, fairly applied and as employed on a consistent basis throughout Biogen’s operations.

          


     

    
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          	6.9.3.	
            Records Retention.  Commencing with the First Commercial Sale of a Product, Biogen will keep complete and accurate
                records pertaining to the sale of Products for a period of [***] after the year in which such sales occurred, and in sufficient detail to permit Ionis to confirm the accuracy of the Net Sales or royalties paid by Biogen hereunder.

          


     

    	6.10.	
            Audits.  After the License Effective Date for a particular Collaboration Program, during the Agreement Term and for a
                period of [***] thereafter, at the request and expense of Ionis, Biogen will permit an independent certified public accountant of nationally recognized standing appointed by Ionis, at reasonable times and upon reasonable notice, but in no
                case more than [***], to examine such records as may be necessary for the purpose of verifying the calculation and reporting of Net Sales and the correctness of any royalty payment made under this Agreement for any period within the
                preceding [***]. As a condition to examining any records of Biogen, such auditor will sign a nondisclosure agreement reasonably acceptable to Biogen in form and substance. Any and all records of Biogen examined by such independent certified
                public accountant will be deemed Biogen’s Confidential Information. Upon completion of the audit, the accounting firm will provide both Biogen and Ionis with a written report disclosing whether the royalty payments made by Biogen are
                correct or incorrect and the specific details concerning any discrepancies (“Audit Report”). If, as a result of any inspection of the books and records of Biogen, it is shown that
                Biogen’s payments under this Agreement were less than the royalty amount which should have been paid, then Biogen will make all payments required to be made by paying Ionis the difference between such amounts to eliminate any discrepancy
                revealed by said inspection within [***] days of receiving the Audit Report, with interest calculated in accordance with Section 6.12. If, as a result of any inspection of the books and records
                of Biogen, it is shown that Biogen’s payments under this Agreement were greater than the royalty amount which should have been paid, then [***]; provided, however,
                that if [***]. Ionis will pay for such audit, except that if Biogen is found to have underpaid Ionis by more than [***] of the amount that should have been paid, Biogen will reimburse Ionis’ reasonable costs of the audit.

          


     

    	6.11.	
            Taxes.

          


     

    	

          	6.11.1.	
            Taxes on Income.  Each Party will be solely responsible for the payment of all taxes imposed on its share of income
                arising directly or indirectly from the activities of the Parties under this Agreement.

          


     

    	

          	6.11.2.	
            Withholding Tax.  The Parties agree to cooperate with one another and use reasonable efforts to lawfully avoid or
                reduce tax withholding or similar obligations in respect of royalties, milestone payments, and other payments, including from subsequent payments, made by the paying Party to the receiving Party under this Agreement. To the extent the
                paying Party is required to deduct and withhold taxes on any payment, the paying Party will pay the amounts of such taxes to the proper governmental authority for the account of the receiving Party and remit the net amount to the receiving
                Party in a timely manner. The paying Party will promptly furnish the receiving Party with proof of payment of such taxes. If documentation is necessary in order to secure an exemption from, or a reduction in, any withholding taxes, the
                Parties will provide such documentation to the extent they are entitled to do so.

          


     

    
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          	6.11.3.	
            Tax Cooperation.  Ionis will provide Biogen with any and all tax forms that may be reasonably necessary in order for
                Biogen to lawfully not withhold tax or to withhold tax at a reduced rate under an applicable bilateral income tax treaty. Following Biogen’s timely receipt of such tax forms from Ionis, Biogen will not withhold tax or will withhold tax at a
                reduced rate under an applicable bilateral income tax treaty, if appropriate under the Applicable Laws.  Ionis will provide any such tax forms to Biogen upon request and in advance of the due date. Each Party will provide the other with
                reasonable assistance to enable the recovery, as permitted by Applicable Law, of withholding taxes resulting from payments made under this Agreement, such recovery to be for the benefit of the Party who would have been entitled to receive
                the money but for the application of withholding tax under this Section 6.11.

          


     

    The provisions of this Section 6.11 are to be read in conjunction with the provisions of Section 12.4 below.

     

    	6.12.	
            Interest.  Any undisputed payments to be made hereunder that are not paid on or before the date such payments are due
                under this Agreement will bear interest at a rate per annum equal to the lesser of (a) the rate announced by Bank of America (or its successor) as its prime rate in effect on the date that such payment would have been first due plus 1% or
                (b) the maximum rate permissible under Applicable Law.

          


     

    ARTICLE 7

    INTELLECTUAL PROPERTY

     

    	7.1.	
            Ownership.

          


     

    	

          	7.1.1.	
            Ionis Technology and Biogen Technology.  As between the Parties, Ionis will own and retain all of its rights, title and
                interests in and to the Licensed Know-How and Licensed Patents and Biogen will own and retain all of its rights, title and interests in and to the Biogen Know-How and Biogen Patents, subject to any assignments, rights or licenses expressly
                granted by one Party to the other Party under this Agreement.

          


     

    
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          	7.1.2.	
            Agreement Technology.  As between the Parties, Biogen is and will be the sole owner of any Know-How discovered,
                developed, invented or created solely by or on behalf of Biogen or its Affiliates under this Agreement (“Biogen Program Know-How”) and any Patent Rights that claim or cover Biogen
                Program Know-How (“Biogen Program Patents” and together with the Biogen Program Know-How, the “Biogen Program Technology”),






                and will retain all of its rights, title and interests thereto, subject to any rights or licenses expressly granted by Biogen to Ionis under this Agreement. As between the Parties, Ionis is and will be the sole owner of any Know-How
                discovered, developed, invented or created solely by or on behalf of Ionis or its Affiliates under this Agreement (“Ionis Program Know-How”) and any Patent Rights that claim or
                cover such Know-How (“Ionis Program Patents” and together with the Ionis Program Know-How, the “Ionis Program Technology”),






                and will retain all of its rights, title and interests thereto, subject to any assignment, rights or licenses expressly granted by Ionis to Biogen under this Agreement. Any Know-How discovered, developed, invented or created jointly under
                this Agreement by or on behalf of both Parties or their respective Affiliates or Third Parties acting on their behalf (“Jointly-Owned Program Know-How”) and any Patent Rights that
                claim or cover such Jointly-Owned Program Know-How (“Jointly-Owned Program Patents” and together with the Jointly-Owned Program Know-How, the “Jointly-Owned Program Technology”), are and will be owned jointly by Biogen and Ionis on an equal and undivided basis, including all rights, title and interests thereto, subject to any rights or licenses
                expressly granted by one Party to the other Party under this Agreement.  Except as expressly provided in this Agreement, neither Party will have any obligation to account to the other for profits with respect to, or to obtain any consent of
                the other Party to license or exploit, Jointly-Owned Program Technology by reason of joint ownership thereof, and each Party hereby waives any right it may have under the Laws of any jurisdiction to require any such consent or accounting.
                Each Party will promptly disclose to the other Party in writing, and will cause its Affiliates to so disclose, the discovery, development, invention or creation of any Jointly-Owned Program Technology. The Biogen Program Patents, Ionis
                Program Patents and Jointly-Owned Program Patents are collectively referred to herein as the “Program Patents.”

          


     

    	

          	7.1.3.	
            Joint Patent Committee.

          


     

    	

          	(a)	
            The Parties will establish a “Joint Patent Committee” or “JPC.”  The JPC will serve as the primary contact and forum
              for discussion between the Parties with respect to intellectual property matters arising under this Agreement, with responsibilities including (i) the preparation of the intellectual property strategy to govern the Parties’ activities set
              forth in the Collaboration Program Research Plans and the activities set forth in this ARTICLE 7, (ii) making recommendations following discussion by the Parties regarding Third Party intellectual property rights that may be necessary
              or useful to perform activities under, and the intellectual property considerations to be taken into account in, Collaboration Program Research Plans, (iii) making recommendations with respect to intellectual property considerations to be
              taken into account in each Development Plan, (iv) the preparation of recommendations with respect to intellectual property considerations in connection with proposed Development Candidates for consideration by the Parties, (v) assessing and
              making recommendations to the Neurology JSC prior to the Completion of IND-Enabling Toxicology Studies regarding any Patent Rights of any Third Party that may be necessary or useful for the Development, Manufacture or Commercialization of any
              Development Candidate that is the subject of such IND-Enabling Toxicology Studies and (vi) evaluating any activities under a Collaboration Program Research Plan or Development Plan that are proposed to be conducted with an academic or
              non-profit collaborator and making recommendations as to where and with whom such activities should be conducted, and in each case will cooperate with respect to any such activities. Ionis’ obligation to participate in the JPC will terminate
              on the later of (A) the end of the Drug Discovery Term and (B) Biogen’s exercise of (or the expiration or termination of) the last Option. Thereafter, Ionis will have the right, but not the obligation, to participate in JPC meetings, but
              shall nevertheless continue to coordinate with Biogen with respect to the activities set forth in this ARTICLE 7 during the Agreement Term.

          


     

    
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          	(b)	
            The JPC will discuss a strategy and make recommendations with regard to intellectual property considerations (i) with respect to the Parties’ activities under the Collaboration Program, Drug Discovery Program and the Drug Development
              Program, promptly following the Amendment Date and (ii) with respect to each Collaboration Program, promptly after such Collaboration Program is designated, which strategies shall include (A) considerations for identifying potential
              inventions and making inventorship determinations, (B) considerations when selecting each Development Candidate, (C) considerations for Prosecution and Maintenance, defense and enforcement of Ionis Product-Specific Patents that would be or
              are licensed to Biogen under Section 4.1.1 in connection with a Product, Biogen Product-Specific Patents and Jointly-Owned Program Patents, (D) defense against allegations of infringement of Third Party Patent Rights and (E) licenses
              to Third Party Patent Rights or Know-How, in each case ((A) through (E)) to the extent such matter would be reasonably likely to have a material impact on the Agreement or the ownership of intellectual property or the licenses granted
              hereunder. The applicable strategy and the JPC’s recommendations, as applicable, will be considered in good faith in the performance of the Collaboration Program Research Plans and Development Plans, the preparation of the intellectual
              property assessment to be included in each Development Candidate Data Package and by the Party entitled to designate a Development Candidate or prosecute, enforce and defend such Patent Rights, as applicable, hereunder, but will not be
              binding on such Party.

          


     

    	

          	(c)	
            Ionis or Biogen (as applicable) will provide the Joint Patent Committee with notice of any Know-How or Patent Rights discovered, developed, invented or created jointly by such Party and a Third Party in the performance of activities under
              the Collaboration Program Research Plans or Development Plans or solely by a Third Party performing activities under the Collaboration Program Research Plans or Development Plans on such Party’s behalf (such Know-How and Patent Rights, the “Collaborator IP”) promptly after such Party receives notice or otherwise becomes aware of the existence of such Collaborator IP. The JPC will determine whether any such Collaborator IP
              would be infringed or misappropriated (as applicable) by the Development, Manufacture or Commercialization of the applicable Development Candidate or any Compound under consideration by Ionis for potential designation as a Development
              Candidate.  If the JPC (or independent patent counsel engaged pursuant to Section 7.1.3(b)) determines that any Collaborator IP would be infringed or misappropriated (as applicable) by the Development, Manufacture or Commercialization
              of such Development Candidate or Compound, [***]; provided that if such Party is unable to obtain [***] license to such Collaborator IP or if the Parties mutually agree that it is not necessary to
              obtain [***] license, then such Party shall use commercially reasonable efforts to obtain [***] license to such Collaborator IP from such Third Party (any such [***] with such Third Party, a “Collaborator License”), and in each case, such Party will endeavor to obtain in such Collaborator License the right to sublicense such Collaborator IP to the other Party on terms that contain no greater restrictions on the
              other Party’s use of such Collaborator IP than those set forth in this Agreement.

          


     

    
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          	(d)	
            Notwithstanding any provision to the contrary in this Agreement, including Section 6.8, if Collaborator IP (other than Additional Core IP) arises from activities performed by a Third Party under the applicable Collaboration Program
              Research Plan, Development Plan or IDP, then any payment obligations arising under the applicable Collaborator License based on the Development or Commercialization of a Product will be [***] as follows: (i) in the case where [***] enters
              into such Collaborator License, [***] will be solely responsible for paying any payment obligations that [***], except that [***] will be solely responsible for paying any payment obligations that
              [***] under any such Collaborator Licenses that [***] approved prior to execution thereof and (ii) in the case where [***] enters into such Collaborator License, [***] will be [***] responsible for paying any payment obligations that [***].

          


     

    	

          	(e)	
            With respect to any such Collaborator IP licensed by Ionis under a Collaborator License with such Third Party, Biogen will have the right in accordance with Section 4.1.4 to elect to exclude any such Collaborator IP from the
              applicable license granted to Biogen under Section 4.1.1 by providing Ionis written notice prior to the License Effective Date for the applicable Collaboration Program. If, Biogen timely provides Ionis with such a written notice to
              exclude certain of such Collaborator IP from such license, then such Collaborator IP will not be included in the Licensed Technology licensed with respect to such Collaboration Program under this Agreement. If Biogen does not provide Ionis
              with such a written notice to exclude such Collaborator IP prior to the License Effective Date for the applicable Collaboration Program hereunder, then such Collaborator IP (and any Third Party Obligations to the extent applicable to
              Products) will be included in the Licensed Technology licensed with respect to the applicable Collaboration Program under this Agreement.

          


     

    
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            	(f)	
              In case of a dispute in the Joint Patent Committee over whether any Collaborator IP would be infringed or misappropriated (as applicable) by the Development, Manufacture or Commercialization of the applicable Development Candidate or any
                Compound under consideration by Ionis for potential designation as the Development Candidate, at the non-contracting Party’s request, such dispute will be resolved by independent patent counsel not engaged or regularly employed in the past
                two years by either Party and reasonably acceptable to both Parties, taking into account any existing prior art.  The decision of such independent patent counsel will be binding on the Parties.  Expenses of such patent counsel will be borne
                by the non-contracting Party.

            


    

     

    

    	

          	(g)	
            In addition, the Joint Patent Committee will be responsible for the determination of inventorship of Patent Rights that claim or cover Know-How discovered, developed, invented or created under this Agreement in accordance with United
              States patent Laws. In case of a dispute in the Joint Patent Committee (or otherwise between Ionis and Biogen) over inventorship of Program Patents, if the Joint Patent Committee cannot resolve such dispute, then such dispute will be resolved
              by independent patent counsel not engaged or regularly employed in the past two years by either Party and reasonably acceptable to both Parties.  The decision of such independent patent counsel will be binding on the Parties.  Expenses of
              such patent counsel will be shared equally by the Parties.

          


     

    	

          	(h)	
            The JPC will comprise an equal number of members from each Party. The Joint Patent Committee will meet as often as agreed by them (and at least semi-Annually), to discuss matters arising out of the activities set forth in this ARTICLE
                7. The JPC will determine by unanimous consent of its members the JPC operating procedures at its first meeting, including the JPC’s policies for replacement of JPC members, and the location of meetings, which will be codified in the
              written minutes of the first JPC meeting. To the extent reasonably requested by either Party, the Joint Patent Committee will solicit the involvement of more senior members of their respective legal departments (up to the most senior
              intellectual property attorney, where appropriate) with respect to critical issues, and may escalate issues to the Executives for input and resolution pursuant to Section 12.1. Each Party’s representatives on the Joint Patent
              Committee will consider comments and suggestions made by the other in good faith. If either Party deems it reasonably advisable, the Parties will enter into a mutually agreeable common interest agreement covering the matters contemplated by
              this Agreement.

          


     

    	7.2.	
            Prosecution and Maintenance of Patents.

          


     

    	

          	7.2.1.	
            Patent Filings.  Subject to Biogen’s right to provide reasonable input and comment as set forth in Section 7.2.4(a),
                the Party responsible for Prosecution and Maintenance of any Patent Rights as set forth in Section 7.2.2 and Section 7.2.3 will endeavor to obtain patent protection for the applicable Product as it Prosecutes and Maintains
                its other patents Covering products in development, using counsel of its own choice but reasonably acceptable to the other Party, in such countries as the responsible Party sees fit.

          


     

    
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          	7.2.2.	
            Licensed Patents and Biogen Patents.

          


     

    	

          	(a)	
            Licensed Patents In General.  Prior to the License Effective Date for a Collaboration Program, and subject to Biogen’s
                right to provide reasonable input and comment as set forth in Section 7.2.4(a), Ionis will control and be responsible for all aspects of the Prosecution and Maintenance of all Licensed Patents that are the subject of such license
                grant for such Collaboration Program, subject to this Section 7.2.2(a) and Section 7.2.3. During the Agreement Term, Ionis will control and be responsible for all aspects of the Ionis Core Technology Patents and Ionis
                Manufacturing and Analytical Patents. Ionis will use commercially reasonable efforts to diligently Prosecute and Maintain all Jointly-Owned Program Patents for which Ionis has the right to Prosecute and Maintain. On a Collaboration
                Program-by-Collaboration Program basis, until the earlier of the License Effective Date with respect to such Collaboration Program and the expiration or termination of Biogen’s right to be granted such license, Ionis will use commercially
                reasonable efforts to diligently Prosecute and Maintain all Ionis Product-Specific Patents that are the subject of such Collaboration Program to the extent that Ionis has the right to Prosecute and Maintain such Patent Rights.

          


     

    	

          	(b)	
            Licensed Patents After License Effective Date.  Upon the License Effective Date with respect to a Collaboration
                Program, Biogen will control and be responsible for all aspects of the Prosecution and Maintenance of all the Ionis Product-Specific Patents and Jointly-Owned Program Patents that are subject to the license under Section 4.1.1 for
                such Collaboration Program to the same extent Ionis had the right to control and was responsible for such Prosecution and Maintenance immediately prior to such License Effective Date, subject to Section 7.2.3, and will grant Ionis
                the license set forth in Section 4.2.2.

          


     

    	

          	(c)	
            Biogen Patents.  Biogen will control and be responsible for all aspects of the Prosecution and Maintenance of all
                Biogen Patents, subject to Section 7.2.3.

          


     

    	

          	7.2.3.	
            Jointly-Owned Program Patents.  Subject to Biogen’s right to provide reasonable input and comment as set forth in Section






                  7.2.4(a), Ionis will control and be responsible for all aspects of the Prosecution and Maintenance of Jointly-Owned Program Patents that do not Cover Products.  Prior to the License Effective Date for a Collaboration Program and
                subject to Biogen’s right to provide reasonable input and comment as set forth in Section 7.2.4(a), Ionis will control and be responsible for all aspects of the Prosecution and Maintenance of Jointly-Owned Program Patents Covering
                Products that are the subject of such Collaboration Program. After the License Effective Date for a Collaboration Program, Biogen will control and be responsible for all aspects of the Prosecution and Maintenance of Jointly-Owned Program
                Patents Covering Products that are the subject of such Collaboration Program.

          


     

    
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          	7.2.4.	
            Other Matters Pertaining to Prosecution and Maintenance of Patents.

          


     

    	

          	(a)	
            Ionis will keep Biogen reasonably informed through the Joint Patent Committee (or directly, if the Joint Patent Committee has been disbanded) as to material developments with respect to the Prosecution and Maintenance of (i) those Ionis
              Core Technology Patents and Ionis Manufacturing and Analytical Patents that Cover any Development Candidate or Product and (ii) the Ionis Product-Specific Patents and Jointly-Owned Program Patents, in each case ((i) and (ii)), for which Ionis
              has the responsibility to Prosecute and Maintain pursuant to Section 7.2.2, Section 7.2.3 or this Section 7.2.4, including by providing copies of material data as it arises. Ionis will timely provide Biogen the timely
              opportunity to have reasonable input into the strategic aspects of such Prosecution and Maintenance, including the countries in which such Patent Rights are filed, and will consider Biogen’s input with respect to such strategic aspects in
              good faith but which will not be binding on Ionis. Additionally, Ionis will promptly provide to Biogen drafts of all patent-related filings and communications related to the such Patent Rights, including copies of office actions or other
              correspondence that Ionis receives from any patent office, drafts of office action responses or other correspondence that Ionis provides to any patent office, and copies and drafts of all interferences, reissues, re-examinations, oppositions
              or requests for patent term extensions, in each case, for Biogen’s review and comment, and Ionis will consider in good faith any reasonable comments timely provided by Biogen with respect to such draft filings and communications.

          


     

    	

          	(b)	
            Following the License Effective Date with respect to a particular Collaboration Program, Biogen will keep Ionis reasonably informed through the Joint Patent Committee (or directly, if the Joint Patent Committee has been disbanded) as to
              material developments with respect to the Prosecution and Maintenance of Product-Specific Patents or Jointly-Owned Program Patents for which Biogen has the responsibility to Prosecute and Maintain pursuant to Section 7.2.2, Section






                7.2.3 or this Section 7.2.4, including by providing copies of material data as it arises and will provide Ionis the timely opportunity to have reasonable input into the strategic aspects of such Prosecution and Maintenance,
              which input Biogen will consider in good faith but which Biogen will not be required to implement. Following the License Effective Date with respect to a particular Collaboration Program, Biogen will have final decision-making authority with
              respect to the Prosecution and Maintenance, enforcement and defense of such Product-Specific Patents or Jointly-Owned Program Patents related to such Collaboration Program, including any Proceeding related to the infringement of such Patent
              Rights and any patent term extensions related to such Patent Rights.

          


     

    
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          	(c)	
            If Biogen elects (i) not to file and prosecute patent applications for the Jointly-Owned Program Patents or Ionis Product-Specific Patents that have been licensed or assigned to Biogen under this Agreement or the Biogen Product-Specific
              Patents (“Biogen-Prosecuted Patents”) in a particular country, (ii) not to continue the Prosecution and Maintenance (including any interferences, oppositions, reissue proceedings,
              re-examinations, and patent term extensions, adjustments, and restorations) of any Biogen-Prosecuted Patent in a particular country or (iii) not to file and prosecute patent applications for the Biogen-Prosecuted Patent in a particular
              country following a written request from Ionis to file and prosecute in such country, then in each case ((i) – (iii)), Biogen will so notify Ionis promptly in writing of its intention (including a reasonably detailed rationale for doing so)
              with sufficient time to enable Ionis to meet any deadlines by which an action must be taken to establish or preserve any such Patent Right in such country; and except as set forth in Section 7.2.4(d), Ionis will have the right, but
              not the obligation, to file, prosecute, maintain, enforce or otherwise pursue such Biogen-Prosecuted Patent in the applicable country at its own expense with counsel of its own choice. In such case, Biogen will cooperate with Ionis to file
              for, or continue to Prosecute and Maintain, enforce or otherwise pursue such Biogen-Prosecuted Patent in such country in Ionis’ own name, but only to the extent that Biogen is not required to take any position with respect to such abandoned
              Biogen-Prosecuted Patent that would be reasonably likely to adversely affect the scope, validity or enforceability of any of the other Patent Rights being prosecuted and maintained by Biogen under this Agreement. Notwithstanding anything to
              the contrary in this Agreement, if Ionis assumes responsibility for the Prosecution and Maintenance of any such Biogen-Prosecuted Patent under this Section 7.2.4(c), then Ionis will have no obligation to notify Biogen if Ionis intends
              to abandon such Biogen-Prosecuted Patent.

          


     

    	

          	(d)	
            Notwithstanding Section 7.2.4(c) above, if, after having consulted with outside counsel, Biogen reasonably determines that filing or continuing to prosecute a patent application in a particular country for a Biogen-Prosecuted
              Patent (the “Conflicting Patent Right”) is reasonably likely to adversely affect the scope, validity or enforceability of a patent application or issued patent in a particular
              country for another Biogen-Prosecuted Patent (the “Superior Patent Right”), in each case where both the Conflicting Patent Right and the Superior Patent Right if issued would meet
              the criteria set forth in clause (i) of Section 6.6.2(a), then so long as Biogen continues to Prosecute and Maintain the Superior Patent Right in accordance with this Agreement, Ionis will not
              have the right under Section 7.2.4(c) above to file or prosecute the Conflicting Patent Right.

          


     

    
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            EXECUTION VERSION

          

        

         

      

    

    	

          	(e)	
            If, during the Agreement Term, Ionis intends not to file or intends to abandon in any jurisdiction any Ionis Product-Specific Patent for which Ionis is responsible for Prosecution and Maintenance without first filing a continuation or
              substitution, then, if Biogen’s right to obtain a license under Section 4.1.1 to such Ionis Product-Specific Patent has not expired or terminated, Ionis will notify Biogen of such intention at least [***] days before such Patent Right
              will become abandoned, and Biogen will have the right, but not the obligation, to assume responsibility and final decision-making authority for the Prosecution and Maintenance thereof at its own expense (subject to Section 7.3.1) with
              counsel of its own choice.  Notwithstanding anything to the contrary in this Agreement, if Biogen assumes responsibility for the Prosecution and Maintenance of any such Ionis Product-Specific Patent under this Section 7.2.4(e), then
              Biogen will have no obligation to notify Ionis if Biogen intends to abandon such Ionis Product-Specific Patent.

          


     

    	

          	(f)	
            The Parties, through the Joint Patent Committee (or directly, if the Joint Patent Committee has been disbanded), will cooperate in good faith to determine if and when any divisional or continuation applications will be filed with respect
              to any Program Patents or Product-Specific Patents, and where a divisional or continuation patent application filing would be practical and reasonable, following which determination such a divisional or continuation filing will be made.

          


     

    	

          	(g)	
            If the Party responsible for Prosecution and Maintenance of a Jointly-Owned Program Patent pursuant to Section 7.2.3 intends to abandon such Jointly-Owned Program Patent without first filing a continuation or substitution, then
              such Party will notify the other Party of such intention at least [***] days before such Jointly-Owned Program Patent will become abandoned, and such other Party will have the right, but not the obligation, to assume responsibility and final
              decision-making authority for the Prosecution and Maintenance thereof at its own expense (subject to Section 7.3.1) with counsel of its own choice, in which case the abandoning Party will, and will cause its Affiliates to, assign to
              the other Party (or, if such assignment is not possible, grant a fully-paid exclusive license in) all of their rights, title and interests in and to such Jointly-Owned Program Patents. If a Party assumes responsibility for the Prosecution and
              Maintenance of any such Jointly-Owned Program Patents under this Section 7.2.4(g), such Party will have no obligation to notify the other Party of any intention of such Party to abandon such Jointly-Owned Program Patents.

          


     

    	

          	(h)	
            In addition, the Parties will consult, through the Joint Patent Committee (or directly, if the Joint Patent Committee has been disbanded), and take into consideration the comments of the other Party for all matters relating to
              interferences, reissues, re-examinations and oppositions with respect to those Patent Rights in which such other Party (i) has an ownership interest, (ii) has received a license thereunder in accordance with this Agreement, or (iii) may in
              the future, in accordance with this Agreement, obtain a license or sublicense thereunder.

          


     

    
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    	7.3.	
            Patent Costs.

          


     

    	

          	7.3.1.	
            Jointly-Owned Program Patents.  Unless the Parties agree otherwise, Ionis and Biogen will share equally the Patent
                Costs associated with the Prosecution and Maintenance of Jointly-Owned Program Patents; provided that either Party may decline to pay its share of costs for filing, prosecuting and maintaining any
                Jointly-Owned Program Patents in a particular country or particular countries, in which case the declining Party will, and will cause its Affiliates to, assign to the other Party (or, if such assignment is not possible, grant a fully-paid
                exclusive license in) all of their rights, title and interests in and to such Jointly-Owned Program Patents.

          


     

    	

          	7.3.2.	
            Licensed Patents and Biogen Patents.  Except as set forth in Section 7.3.1, each Party will be responsible for
                all Patent Costs incurred by such Party prior to and after the Effective Date in all countries in the Prosecution and Maintenance of Patent Rights for which such Party is responsible under Section 7.2; provided, however, that after the License Effective Date for a Collaboration Program, Biogen will be solely responsible for Patent Costs arising from the Prosecution and Maintenance
                of the Ionis Product-Specific Patents related to such Collaboration Program.

          


     

    	7.4.	
            Defense of Claims Brought by Third Parties.

          


     

    	

          	7.4.1.	
            If a Third Party initiates a Proceeding claiming a Patent Right owned by or licensed to such Third Party is infringed by the Development, Manufacture or Commercialization of a Product, (a) Ionis will have the first right, but not the
              obligation, to defend against any such Proceeding initiated prior to the License Effective Date for the applicable Collaboration Program at its sole cost and expense and (b) Biogen will have the first right, but not the obligation, to defend
              against any such Proceeding initiated after the License Effective Date for the applicable Collaboration Program at its sole cost and expense. If the Party having the first right to defend against such Proceeding (the “Lead Party”) elects to defend against such Proceeding, then the Lead Party will have the sole right to direct the defense and to elect whether to settle such claim (but only with the
              prior written consent of the other Party, not to be unreasonably withheld, conditioned or delayed). The other Party will reasonably assist the Lead Party in defending such Proceeding and cooperate in any such litigation at the request and
              expense of the Lead Party. The Lead Party will provide the other Party with prompt written notice of the commencement of any such Proceeding that is of the type described in this Section 7.4, and the Lead Party will keep the other
              Party apprised of the progress of such Proceeding.  Notwithstanding the foregoing, (i) if Ionis is the Lead Party, then Ionis will cooperate in good faith with Biogen on the institution, prosecution and control of such Proceeding, will
              provide Biogen with copies of filings, submissions and communications related to such Proceeding in sufficient time to allow Biogen to review and comment thereon, and will incorporate any reasonable comments timely provided by Biogen with
              respect to such filings, submissions and communications and (ii) if Biogen is the Lead Party and Ionis is a named party, then Biogen will cooperate in good faith with Ionis on the institution, prosecution and control of such Proceeding and
              will provide Ionis the timely opportunity to have reasonable input into the strategic aspects of such Proceeding, which Biogen will consider in good faith but which Biogen will not be required to implement. If the Lead Party elects not to
              defend against a Proceeding, then the Lead Party will so notify the other Party in writing within [***] days after the Lead Party first receives written notice of the initiation of such Proceeding, and the other Party (the “Step-In Party”) will have the right, but not the obligation, to defend against such Proceeding at its sole cost and expense and thereafter the Step-In Party will have the sole right to
              direct the defense thereof, including the right to settle such claim. In any event, the Party not defending such Proceeding will reasonably assist the other Party and cooperate in any such litigation at the request and expense of the Party
              defending such Proceeding.  Each Party may at its own expense and with its own counsel join any defense initiated or directed by the other Party under this Section 7.4.  Each Party will provide the other Party with prompt written
              notice of the commencement of any such Proceeding under this Section 7.4, and such Party will promptly furnish the other Party with a copy of each communication relating to the alleged infringement that is received by such Party.

          


     

    
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          	7.4.2.	
            Discontinued Product.  If a Third Party initiates a Proceeding claiming that any Patent Right or Know-How owned by or
                licensed to such Third Party is infringed by the Development, Manufacture or Commercialization of a Discontinued Product, then Ionis will have the first right, but not the obligation, to defend against and settle such Proceeding at its sole
                cost and expense. Biogen will reasonably assist Ionis in defending such Proceeding and cooperate in any such litigation at the request and expense of Ionis.  Each Party may at its own expense and with its own counsel join any defense
                directed by the other Party. Ionis will provide Biogen with prompt written notice of the commencement of any such Proceeding, or of any allegation of infringement of which Ionis becomes aware and that is of the type described in this Section






                  7.4.2, and Ionis will promptly furnish Biogen with a copy of each communication relating to the alleged infringement received by Ionis.

          


     

    	

          	7.4.3.	
            Interplay Between Enforcement of IP and Defense of Third Party Claims.  Notwithstanding the provisions of Section
                  7.4.1 and Section 7.4.2, to the extent that a Party’s defense against a Third Party claim of infringement under this Section 7.4 involves (a) the enforcement of the other Party’s Know-How or Patent Rights (e.g.,
                a counterclaim of infringement), or (b) the defense of an invalidity claim with respect to such other Party’s Know-How or Patent Rights, then, in each case, the general concepts of Section 7.5 will apply to the enforcement of such
                other Party’s Know-How or Patent Rights or the defense of such invalidity claim (i.e., each Party has the right to enforce its own intellectual property, except that the relevant Commercializing Party will have the initial right, to
                the extent provided in Section 7.5, to enforce such Know-How or Patent Rights or defend such invalidity claim, and the other Party will have a step-in right, to the extent provided in Section 7.5, to enforce such Know-How or
                Patent Rights or defend such invalidity claim).

          


     

    
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    	7.5.	
            Enforcement of Patents against Competitive Infringement.

          


     

    	

          	7.5.1.	
            Duty to Notify of Competitive Infringement.  If either Party learns of an infringement, unauthorized use,
                misappropriation or threatened infringement by a Third Party to which such Party does not owe any conflicting obligation of confidentiality with respect to any Licensed Patents by reason of the development, manufacture, use or
                commercialization of a product directed against the RNA that encodes a Collaboration Target in the Field (“Competitive Infringement”), such Party will promptly notify the other Party in writing and will provide such other Party with available evidence of such Competitive Infringement; provided, however, that for cases of Competitive Infringement under Section 7.5.8 below, such written notice will be given within 10 days.

          


     

    	

          	7.5.2.	
            Prior to License Grant.  For any Competitive Infringement with respect to a Product occurring after the Effective Date
                but before the License Effective Date for the Collaboration Program of which such Product is the subject, Ionis will have the first right, but not the obligation, to institute, prosecute, and control a Proceeding with respect thereto, by
                counsel of its own choice, and Biogen will have the right to be represented in that action by counsel of its own choice at its own expense. Ionis will provide Biogen with prompt written notice of the commencement of any such Proceeding, and
                Ionis will keep Biogen apprised of the progress of such Proceeding. Additionally, Ionis will provide Biogen with copies of filings, submissions and communications related to such Proceeding in sufficient time to allow Biogen to review and
                comment thereon, and will consider in good faith any reasonable comments timely provided by Biogen with respect to such filings, submissions and communications. Subject to the preceding sentence, Ionis will have the sole right to control
                such litigation. If Ionis fails to initiate a Proceeding within a period of 90 days after receipt of written notice of such Competitive Infringement (subject to a 90 day extension to conclude negotiations, which extension will apply only in
                the event that Ionis has commenced good faith negotiations with an alleged infringer for elimination of such Competitive Infringement within such 90 day period), Biogen will have the right to initiate and control a Proceeding with respect
                to such Competitive Infringement by counsel of its own choice; provided that Ionis will have the right to be represented in any such action by counsel of its own choice at its own expense.
                Notwithstanding the foregoing, Ionis will at all times have the sole right to institute, prosecute, and control any Proceeding under this Section 7.5.2 to the extent involving any Ionis Core Technology Patents or Ionis Manufacturing
                and Analytical Patents.

          


     

    
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          	7.5.3.	
            Biogen Enforcement Rights.  Notwithstanding Section 7.5.2 and Section 7.5.4, in the case where a Third
                Party is infringing an Ionis Core Technology Patent and a Patent Right Controlled by Biogen by reason of the development, manufacture, use or commercialization of a product directed against the RNA that encodes a High Interest Target or a
                Collaboration Target in the Field, then the Party with knowledge of such infringement will promptly notify the other Party in writing. If Biogen also enforces any Patent Rights Controlled by Biogen (including any Ionis Product-Specific
                Patents assigned by Ionis to Biogen under this Agreement) against such infringement, then Biogen may elect to have Ionis and Biogen enforce the applicable Ionis Core Technology Patents and the applicable Patent Rights Controlled by Biogen
                against such infringing Third Party.

          


     

    	

          	7.5.4.	
            Following License Grant.  For any Competitive Infringement with respect to a particular Product (except for a
                Discontinued Product) occurring after the License Effective Date for the Collaboration Program of which such Product is the subject, so long as part of such Proceeding Biogen also enforces any Patent Rights Controlled by Biogen (including
                any Ionis Product-Specific Patents assigned by Ionis to Biogen under this Agreement) being infringed that Cover the Product, then Biogen will have the first right, but not the obligation, to institute, prosecute, and control a Proceeding
                with respect thereto by counsel of its own choice at its own expense, and Ionis will have the right, at its own expense, to be represented in that action by counsel of its own choice, however,
                Biogen will have the right to control such litigation. If Biogen fails to initiate a Proceeding within a period of 90 days after receipt of written notice of such Competitive Infringement (subject to a 90 day extension to conclude
                negotiations, if Biogen has commenced good faith negotiations with an alleged infringer for elimination of such Competitive Infringement within such 90 day period), Ionis will have the right to initiate and control a Proceeding with respect
                to such Competitive Infringement by counsel of its own choice, and Biogen will have the right to be represented in any such action by counsel of its own choice at its own expense. Notwithstanding the foregoing, Ionis will at all times have
                the sole right to institute, prosecute, and control any Proceeding under this Section 7.5.4 to the extent involving any Ionis Core Technology Patents or Ionis Manufacturing and Analytical Patents.

          


     

    	

          	7.5.5.	
            Joinder.

          


     

    	

          	(a)	
            If a Party initiates a Proceeding in accordance with this Section 7.5, then the other Party agrees to be joined as a party plaintiff where necessary and to give the first Party reasonable assistance and authority to file and
              prosecute the Proceeding. Subject to Section 7.5.6, the costs and expenses of each Party incurred pursuant to this Section 7.5.5(a) will be borne by the Party initiating such Proceeding.

          


     

    	

          	(b)	
            If one Party initiates a Proceeding in accordance with this Section 7.5.5, then the other Party may join such Proceeding as a party plaintiff where necessary for such other Party to seek lost profits with respect to such
              infringement or where such Proceeding relates to Jointly-Owned Program Patents.

          


     

    	

          	7.5.6.	
            Share of Recoveries.  Any damages or other monetary awards recovered with respect to a Proceeding brought pursuant to
                this Section 7.5 will be shared as follows:

          


     

    
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          	(a)	
            the amount of such recovery will first be applied to the Parties’ reasonable out-of-pocket costs incurred in connection with such Proceeding (which amounts will be allocated pro rata if
              insufficient to cover the totality of such expenses); then

          


     

    	

          	(b)	
            any remaining proceeds constituting direct or actual damages for acts of infringement occurring prior to the License Effective Date for the Collaboration Program of which the applicable Product is the subject will be (i) [***]; or (ii)
              [***]; then

          


     

    	

          	(c)	
            any remaining proceeds constituting direct or actual damages for acts of infringement occurring after the License Effective Date for the Collaboration Program of which the applicable Product is the subject [***]; then

          


     

    	

          	(d)	
            any remaining proceeds constituting punitive or treble damages will be allocated between the Parties as follows: the Party initiating the Proceeding will receive and retain [***]% of such proceeds and the other Party will receive and
              retain [***]% of such proceeds.

          


     

    	

          	7.5.7.	
            Settlement.  Notwithstanding anything to the contrary under this ARTICLE 7, neither Party may enter a
                settlement, consent judgment or other voluntary final disposition of a suit under this ARTICLE 7 that disclaims, limits the scope of, admits the invalidity or unenforceability of, or grants a license, covenant not to sue or similar
                immunity under a Patent Right Controlled by the other Party without first obtaining the written consent of the Party that Controls the relevant Patent Right.

          


     

    	

          	7.5.8.	
            35 USC §271(e)(2) Infringement.  Notwithstanding anything to the contrary in this Section 7.5, solely with
                respect to Licensed Patents that have not been assigned to Biogen under this Agreement for a Competitive Infringement under 35 USC §271(e)(2), the time period set forth in Section 7.5.2 during which a Party will have the initial
                right to bring a Proceeding will be shortened to a total of 25 days, so that, to the extent the other Party has the right, pursuant to Section 7.5.2 to initiate a Proceeding if the first Party does not initiate a Proceeding, such
                other Party will have such right if the first Party does not initiate a Proceeding within 25 days after such first Party’s receipt of written notice of such Competitive Infringement.

          


     

    	7.6.	
            Other Infringement.

          


     

    	

          	7.6.1.	
            Jointly-Owned Program Patents.  With respect to the infringement of a Jointly-Owned Program Patent which is not a
                Competitive Infringement, the Parties will cooperate in good faith to bring suit together against such infringing party or the Parties may decide to permit one Party to solely bring suit. Any damages or other monetary awards recovered with
                respect to a Proceeding brought pursuant to this Section 7.6.1 will be shared as follows: (a) the amount of such recovery will first be applied to the Parties’ reasonable out-of-pocket costs incurred in connection with such
                Proceeding (which amounts will be allocated pro rata if insufficient to cover the totality of such expenses); (b) any remaining proceeds constituting direct damages will be [***], and (c) any
                remaining proceeds constituting punitive or treble damages will be allocated as follows: (i) if the Parties jointly initiate a Proceeding pursuant to this Section 7.6.1, [***]; and (ii) if only one Party initiates the Proceeding
                pursuant to this Section 7.6.1, such Party will receive [***]% of such proceeds and the other Party will receive [***]% of such proceeds.

          


     

    
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          	7.6.2.	
            Patents Solely Owned by Ionis.  Ionis will retain all rights to pursue an infringement of any Patent Right solely owned
                by Ionis which is other than a Competitive Infringement and Ionis will retain all recoveries with respect thereto.

          


     

    	

          	7.6.3.	
            Patents Solely Owned by Biogen.  Biogen will retain all rights to pursue an infringement of any Patent Right solely
                owned by Biogen which is other than a Competitive Infringement and Biogen will retain all recoveries with respect thereto.

          


     

    	7.7.	
            Patent Listing.

          


     

    	

          	7.7.1.	
            Biogen’s Obligations.  Biogen will promptly, accurately and completely list, with the applicable Regulatory Authorities
                during the Agreement Term, all applicable Patent Rights that Cover a Product.  Prior to such listings, the Parties will meet, through the Joint Patent Committee, to evaluate and identify all applicable Patent Rights, and Biogen will have
                the right to review, where reasonable, original records relating to any invention for which Patent Rights are being considered by the Joint Patent Committee for any such listing. Notwithstanding the preceding sentence, Biogen will retain
                final decision-making authority as to the listing of all applicable Patent Rights for the Product that are not Ionis Core Technology Patents or Ionis Manufacturing and Analytical Patents, regardless of which Party owns such Patent Rights.

          


     

    	

          	7.7.2.	
            Ionis’ Obligations.  Ionis will promptly, accurately and completely list, with the applicable Regulatory Authorities
                during the Agreement Term, all applicable Patent Rights that Cover a Discontinued Product. Prior to such listings, the Parties will meet, through the Joint Patent Committee, to evaluate and identify all applicable Patent Rights, and Ionis
                will have the right to review, where reasonable, original records relating to any invention for which Patent Rights are being considered by the Joint Patent Committee for any such listing. Notwithstanding the preceding sentence, Ionis will
                retain final decision-making authority as to the listing of all applicable Patent Rights for such Discontinued Products, as applicable, regardless of which Party owns such Patent Rights.

          


     

    	7.8.	
            Joint Research Agreement under the Leahy-Smith America Invents Act.  Notwithstanding anything to the contrary in this ARTICLE






                  7, neither Party will have the right to make an election under 35 U.S.C. § 102(c) of the Leahy-Smith America Invents Act when exercising its rights under this ARTICLE 7 without the prior written consent of the other Party,
                which will not be unreasonably withheld, conditioned or delayed.  With respect to any such permitted election, each Party will use reasonable efforts to cooperate and coordinate their activities with the other Party with respect to any
                submissions, filings or other activities in support thereof. The Parties acknowledge and agree that this Agreement is a “joint research agreement” as defined in 35 U.S.C. § 100(h).

          


     

    
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    	7.9.	
            Obligations to Third Parties.  Notwithstanding any of the foregoing, each Party’s rights and obligations with respect
                to Licensed Technology under this ARTICLE 7 will be subject to the Third Party rights and obligations under any (a) New Third Party License, the restrictions and obligations of which Biogen has agreed to under Section 6.8.2,
                (b) Prior Agreements and (c) Ionis In-License Agreements; provided, however, that, to the extent that Ionis has a non-transferable right to prosecute,
                maintain or enforce any Patent Rights licensed to Biogen hereunder and this Agreement purports to grant any such rights to Biogen, Ionis will act in such regard with respect to such Patent Rights at Biogen’s direction.

          


     

    	7.10.	
            Additional Right and Exceptions.  Notwithstanding any provision of this ARTICLE 7, Ionis retains the sole right
                to Prosecute and Maintain Ionis Core Technology Patents and Ionis Manufacturing and Analytical Patents during the Agreement Term and to control any enforcement of Ionis Core Technology Patents and Ionis Manufacturing and Analytical Patents,
                and will take the lead on such enforcement solely to the extent that the scope or validity of any Patent Rights Controlled by Ionis and Covering the Ionis Core Technology Patents or Ionis Manufacturing and Analytical Patents is at risk.

          


     

    	7.11.	
            Patent Term Extension.  The Parties will cooperate with each other in gaining patent term extension wherever applicable
                to the Product. After the License Effective Date for the Collaboration Program of which such Product is the subject, Biogen will have the sole right to determine which relevant patents will be extended.

          


     

    ARTICLE 8

    REPRESENTATIONS AND WARRANTIES

     

    	8.1.	
            Representations and Warranties of Both Parties.  Each Party hereby represents and warrants to the other Party, as of
                the Amendment Date, that:

          


     

    	

          	8.1.1.	
            such Party is duly organized, validly existing and in good standing under the Laws of the jurisdiction of its incorporation or organization and has full corporate power and authority to enter into this Agreement and to carry out the
              provisions hereof;

          


     

    	

          	8.1.2.	
            such Party has taken all necessary action on its part to authorize the execution and delivery of this Agreement and the performance of its obligations hereunder;

          


     

    	

          	8.1.3.	
            this Agreement has been duly executed and delivered on behalf of such Party, and constitutes a legal, valid and binding obligation, enforceable against it in accordance with the terms hereof;

          


     

    	

          	8.1.4.	
            the execution, delivery and performance of this Agreement by such Party will not constitute a default under or conflict with any agreement, instrument or understanding, oral or written, to which it is a party or by which it is bound, or
              violate any Law or regulation of any court, governmental body or administrative or other agency having jurisdiction over such Party;

          


     

    
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          	8.1.5.	
            no government authorization, consent, approval, license, exemption of or filing or registration with any court or governmental department, commission, board, bureau, agency or instrumentality, domestic or foreign, under any Applicable
              Laws, rules or regulations currently in effect, is or will be necessary for, or in connection with, the transaction contemplated by this Agreement or any other agreement or instrument executed in connection herewith, or for the performance by
              it of its obligations under this Agreement and such other agreements; and

          


     

    	

          	8.1.6.	
            it has not employed (and, to the best of its knowledge, has not used a contractor or consultant that has employed) and in the future will not employ (or, to the best of its knowledge, use any contractor or consultant that employs (provided that such Party may reasonably rely on a representation made by such contractor or consultant)) any Person debarred by the FDA (or subject to a similar sanction of EMA or foreign equivalent), or
              any Person which is the subject of an FDA debarment investigation or proceeding (or similar proceeding of EMA or foreign equivalent), in the conduct of the Pre-Clinical Studies or Clinical Studies of the Product and its activities under each
              Collaboration Program.

          


     

    	8.2.	
            Representations and Warranties of Ionis.  Ionis hereby represents and warrants to Biogen, as of the Effective Date,
                that:

          


     

    	

          	8.2.1.	
            To the best of its knowledge and belief, there are no additional licenses (beyond those that would be granted to Biogen under Section 4.1.1 upon the exercise of the Option for a Product arising under the Collaboration Programs)
              under any intellectual property owned or Controlled by Ionis or its Affiliates as of the Effective Date that would be required in order for Biogen to further Develop and Commercialize a Product.

          


     

    	

          	8.2.2.	
            The Licensed Technology existing as of the Effective Date constitutes all of the Patent Rights and Know-How Controlled by Ionis as of the Effective Date that are necessary to Develop, Manufacture or Commercialize Compounds contemplated
              under the Collaboration Programs in the Field.  Ionis has not previously assigned, transferred, conveyed or otherwise encumbered its rights, title and interests in the Licensed Technology in a manner that conflicts with any rights granted to
              Biogen hereunder.

          


     

    	

          	8.2.3.	
            Neither Ionis nor its Affiliates owns or Controls any Patent Rights or Know-How covering formulation or delivery technology as of the Effective Date that would be useful or necessary in order for Biogen to further Develop or Commercialize
              Compounds contemplated under the Collaboration Programs.

          


     

    	

          	8.2.4.	
            Schedule 8.2.4(a), Schedule
                  8.2.4(b) and Schedule 8.2.4(c) set forth true, correct and complete lists of all Ionis Core Technology Patents, and Ionis Manufacturing and Analytical Patents that apply to
                the Compounds contemplated under the Collaboration Programs as of the Effective Date (the “Ionis Platform Technology”), respectively, and indicates whether each such Patent Right
                is owned by Ionis or licensed by Ionis from a Third Party and if so, identifies the licensor or sublicensor from which the Patent Right is licensed.  Ionis Controls such Patent Rights existing as of the Effective Date and is entitled to
                grant all rights and licenses (or sublicenses, as the case may be) under such Patent Rights it purports to grant to Biogen under this Agreement.

          


     

    
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          	8.2.5.	
            There are no claims, judgments or settlements against or owed by Ionis or its Affiliates or pending against Ionis or, to the best of Ionis’ knowledge, threatened against Ionis, in each case relating to the Ionis Platform Technology, Ionis
              Manufacturing and Analytical Know-How, Ionis Know-How, Collaboration Targets or High Interest Targets that could impact activities under this Agreement. To the best of Ionis’ knowledge, there are no claims, judgments or settlements against or
              owed by any Third Party that is party to a Prior Agreement, or pending or threatened claims or litigation against any Third Party that is party to a Prior Agreement, in each case relating to the Ionis Platform Technology, Ionis Manufacturing
              and Analytical Know-How, Ionis Know-How, Collaboration Targets or High Interest Targets that would impact activities under this Agreement.

          


     

    	

          	8.2.6.	
            At the Effective Date (a) there is no fact or circumstance known by Ionis that would cause Ionis to reasonably conclude that any Ionis Core Technology Patent or Ionis Manufacturing and Analytical Patent is invalid or un-enforceable, (b)
              there is no fact or circumstance known by Ionis that would cause Ionis to reasonably conclude the inventorship of each Ionis Core Technology Patent or Ionis Manufacturing and Analytical Patent is not properly identified on each patent, and
              (c) all official fees, maintenance fees and annuities for the Ionis Core Technology Patent or Ionis Manufacturing and Analytical Patent have been paid and all administrative procedures with governmental agencies have been completed.

          


     

    	

          	8.2.7.	
            Ionis has set forth on Schedule 6.8.1 or in a separate written agreement with Biogen true, correct and complete lists of the agreements with Third Party licensors or sellers
              pursuant to which Ionis has licensed or acquired the Licensed Technology Controlled by Ionis as of the Effective Date licensed to Biogen under Section 4.1.1 that is necessary or useful to conduct the research, Development, Manufacture
              or Commercialization of any High Interest Target listed on the High Interest Target List as of the Effective Date and any Compounds as contemplated under the Collaboration Program targeting [***].  All Ionis In-License Agreements are in full
              force and effect and have not been modified or amended. Neither Ionis nor, to the best knowledge of Ionis, the Third Party licensor in an Ionis In-License Agreement is in default with respect to a material obligation under such Ionis
              In-License Agreement, and neither such party has claimed or has grounds upon which to claim that the other party is in default with respect to a material obligation under, any Ionis In-License Agreement.

          


     

    	

          	8.2.8.	
            Schedule 8.2.8 is a complete and accurate list of all agreements
                that create Third Party Obligations with respect to the Ionis Core Technology Patents and Ionis Manufacturing and Analytical Patents that affect the rights granted by Ionis to Biogen under this Agreement.

          


     

    	8.3.	
            Ionis Covenants.  Ionis hereby covenants to Biogen that, except as expressly permitted under this Agreement:

          


     

    
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          	8.3.1.	
            Ionis will promptly amend Schedule 8.2.4(a), Schedule 8.2.4(b) and Schedule
                8.2.4(c) and submit such amended Schedules to Biogen if Ionis becomes aware that any Ionis Core Technology Patents,
              Ionis Manufacturing and Analytical Patents or Ionis Product-Specific Patents are not properly identified on such Schedule.

          


     

    	

          	8.3.2.	
            during the Agreement Term, Ionis will maintain and not breach any Ionis In-License Agreements and any agreements with Third Parties entered into after the Effective Date (“New Third
                Party Licenses”) that provide a grant of rights from such Third Party to Ionis that are Controlled by Ionis and are licensed or may become subject to a license from Ionis to Biogen for the Development Candidate under this Agreement;

          


     

    	

          	8.3.3.	
            Ionis will promptly notify Biogen of any material breach by Ionis or a Third Party of any New Third Party License, and in the event of a breach by Ionis, will permit Biogen to cure such breach on Ionis’ behalf upon Biogen’s request;

          


     

    	

          	8.3.4.	
            Ionis will not amend, modify or terminate any Ionis In-License Agreement or New Third Party License in a manner that would adversely affect Biogen’s rights hereunder without first obtaining Biogen’s written consent, which consent may be
              withheld in Biogen’s sole discretion;

          


     

    	

          	8.3.5.	
            Ionis will not enter into any new agreement or other obligation with any Third Party, or amend an existing agreement with a Third Party, in each case that restricts, limits or encumbers the rights granted to Biogen under this Agreement;

          


     

    	

          	8.3.6.	
            Ionis will cause its Affiliates to comply with the terms of Section 2.1 and will not permit any Affiliates to conduct any activities that Ionis is prohibited from conducting under Section 2.1;

          


     

    	

          	8.3.7.	
            all employees and contractors of Ionis performing Development activities hereunder on behalf of Ionis will be obligated to assign all rights, title and interests in and to any inventions developed by them, whether or not patentable, to
              Ionis or such Affiliate, respectively, as the sole owner thereof; and

          


     

    	

          	8.3.8.	
            If, after the Effective Date, Ionis becomes the owner or otherwise acquires Control of any formulation or delivery technology that would be necessary or useful in order for Biogen to further Develop, Manufacture or Commercialize a Product,
              and Biogen has exercised its Option and the license granted to Biogen under this Agreement is in effect, Ionis will make such technology available to Biogen on commercially reasonable terms.

          


     

    	8.4.	
            DISCLAIMER.  EXCEPT AS OTHERWISE EXPRESSLY SET FORTH IN THIS AGREEMENT, NEITHER PARTY NOR ITS AFFILIATES MAKES ANY
                REPRESENTATION OR EXTENDS ANY WARRANTY OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING ANY WARRANTY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. BIOGEN AND IONIS UNDERSTAND THAT EACH PRODUCT IS THE SUBJECT OF ONGOING RESEARCH
                AND DEVELOPMENT AND THAT NEITHER PARTY CAN ASSURE THE SAFETY, USEFULNESS OR COMMERCIAL OR TECHNICAL VIABILITY OF EACH PRODUCT.

          


     

    
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    ARTICLE 9

    INDEMNIFICATION; INSURANCE

     

    	9.1.	
            Indemnification by Biogen.  Biogen will indemnify, defend and hold harmless Ionis and its Affiliates, and its or their
                respective directors, officers, employees and agents, from and against any and all liabilities, damages, losses, costs and expenses including the reasonable fees of attorneys (collectively “Losses”) arising out of or resulting from any and all Third Party suits, claims, actions, proceedings or demands (“Claims”) based upon:

          


     

    	

          	9.1.1.	
            the gross negligence or willful misconduct of Biogen, its Affiliates or Sublicensees and its or their respective directors, officers, employees and agents, in connection with Biogen’s performance
              of its obligations or exercise of its rights under this Agreement;

          


     

    	

          	9.1.2.	
            any breach of any representation or warranty or express covenant made by Biogen under ARTICLE 8 or any other provision under this Agreement;

          


     

    	

          	9.1.3.	
            the Development or Manufacturing activities that are conducted by or on behalf of Biogen or its Affiliates or Sublicensees (which will exclude any Development or Manufacturing activities that are
              conducted by or on behalf of Ionis pursuant to this Agreement); or

          


     

    	

          	9.1.4.	
            the Commercialization of a Product by or on behalf of Biogen or its Affiliates or Sublicensees;

          


     

    except, in each case above, to the extent such Claim arose out of or resulted from or is
        attributable to any acts or omissions of Ionis or its Affiliates, licensees, Sublicensees or contractors, and its or their respective directors, officers, employees and agents or other circumstance for
        which Ionis has an indemnity obligation pursuant to Section 9.2.

     

    	9.2.	
            Indemnification by Ionis.  Ionis will indemnify, defend and hold harmless Biogen and its Affiliates, and its or their
                respective directors, officers, employees and agents, from and against any and all Losses arising out of or resulting from any and all Claims based upon:

          


     

    	

          	9.2.1.	
            the gross negligence or willful misconduct of Ionis, its Affiliates or Sublicensees or its or their respective directors, officers, employees and agents,
              in connection with Ionis’ performance of its obligations or exercise of its rights under this Agreement;

          


     

    	

          	9.2.2.	
            any breach of any representation or warranty or express covenant made by Ionis under ARTICLE 8 or any other provision under this Agreement;

          


     

    	

          	9.2.3.	
            any Development or Manufacturing activities that are conducted by or on behalf of Ionis or its Affiliates or Sublicensees (which will exclude any Development or Manufacturing activities that are
              conducted by or on behalf of Biogen pursuant to this Agreement); or

          


     

    
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          	9.2.4.	
            any development, manufacturing or commercialization activities that are conducted by or on behalf of Ionis or its Affiliates or Sublicensees with respect to a Discontinued Product;

          


     

    except, in each case above, to the extent such Claim arose out of or resulted from or is
        attributable to any acts or omissions of Biogen or its Affiliates, licensees, Sublicensees or contractors and its or their respective directors, officers, employees and agents or other circumstance for
        which Biogen has an indemnity obligation pursuant to Section 9.1.

     

    	9.3.	
            Procedure.  If a Person entitled to indemnification under Section 9.1 or Section 9.2 (an “Indemnitee”) seeks such indemnification, such Indemnitee will (a) inform the indemnifying Party in writing of a Claim as soon as reasonably practicable after such Indemnitee receives
                notice of such Claim, (b) permit the indemnifying Party to assume direction and control of the defense of the Claim (including the sole right to settle such Claim at the sole discretion of the indemnifying Party; provided that (i) such settlement or compromise does not admit any fault or negligence on the part of the Indemnitee, or impose any obligation on, or otherwise materially adversely affect, the Indemnitee or other Party
                and (ii) the indemnifying Party first obtain the written consent of the Indemnitee with respect to such settlement, which consent will not be unreasonably withheld), (c) cooperate as reasonably requested (at the expense of the indemnifying
                Party) in the defense of the Claim, and (d) undertake reasonable steps to mitigate any Losses with respect to the Claim. The provisions of Section 7.4 will govern the procedures for responding to a Claim of infringement described
                therein. Notwithstanding anything in this Agreement to the contrary, the indemnifying Party will have no liability under Section 9.1 or Section 9.2, as the case may be, for Claims settled or compromised by the Indemnitee
                without the indemnifying Party’s prior written consent.

          


     

    	9.4.	
            Insurance.

          


     

    	

          	9.4.1.	
            Ionis’ Insurance Obligations.  Ionis will maintain, at its cost, reasonable insurance against liability and other risks
                associated with its activities contemplated by this Agreement; provided that at a minimum, Ionis will maintain, in force from [***] days prior to enrollment
                of the first patient in a Clinical Study, a [***] insurance policy providing coverage of at least $[***] per claim and $[***] Annual aggregate. Ionis will furnish to Biogen evidence of such insurance upon request.

          


     

    	

          	9.4.2.	
            Biogen’s Insurance Obligations.  Biogen will maintain, at its cost, reasonable insurance against liability and other
                risks associated with its activities contemplated by this Agreement; provided that at a minimum, Biogen will maintain, in force from [***] days prior to
                enrollment of the first patient in a Clinical Study, a [***] insurance policy providing coverage of at least $[***] per claim and $[***] Annual aggregate and, provided further that such coverage is
                increased to at least $[***] at least [***] days before Biogen initiates the First Commercial Sale of a Product hereunder. Biogen will furnish to Ionis evidence of such insurance upon request.
                Notwithstanding the foregoing, Biogen may self-insure to the extent that it self-insures for its other products, but at a minimum will self-insure at levels that are consistent with levels customarily maintained against similar risks by
                similar companies in Biogen’s industry.

          


     

    
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    	9.5.	
            LIMITATION OF CONSEQUENTIAL DAMAGES.  EXCEPT FOR (A) CLAIMS OF A THIRD PARTY THAT ARE SUBJECT TO INDEMNIFICATION UNDER
                THIS ARTICLE 9, (B) CLAIMS ARISING OUT OF A PARTY’S WILLFUL MISCONDUCT OF THIS AGREEMENT, (C) A PARTY’S BREACH OF ARTICLE 2, OR A BREACH OF SECTION 10.4.3(a) BY BIOGEN OR ITS AFFILIATES OR (D) CLAIMS ARISING OUT OF A
                PARTY’S BREACH OF ITS CONFIDENTIALITY OBLIGATIONS UNDER THIS AGREEMENT, NEITHER PARTY NOR ANY OF ITS AFFILIATES WILL BE LIABLE TO THE OTHER PARTY TO THIS AGREEMENT OR ITS AFFILIATES FOR ANY INCIDENTAL, CONSEQUENTIAL, SPECIAL, PUNITIVE OR
                OTHER INDIRECT DAMAGES OR LOST OR IMPUTED PROFITS OR ROYALTIES, LOST DATA OR COST OF PROCUREMENT OF SUBSTITUTE GOODS OR SERVICES, WHETHER LIABILITY IS ASSERTED IN CONTRACT, TORT (INCLUDING NEGLIGENCE AND STRICT PRODUCT LIABILITY), INDEMNITY
                OR CONTRIBUTION, AND IRRESPECTIVE OF WHETHER THAT PARTY OR ANY REPRESENTATIVE OF THAT PARTY HAS BEEN ADVISED OF, OR OTHERWISE MIGHT HAVE ANTICIPATED THE POSSIBILITY OF, ANY SUCH LOSS OR DAMAGE.

          


     

    ARTICLE 10

    TERM; TERMINATION

     

    	10.1.	
            Agreement Term; Expiration.  This Agreement is effective as of the Effective Date and, unless earlier terminated
                pursuant to the other provisions of this ARTICLE 10, will continue in full force and effect until this Agreement expires as follows:

          


     

    	

          	10.1.1.	
            on a country-by-country basis, on the date of expiration of all payment obligations by the Commercializing Party under this Agreement with respect to all Products (or Discontinued Product(s)) in such country;

          


     

    	

          	10.1.2.	
            in its entirety upon the expiration of all payment obligations under this Agreement with respect to all Products (or Discontinued Products) in all countries pursuant to Section 10.1.1; and

          


     

    	

          	10.1.3.	
            where every Option has expired as a result of Biogen not providing Ionis a written notice stating Biogen is exercising such Options and paying Ionis the applicable license fees under Section 6.3 by the Option Deadline, or as a
              result of Section 1.5.2(d) or Section 10.4.2.

          


     

    The period from the Effective Date until the date of expiration of this Agreement pursuant to this Section 10.1 is the “Agreement Term.”

     

    	10.2.	
            Termination of the Agreement.

          


     

    	

          	10.2.1.	
            Biogen’s Termination for Convenience.  At any time following payment by Biogen of the upfront fee under Section 6.1,
                subject to Section 10.4.1 below, Biogen will be entitled to terminate this Agreement as a whole, or terminate this Agreement in part with respect to a particular Collaboration Program, for convenience by providing 90 days written
                notice to Ionis of such termination.

          


     

    
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          	10.2.2.	
            Termination for Failure to Divest Competitive Product.  If, after the acquisition by a Party of a Third Party that is
                developing or commercializing an Acquired Competitive Product or an Acquired Competitive Program, such Party does not, by the end of the Collaboration Divestiture Period, divest itself of a Competitive Product or Competitive Program, as
                applicable, or terminate the development and commercialization of such Acquired Competitive Product or activities under such Acquired Competitive Program or assign this Agreement to a Third Party that is not itself developing or
                commercializing a Competitive Product or engaged in a Competitive Program, as set forth in Section 12.5.2, then the non-acquiring Party may terminate this Agreement solely with respect to the Collaboration Program(s) affected
                thereby immediately upon providing written notice to the acquiring Party.

          


     

    	

          	10.2.3.	
            Termination Due to Failure to Obtain HSR Clearance.

          


     

    	

          	(a)	
            If the Parties make an HSR Filing with respect to a Collaboration Program under Section 3.1.4 of this Agreement and the HSR Clearance Date has not occurred on or prior to 90 days after the effective date of the latest HSR Filing
              made by the Parties, this Agreement will terminate solely with respect to such Collaboration Program (i) at the election of either Party immediately upon notice to the other Party, if the FTC or the
              DOJ has instituted (or threatened to institute) any action, suit or proceeding including seeking, threatening to seek or obtaining a preliminary injunction under the HSR Act against Biogen and Ionis to enjoin or otherwise prohibit the
              transactions contemplated by this Agreement related to such Collaboration Program, or (ii) at the election of either Party, immediately upon notice to the other Party, if the Parties have not resolved any and all objections of the FTC and DOJ
              as contemplated by Section 3.1.4(b).  Notwithstanding the foregoing, this Section 10.2.3 will not apply if an HSR Filing is not required to fully perform this Agreement with respect to a Collaboration Program.

          


     

    	

          	(b)	
            If this Agreement is terminated with respect to a Collaboration Program in accordance with Section 10.2.3(a), then, until [***] as follows:

          


     

    	

          	(i)	
            If Ionis [***]; and

          


     

    	

          	(ii)	
            If Ionis, its Affiliates or the licensee [***].

          


     

    Nothing in this Section 10.2.3(b) obligates Ionis to (A) [***] or (B) [***].

     

    
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              	10.2.4.	
                Termination for Material Breach.

              


         

        	

              	(a)	
                Biogen’s Right to Terminate.  If Biogen believes that Ionis is in material breach of this Agreement (other than
                    with respect to a failure to use Commercially Reasonable Efforts under Section 1.5.3, which is governed by Section 10.2.5 below), then Biogen may deliver notice of such material breach to Ionis.  If the breach is
                    curable, Ionis will have [***] days to cure such breach.  If Ionis fails to cure such breach within the [***] day period, or if the breach is not subject to cure, Biogen may terminate this Agreement with respect to the Collaboration
                    Program affected by such breach by providing written notice to Ionis.  Without limiting the foregoing, breach by a Party of ARTICLE 2 of this Agreement constitutes a material breach of this Agreement with respect to the
                    Collaboration Program affected by such breach.  Notwithstanding the foregoing, if Biogen is entitled to terminate this Agreement under this Section 10.2.4(a) with respect to a breach by Ionis that negatively and materially
                    impacts the value of a particular Collaboration Program, in lieu of such termination (and as its sole and exclusive remedy for such breach), Biogen may elect to substitute another High Interest Target for the applicable Collaboration
                    Target by sending Ionis a written notice within [***] days of Biogen becoming aware of such breach, in which case, such substitution will not be counted for purposes of determining whether Biogen
                    has exceeded the Substitution Limit.

              


         

        	

              	(b)	
                Ionis’ Right to Terminate.  If Ionis believes that Biogen is in material breach of (i) a payment obligation under ARTICLE


                      6 or (ii) one or more material provisions of this Agreement where such material breaches have occurred multiple times over the course of at least a [***] period (where such material breach is not a single continuous event)
                    demonstrating a pattern of failing to timely comply with Biogen’s obligations under this Agreement (other than with respect to a failure to use Commercially Reasonable Efforts under Section 5.1, which is governed by Section
                      10.2.5 below), then Ionis may deliver notice of such material breach to Biogen. If the breach is curable, Biogen will have [***] days to cure such breach (except to the extent such breach involves the failure to make a payment
                    when due, which breach must be cured within [***] days following such notice). If Biogen fails to cure such breach within the [***] day or [***] day period, as applicable, or if the breach is not subject to cure, Ionis in its sole
                    discretion may terminate this Agreement with respect to the Collaboration Program affected by such breach by providing written notice thereof to Biogen.

              


         

        
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              	10.2.5.	
                Remedies for Failure to Use Commercially Reasonable Efforts.

              


         

        	

              	(a)	
                If Ionis, in Biogen’s reasonable determination, fails to use Commercially Reasonable Efforts in the activities contemplated in Section 1.5.3 prior to the License Effective Date with respect to a particular Collaboration
                  Program, Biogen will notify Ionis and, within [***] days thereafter, Ionis and Biogen will meet and confer to discuss and resolve the matter in good faith, and attempt to devise a mutually agreeable plan to address any outstanding issues
                  related to Ionis’ use of Commercially Reasonable Efforts in Section 1.5.3.  Following such a meeting, if Ionis fails to use Commercially Reasonable Efforts as contemplated by Section 1.5.3 with respect to such
                  Collaboration Program, then subject to Section 10.2.6 below, Biogen will have the right, at its sole discretion, to (i) terminate this Agreement as it relates to the applicable Collaboration Program or, (ii) prior to the License
                  Effective Date for such Collaboration Program, Biogen may elect to trigger the alternative remedy provisions of Section 10.3 below as it relates to the applicable Collaboration Program in lieu of terminating this Agreement for
                  such Collaboration Program by providing written notice to Ionis.  This Section 10.2.5(a) sets forth Biogen’s sole and exclusive remedies if Ionis fails to use Commercially Reasonable Efforts in the activities contemplated in Section







                    1.5.3 prior to the License Effective Date for a particular Collaboration Program.

              


         

        	

              	(b)	
                If Biogen, in Ionis’ reasonable determination, fails to use Commercially Reasonable Efforts under Section 5.1 with respect to a Collaboration Program above, Ionis will notify Biogen and, within [***] days thereafter, Ionis and
                  Biogen will meet and confer to discuss and resolve the matter in good faith, and attempt to devise a mutually agreeable plan to address any outstanding issues related to Biogen’s use of Commercially Reasonable Efforts in Section 5.1. 








                  Following such a meeting, if Biogen fails to use Commercially Reasonable Efforts with respect to the applicable Collaboration Program as contemplated by Section 5.1, then subject to Section 10.2.6 below, Ionis will have
                  the right, at its sole discretion, to terminate this Agreement as it relates to such Collaboration Program.

              


         

        	

              	10.2.6.	
                Disputes Regarding Material Breach.  Notwithstanding the foregoing, if the Breaching Party in Section 10.2.4
                    or Section 10.2.5 disputes in good faith the existence, materiality, or failure to cure of any such breach which is not a payment breach, and provides notice to the Non-Breaching Party of such dispute within such [***] day
                    period, then the Non-Breaching Party will not have the right to terminate this Agreement in accordance with Section 10.2.4 or Section 10.2.5, or trigger the substitution right under Section 10.2.4(a) or the
                    alternative remedy provisions of Section 10.2.5, as applicable, unless and until it has been determined in accordance with Section 12.1 that this Agreement was materially breached by the Breaching Party and the Breaching
                    Party fails to cure such breach within [***] days following such determination.  It is understood and acknowledged that during the pendency of such dispute, all the terms and conditions of this Agreement will remain in effect and the
                    Parties will continue to perform all of their respective obligations hereunder, including satisfying any payment obligations.

              


         

        
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              	10.2.7.	
                Termination for Insolvency.

              


         

        	

              	(a)	
                Either Party may terminate this Agreement if, at any time, the other Party files in any court or agency pursuant to any statute or regulation of any state or country a petition in bankruptcy or insolvency or for reorganization or for
                  an arrangement or for the appointment of a receiver or trustee of the Party or of substantially all of its assets; or if the other Party proposes a written agreement of composition or extension of substantially all of its debts; or if the
                  other Party will be served with an involuntary petition against it, filed in any insolvency proceeding, and such petition will not be dismissed within 90 days after the filing thereof; or if the other Party will propose or be a party to
                  any dissolution or liquidation; or if the other Party will make an assignment of substantially all of its assets for the benefit of creditors.

              


         

        	

              	(b)	
                All rights and licenses granted under or pursuant to any section of this Agreement are and will otherwise be deemed to be for purposes of Section 365(n) of Title 11, United States Code (the “Bankruptcy Code”) licenses of rights to “intellectual property” as defined in Section 101(56) of the Bankruptcy Code. The Parties will retain and may fully exercise all of their respective rights and elections under the
                  Bankruptcy Code.  Upon the bankruptcy of any Party, the non-bankrupt Party will further be entitled to a complete duplicate of, or complete access to, any such intellectual property, and such, if not already in its possession, will be
                  promptly delivered to the non-bankrupt Party, unless the bankrupt Party elects in writing to continue, and continues, to perform all of its obligations under this Agreement.

              


         

        	

              	10.2.8.	
                Termination for Patent Challenge.  Ionis may terminate this Agreement if Biogen (i) commences or otherwise
                    voluntarily determines to participate in any action or proceeding, challenging or denying the enforceability or validity of any claim within an issued patent or patent application within such Licensed Patents, or (ii) directs, supports
                    or actively assists any other Person in bringing or prosecuting any action or proceeding challenging or denying the validity of any claim within an issued patent or patent application within such Licensed Patents and, in each case ((i)
                    or (ii)), within [***] days’ written notice from Ionis, Biogen fails to rescind any and all of such actions, provided, however that, nothing in this
                    clause prevents Biogen from taking any of the actions referred to in this clause and provided further that Ionis will not have the right to terminate if Biogen:

              


         

        	

              	(a)	
                takes any such action as described in clause (i) or (ii) above as may be necessary or reasonably required to assert a cross-claim or a counter-claim or to respond to a court request or order or administrative law request or order,
                  including asserting invalidity as a defense in any court proceeding brought by Ionis asserting infringement of a Licensed Patent; or

              


         

        	

              	(b)	
                Acquires a Third Party that has an existing challenge, whether in a court or administrative proceeding, against a Licensed Patent; or

              


         

        	

              	(c)	
                licenses a product for which Ionis has an existing challenge, whether in a court or administrative proceeding, against a Licensed Patent.

              


         

        
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        	10.3.	
                Alternative Remedies to Termination Available to Biogen Prior to the License Effective Date.  If, prior to the
                    License Effective Date with respect to a particular Collaboration Program, Biogen elects to (i) exercise the alternative remedy provisions of this Section 10.3 in lieu of terminating this Agreement for such Collaboration Program
                    by providing written notice of such election to Ionis in accordance with Section 10.2.5(a), or (ii) exercise the Option in accordance with [***], then, in each case, solely with respect
                      to the Collaboration Program giving rise to Biogen’s exercise of these alternative remedy provisions, this Agreement will continue in full force and effect with the following modifications:

              


         

        	

              	(a)	
                Ionis will have no further rights or obligations to Develop the Product under the applicable Collaboration Program or participate in the Neurology JSC, JPC or any other subcommittees or working groups established pursuant to this
                  Agreement.  Biogen will solely make all decisions that this Agreement would otherwise require or permit the Neurology JSC, JPC or any other subcommittees or working groups, or the Parties collectively, to make; provided, however, that Biogen will not have the right to create any obligations or incur any liabilities for or on behalf of Ionis;

              


         

        	

              	(b)	
                effective as of the date of Biogen’s notice to Ionis electing the alternative remedy provisions of this Section 10.3, Biogen will be deemed for all purposes of this Agreement to have exercised the applicable Option;

              


         

        	

              	(c)	
                Biogen will have and Ionis grants, the exclusive license granted to Biogen under Section 4.1.1 for the applicable Collaboration Program;

              


         

        	

              	(d)	
                Biogen may exclude Ionis from all discussions with Regulatory Authorities regarding the applicable Products, except to the extent Ionis’ participation is required by a Regulatory Authority or is otherwise reasonably necessary to comply
                  with Applicable Law;

              


         

        	

              	(e)	
                Biogen’s obligation to make further disclosures of Know-How or other information to Ionis regarding the applicable Products pursuant to this Agreement (including pursuant to Section 4.8 and Section 5.2.2) will
                  terminate, other than reports required by Section 6.9.1, Section 10.4.3 (if applicable), and as reasonably required to permit Ionis to perform its obligations under this Agreement, provided







                  such remedy will not limit or diminish the scope of any licenses granted by Biogen to Ionis under this Agreement ;

              


         

        	

              	(f)	
                Ionis will perform its obligations under Section 4.8 with respect to the applicable Product within [***] days of Biogen electing to exercise its alternative remedies under this Section 10.3 or exercising the Option in
                  accordance with [***], and will provide to Biogen and its Third Party contractors all Know-How, assistance, assignments and other support reasonably requested to assist Biogen in assuming complete responsibility for the Development
                  and Manufacture of the applicable Products in an efficient and orderly manner; and

              


         

        
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              	(g)	
                the financial provisions of ARTICLE 6 as they apply to such Collaboration Program will be modified as follows:

              


         

        	

              	(i)	
                [***] Payments.  Biogen will [***]; and

              


         

        	

              	(ii)	
                License Fee.  The license fee set forth in Section 6.3 for the applicable Product will be [***].  Such
                    [***] will be due within 90 days after [***] and Biogen’s [***].

              


         

        The milestone provisions of Section 6.4 and the royalty provisions of Section 6.6 will [***].

         

        	10.4.	
                Consequences of Expiration or Termination of the Agreement.

              


         

        	

              	10.4.1.	
                In General.  If this Agreement expires or is terminated by a Party in accordance with this ARTICLE 10 at
                    any time and for any reason, the following terms will apply to any Collaboration Program that is the subject of such expiration or termination:

              


         

        	

              	(a)	
                Return of Information and Materials.  The Parties will return (or destroy, as directed by the other Party) all
                    data, files, records and other materials containing or comprising the other Party’s Confidential Information, except to the extent such Confidential Information is necessary or useful to conduct activities under a surviving
                    Collaboration Program. Notwithstanding the foregoing, the Parties will be permitted to retain one copy of such data, files, records, and other materials for archival and legal compliance purposes.

              


         

        	

              	(b)	
                Perpetual, Royalty-Free Non-Exclusive License.  If Biogen has exercised its Option for a particular Collaboration
                    Program, then upon expiration of the Reduced Royalty Period in all countries in which the applicable Products are being or have been sold, Ionis will and hereby does grant to Biogen a perpetual, nonexclusive, worldwide, royalty-free,
                    fully paid-up, sublicensable license under the Ionis Know-How to Manufacture, Develop and Commercialize any Product under such Collaboration Program.

              


         

        	

              	(c)	
                Accrued Rights.  Termination or expiration of this Agreement for any reason will be without prejudice to any rights
                    or financial compensation that will have accrued to the benefit of a Party prior to such termination or expiration. Such termination or expiration will not relieve a Party from obligations that are expressly indicated to survive the
                    termination or expiration of this Agreement. For purposes of clarification, milestone payments under ARTICLE 6 accrue as of the date the applicable Milestone Event is achieved even if the payment is not due at that time.

              


         

        
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              	(d)	
                Survival.  The following provisions of this Agreement will survive the expiration or termination of this Agreement:
                    Section 4.1.2(c) (Effect of Termination on Sublicenses), Section 4.2.2, Section 4.3.2 (Enabling Licenses to Biogen), Section 4.3.3 (Enabling Licenses to Ionis), Section 4.4 (Licenses to Ionis for
                    Biogen Results), Section 4.5 (Right to Obtain Direct License from Biogen to Ionis Partners; Sublicensees of Ionis), Section 4.8 (Technology Transfer after the License Effective Date) (but only to the extent necessary to
                    satisfy the requirements of Section 10.4.3), Section 6.7 (Reverse Royalty Payments to Biogen for a Discontinued Product), Section 6.9.3 (Records Retention), Section 6.10 (Audits), Section 7.1.1
                    (Ionis Technology and Biogen Technology), Section 7.1.2 (Agreement Technology), Section 7.4.2 (Discontinued Product) Section 8.4 (Disclaimer), ARTICLE 9 (Indemnification; Insurance), Section 10.2.3(b),
                    Section 10.2.7 (Termination for Insolvency), Section 10.4 (Consequences of Expiration or Termination of the Agreement) (except Section 10.4.4 (Remedies Available to Biogen for Ionis’ Material Breach After the
                    License Effective Date)), ARTICLE 11 (Confidentiality), ARTICLE 12 (Miscellaneous) and Appendix 1 (Definitions) (to the extent definitions are embodied in the
                    foregoing listed Articles and Sections). In addition, subject to Section 10.4.3(d)(vi) (if applicable), the following provisions of this Agreement will survive the expiration or termination of this Agreement, solely as they
                    relate to Jointly-Owned Program Patents: Section 7.2.3 (Jointly-Owned Program Patents), Section 7.2.4 (Other Matters Pertaining to Prosecution and Maintenance of Patent Rights), Section 7.3.1 (Jointly-Owned
                    Program Patents), Section 7.4 (Defense of Claims Brought by Third Parties), Section 7.5 (Enforcement of Patents against Competitive Infringement) and Section 7.6.1 (Jointly-Owned Program Patents).

              


         

        	

              	10.4.2.	
                Termination Prior to the License Effective Date.  If this Agreement expires or is terminated by a Party in
                    accordance with this ARTICLE 10 prior to or on the License Effective Date with respect to a Collaboration Program, or Biogen’s Option for an applicable Collaboration Program expires pursuant to Section 3.1.3, then, in addition to the terms set forth in Section 10.4.1, the following terms will apply to each Collaboration Program that is the subject of
                    such expiration or termination:

              


         

        	

              	(a)	
                Biogen’s Option under Section 3.1 will expire and Ionis will be free to Develop and Commercialize the applicable Product (and any other applicable Compounds) on its own or with a Third Party.

              


         

        	

              	(b)	
                Neither Party will have any further obligations under Section 2.1 of this Agreement with respect to the terminated Collaboration Program(s).

              


         

        	

              	(c)	
                To the extent requested by Ionis, Biogen will promptly (i) assign to Ionis any manufacturing agreements with a CMO identified by Ionis to which Biogen is a party, solely to the extent such manufacturing agreements relate to the
                  terminated Collaboration Program and (ii) transfer to Ionis all data, results and information (including Biogen’s Confidential Information and any regulatory documentation (including drafts)) related to the testing and Clinical Studies
                  under the terminated Collaboration Program(s) in the possession of Biogen and its contractors to the extent such data, results and information were generated by or on behalf of Biogen under this Agreement; and Ionis will pay all
                  out-of-pocket direct Third Party costs and expenses in transferring such data, results and information together with Biogen’s FTE Cost in transferring such data, results and information.

              


         

        
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              	(d)	
                If Biogen terminates this Agreement for convenience with respect to a Collaboration Program after the 30th day following Biogen’s receipt of the
                  Development Candidate Data Package for such Collaboration Program, but prior to or on the License Effective Date for such Collaboration Program, then Biogen will [***].

              


         

        	

              	(e)	
                Except as explicitly set forth in Section 10.4.1(a), Section 10.4.1(c) or Section 10.4.1(d), Biogen will have no further rights and Ionis will have no further obligations with respect to each terminated
                  Collaboration Program.

              


         

        	

              	10.4.3.	
                Termination After the License Effective Date.  If this Agreement is terminated by a Party in accordance with this ARTICLE


                      10 after the License Effective Date for a Collaboration Program, then, in addition to the terms set forth in Section 10.4.1, the following terms will apply to any Collaboration Program that is the subject of such
                    termination:

              


         

        	

              	(a)	
                The applicable licenses granted by Ionis to Biogen under this Agreement will terminate and Biogen, its Affiliates and Sublicensees will cease selling the applicable Products, unless Ionis elects to have Biogen continue to sell the
                  applicable Products as part of the Transition Services to the extent provided in Section 10.4.5.

              


         

        	

              	(b)	
                Neither Party will have any further obligations under Section 2.1 of this Agreement with respect to the terminated Collaboration Program(s).

              


         

        	

              	(c)	
                Except as explicitly set forth in Section 10.4.1(a), Biogen will have no further rights and Ionis will have no further obligations with respect to the terminated Collaboration Program.

              


         

        	

              	(d)	
                If (i) Biogen terminates the Agreement under Section 10.2.1 (Biogen’s Termination for Convenience) or (ii) Ionis terminates this Agreement under Section 10.2.4(b) (Ionis’ Right to Terminate) or Section 10.2.5
                  (Remedies for Failure to Use Commercially Reasonable Efforts), then the following additional terms will also apply solely with respect to the terminated Collaboration Program(s):

              


         

        	

              	(i)	
                Biogen will, and does hereby, grant to Ionis a sublicensable, worldwide, exclusive license or sublicense, as the case may be, to all Biogen Technology Controlled by Biogen as of the date of such reversion that Covers the applicable
                  Discontinued Product(s) solely as necessary to Develop, make, have made, use, sell, offer for sale, have sold, import and otherwise Commercialize the applicable Discontinued Product(s) in the Field (such license will be sublicensable by
                  Ionis in accordance with Section 4.1.2, mutatis mutandis);

              


         

        
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              	(ii)	
                Within [***] days following the date of the termination, Biogen will assign back to Ionis any Product-Specific Patents and Ionis’ interest in any Program Patents that relate to the applicable Discontinued Product(s) previously assigned
                  by Ionis to Biogen under this Agreement;

              


         

        	

              	(iii)	
                Within [***] days following the date of the termination, Biogen will transfer to Ionis for use with respect to the Development and Commercialization of the applicable Discontinued Product(s), any Know-How data, results, and copies of
                  Regulatory Materials in the possession of Biogen as of the date of such reversion to the extent related to such Discontinued Product(s), and any other information or material specified in Section 4.8, provided that, for the avoidance of doubt, as between the Parties, title to any intellectual property that is Biogen Technology within any of the foregoing will remain with Biogen subject to the license granted to Ionis
                  under Section 10.4.3(d)(i), except as otherwise provided in Section 10.4.3(d)(iv) below;

              


         

        	

              	(iv)	
                Within [***] days following the date of the termination, Biogen will assign, and hereby does assign, to Ionis all of Biogen’s right, title and interest in and to all Regulatory Materials, including any NDA, IND and orphan drug
                  designation that relate to the applicable terminated Product(s), provided that, (x) notwithstanding the foregoing, and subject to the provisions of Section 2.1, the Parties acknowledge
                  that Biogen shall be permitted to use excerpts or portions of any such assigned Regulatory Materials in any other regulatory submissions, notifications, registrations, approvals and/or other filings and correspondence made to or with a
                  Regulatory Authority in any country or jurisdiction related to products under the Ionis/Biogen Additional Agreements or products that do not include an Oligonucleotide as an active pharmaceutical ingredient, provided, further that, for such products that do not include an Oligonucleotide as an active pharmaceutical ingredient, such excerpts or portions shall not include any Confidential Information of Ionis, and (y) for
                  clarity, such assignment of Biogen’s right, title and interest in and to such Regulatory Materials shall not include the assignment of any Know-How (including any data) contained therein.  If Biogen intends to use any excerpt or portion
                  of any such assigned Regulatory Materials in accordance with clause (x) of the preceding sentence, Biogen shall, at least [***] days in advance of the anticipated submission of such excerpt or portion to a Regulatory Authority, notify
                  Ionis of such intent and provide to Ionis a copy of such proposed excerpt or portion for review and comment.  The Parties shall discuss in good faith any comments of Ionis with respect to such proposed excerpt or portion prior to
                  submission thereof;

              


         

        
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              	(v)	
                Within [***] days following the date of the termination, Biogen will, and does hereby, exclusively license to Ionis any trademarks that are specific to a Discontinued Product(s) solely for use with such Discontinued Product(s), in
                  accordance with Section 4.1.5, mutatis mutandis; provided, however, that in no event will Biogen have any
                  obligation to license to Ionis any trademarks used by Biogen both in connection with the Product and in connection with the sale of any other product or service, including any BIOGEN- or BIOGEN-formative marks;

              


         

        	

              	(vi)	
                Ionis will control and be responsible for all aspects of the Prosecution and Maintenance of all Jointly-Owned Program Patents arising from the terminated Collaboration Program, and Biogen will provide Ionis with (and will instruct its
                  counsel to provide Ionis with) all of the information and records in Biogen’s and its counsel’s possession related to the Prosecution and Maintenance of such Jointly-Owned Program Patents; provided, however, that if Ionis intends to abandon any such Jointly-Owned Program Patents without first filing a continuation or substitution, then Ionis will notify Biogen of such intention at least [***]
                  days before such Patent Right will become abandoned, and Biogen will have the right, but not the obligation, to assume responsibility for the Prosecution and Maintenance thereof at its own expense with counsel of its own choice; and

              


         

        	

              	(vii)	
                Ionis will have the obligation to pay royalties to Biogen under Section 6.7 with respect to the applicable Discontinued Product(s).  Such payments will be governed by the financial provisions in Section 6.9, and the
                  definition of Net Sales will apply to sales of Discontinued Product(s) by Ionis, in each case mutatis mutandis.

              


         

        	

              	(e)	
                If Ionis terminates this Agreement due to Biogen’s material breach or Biogen terminates this Agreement for convenience, then upon Ionis’ written request pursuant to a mutually agreed supply agreement, Biogen will sell to Ionis any bulk
                  API, Clinical Supplies and Finished Drug Product in Biogen’s possession at the time of such termination, at a price equal to [***].

              


         

        	

              	(f)	
                To the extent requested by Ionis, Biogen will promptly assign to Ionis any manufacturing agreements solely to the extent related to the applicable Discontinued Products and identified by Ionis to which Biogen is a party.

              


         

        
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              	10.4.4.	
                Remedies Available to Biogen for Ionis’ Material Breach After the License Effective Date.

              


         

        	

              	(a)	
                Termination of Committees and Information Sharing. If, after the License Effective Date for a particular
                    Collaboration Program, Ionis materially breaches this Agreement and fails to cure such breach within the time periods set forth under Section 10.2.4(a), and Biogen does not wish to terminate this Agreement in its entirety (an “Ionis Breach Event”), then, in addition to any other remedies Biogen may have under this Agreement or otherwise, Biogen will have the right to do any or all of the following in
                    Biogen’s discretion solely with respect to the Collaboration Programs that are the subject of the Ionis Breach Event:

              


         

        	

              	(i)	
                Terminate Ionis’ right to participate in the Neurology JSC, JPC and any other subcommittees or working groups established pursuant to this Agreement;

              


         

        	

              	(ii)	
                Terminate Ionis’ participation in any ongoing research and development programs under the applicable Collaboration Program and Biogen’s funding obligations associated therewith;

              


         

        	

              	(iii)	
                Solely make all decisions required or permitted to be made by such committees or the Parties collectively under this Agreement in connection with the Development and Commercialization of the applicable Product; provided, however, that Biogen will not have the right to create any obligations or incur any liabilities for or on behalf of Ionis;

              


         

        	

              	(iv)	
                Exclude Ionis from all discussions with Regulatory Authorities regarding applicable Products, except to the extent Ionis’ participation is required by a Regulatory Authority or is otherwise
                  reasonably necessary to comply with Applicable Law;

              


         

        	

              	(v)	
                Terminate Biogen’s obligation to make further disclosures of Know-How or other information to Ionis pursuant to this Agreement related to the applicable Products, including pursuant to Section 4.8 and Section 5.2.2,
                  other than reports required by Section 6.9.1, Section 10.4.3 (if applicable), and as reasonably required to permit Ionis to perform its obligations under this Agreement, provided such








                  remedy will not limit or diminish the scope of any licenses granted by Biogen to Ionis under this Agreement; and

              


         

        	

              	(vi)	
                If Ionis has not completed the Development activities that are its responsibility under the applicable Collaboration Program Research Plan and Development Plan, then Biogen may, but will not be obligated to, assume all responsibility
                  for all such Development activities that would have otherwise been Ionis’ responsibility under this Agreement.

              


         

        
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        Ionis will cooperate with the foregoing and provide to Biogen and its Third Party contractors all Know-How, assistance, assignments and other support reasonably requested to assist Biogen in
          assuming complete responsibility for the Development and Manufacture of the applicable Products in an efficient and orderly manner.

         

        	

              	(b)	
                Biogen’s Right of Setoff.  If there is [***] and Biogen does not wish to [***], then, in addition to any other
                    remedies Biogen may have under this Agreement or otherwise, Biogen may setoff against any amounts owed to Ionis pursuant to ARTICLE 6 (Financial Provisions) solely with respect to the
                    Collaboration Program that is the subject of the [***] (the “Setoff Amount”).  If Biogen exercises its setoff right under this Section 10.4.4(b), Biogen will provide
                    Ionis with a written certificate, signed by Biogen’s Chief Financial Officer, certifying that the amount setoff by Biogen represents [***].  Notwithstanding the foregoing, if Ionis notifies Biogen in writing (a “Setoff Dispute Notice”) that it disputes Biogen’s assertion that Ionis is in material breach of this Agreement or the amount setoff by Biogen (a “Setoff Dispute”), then (i) both Parties will participate in the dispute resolution process set forth on Schedule 10.4.4(b), and (ii) pending the
                    Parties’ agreement regarding the appropriate setoff (if any) or a determination by the Advisory Panel of the proper amount that Biogen may setoff (if any) in accordance with Schedule
                      10.4.4(b), Biogen will pay the Setoff Amount into an interest-bearing escrow account established for the purpose at a bank. If the Parties cannot settle their dispute by mutual agreement, then, in accordance with Schedule 10.4.4(b) the Advisory Panel will determine (A) the amount (if any) that Biogen may setoff against future payments solely with
                    respect to the Collaboration Program that is the subject of the Ionis Breach Event to Ionis going forward, and (B) whether any portion of the escrow account should be released to Ionis or returned to Biogen; provided that any decision or determination by the Advisory Panel (a “Panel Decision”) will not be treated as an arbitral award but will be binding on the
                    Parties until and unless a court of competent jurisdiction (the “Trial Court”) has determined in a judgment regarding some or all of the issues decided in the Panel Decision,
                    and in any Action contemplated by the next sentence hereof the Trial Court will determine the facts and the law de novo, and will give a Panel Decision only such persuasive effect, if any, that
                    after review of all of the facts and the law presented to the Trial Court by the Parties, the Trial Court deems appropriate; provided further that the
                    escrow agent will comply with a Panel Decision that determines that any portion of the escrow account should be released to Ionis or returned to Biogen. If it is determined in a judgment by the Trial Court that Ionis owes Biogen any
                    damages, then, during the pendency of any appeal of the Trial Court’s decision (or, if the Trial Court’s decision is not appealed, until Biogen recoups such amount), Biogen may setoff against any future payments solely with respect to the Collaboration Programs that are the subject of the Ionis Breach Event to Ionis under this Agreement the amount of any such damages not paid by Ionis.  If it is determined
                    in a Trial Court that Biogen has setoff an amount that exceeds the amount of losses, damages and expenses actually incurred by Biogen as a result of Ionis’ breach of this Agreement, then Biogen will promptly pay to Ionis the amount of
                    such excess, plus interest on such amount as provided for in Section 6.12 (Interest on Late Payments), with interest accruing from the time Biogen applied such excess setoff.  If, with respect to a Setoff Dispute, Ionis provides
                    a Setoff Dispute Notice to Biogen and Biogen fails to do any of the following: (I) appoint a member of the Advisory Panel to the extent required in Section 2 of Schedule
                      10.4.4(b); (II) meet with the Advisory Panel as required in Section 3 of Schedule 10.4.4(b); or (III) pay the Setoff Amount into an interest-bearing escrow account
                    established for the purpose at a bank, then Biogen will forfeit its right to set off under this Section 10.4.4(b) and Schedule 10.4.4(b) with respect to any and all
                    Setoff Disputes.

              


         

        
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              	10.4.5.	
                Transition Services.

              


         

        	

              	(a)	
                In the case where (i) Biogen terminates the Agreement under Section 10.2.1 (Biogen’s Termination for Convenience) or (ii) Ionis terminates this Agreement under Section 10.2.4(b) (Ionis’ Right to Terminate) or Section








                    10.2.5(b) (Remedies for Failure to Use Commercially Reasonable Efforts) with respect to one or more Products, the terms of this Section 10.4.5 shall apply.

              


         

        	

              	(b)	
                In such event, the Parties wish to provide a mechanism to ensure that patients who were being treated with the applicable Product prior to such termination or who desire access to such Product can continue to have access to such
                  Product until the regulatory and commercial responsibilities for the Product are transitioned from Biogen to Ionis following termination of the applicable Product. As such, Ionis may request Biogen perform transition services as listed on
                  Schedule 10.4.5 and such other transition services that the Parties mutually agree in writing to (i) provide patients with continued access to the applicable Products, (ii) following
                  termination of this Agreement with respect to the applicable Product, transition the responsibilities under all Approvals and ongoing Clinical Studies for the applicable Products to Ionis or its designee and (iii) following termination of
                  this Agreement with respect to the applicable Product, transition the then-current supply process and responsibilities for the Product to Ionis or its designee (collectively, the “Transition








                    Services”). Subject to the Parties agreeing on a transition plan as described in Section 10.4.5(c), Biogen will perform such Transition Services using reasonable efforts for a period not to exceed [***] months from the
                  termination date; provided that Biogen and Ionis may mutually agree to conduct the Transition Services for a longer period of time. Notwithstanding the provision of the Transition Services under
                  this Section 10.4.5, Ionis shall not conduct activities with respect to any Discontinued Products to the extent prohibited by ARTICLE 2 of this Agreement.

              


         

        
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              	(c)	
                Ionis may elect to have Biogen perform the Transition Services by providing written notice to Biogen no later than the earlier of (i) [***] days following the effective date of the termination and (ii) [***] days following written
                  notice by Biogen to Ionis asking Ionis to confirm if Ionis wishes to have Biogen perform the Transition Services (provided that Biogen did not send such a notice earlier than [***] days following
                  the effective date of the termination). If Ionis requests Transition Services, then Ionis shall propose a transition plan setting forth the Transition Services to be performed by Biogen, including delivery and transition dates consistent
                  with those set forth on Schedule 10.4.5, and, for a period of [***] days after such request, the Parties will use good faith efforts to negotiate a mutually agreeable version of such
                  transition plan. In addition, the Parties will, within [***] days after such request, establish a transition committee consisting of at least each Party’s Alliance Managers, a representative from each Party’s CMC group who was responsible
                  for the Product prior to the termination, and up to two additional representatives from each Party who are from other relevant functional groups to facilitate a smooth transition. While Biogen is providing Transition Services, Biogen and
                  Ionis will mutually agree on talking points and a communication plan to customers, specialty pharmacies, physicians, Regulatory Authorities, patient advocacy groups and clinical study investigators, and Biogen will make all such
                  communication to such entities in accordance with the mutually agreed talking points.

              


         

        	

              	(d)	
                Ionis will pay Biogen for the Transition Services at [***] to perform the Transition Services, calculated [***]. In addition, Ionis will reimburse [***] to perform the Transition Services. Ionis will own all revenue derived from the
                  Product after the termination date and Biogen will remit all such revenues to Ionis no later than the [***] day following the end of the month in which such revenue was received.

              


         

        	

              	(e)	
                Ionis or its designee will be sufficiently prepared to accept the transition of Development, Manufacturing and Commercialization activities with respect to the Products to Ionis or such designee on the timelines set forth on Schedule 10.4.5 for the Transition Services. Biogen will have no liability under this Agreement with respect to a failure of or delay in the Transition Services to the extent caused by any
                  failure or delay by Ionis or its designee in accepting the transition of Development, Manufacturing and Commercialization activities with respect to the Products. In the event that Biogen encounters any delays beyond Biogen’s reasonable
                  control, the Parties shall discuss in good faith and agree upon extended timelines for completion of the Transition Services.

              


         

        
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        ARTICLE 11

        CONFIDENTIALITY

         

        	11.1.	
                Confidentiality; Exceptions.  Except to the extent expressly authorized by this Agreement or otherwise agreed in
                    writing, the Parties agree that, during the Agreement Term and for five years thereafter, the receiving Party (the “Receiving Party”) and its Affiliates will keep confidential
                    and will not publish or otherwise disclose or use for any purpose other than as provided for in this Agreement any confidential or proprietary information or materials, patentable or otherwise,
                    in any form (written, oral, photographic, electronic, magnetic, or otherwise) which is disclosed to it by the other Party (the “Disclosing Party”) or its Affiliates or
                    otherwise received or accessed by a Receiving Party in the course of performing its obligations or exercising its rights under this Agreement, including trade secrets, Know-How, inventions or discoveries, proprietary information,
                    formulae, processes, techniques and information relating to the past, present and future marketing, financial, and research and development activities of any product or potential product or useful technology of the Disclosing Party or
                    its Affiliates and the pricing thereof (collectively, “Confidential Information”).

              


         

        	11.2.	
                Prior Confidentiality Agreement Superseded.  As of the Effective Date, this Agreement supersedes the Confidential
                    Disclosure Agreement executed by Ionis and Biogen on February 28, 2011 (including any and all amendments thereto). All information exchanged between the Parties under such Confidential Disclosure Agreement will be deemed Confidential
                    Information hereunder and will be subject to the terms of this ARTICLE 11.

              


         

        	11.3.	
                Authorized Disclosure.  Except as expressly provided otherwise in this Agreement, a Receiving Party or its
                    Affiliates may use and disclose to Third Parties Confidential Information of the Disclosing Party as follows: (a) solely in connection with the performance of its obligations or exercise of rights granted or reserved in this Agreement
                    under confidentiality provisions no less restrictive than those in this Agreement; provided that Confidential Information may be disclosed by a Receiving Party to a governmental entity or agency
                    without requiring such entity or agency to enter into a confidentiality agreement; (b) to the extent reasonably necessary to file or prosecute patent, copyright and trademark applications (subject to Section 11.4 below),
                    complying with applicable governmental regulations, obtaining Approvals, conducting Pre-Clinical Studies or Clinical Studies, marketing the Product, or as otherwise required by Applicable Law, regulation, rule or legal process
                    (including the rules of the SEC and any stock exchange); provided, however, that if a Receiving Party or any of its Affiliates is required by Law or
                    regulation to make any such disclosure of a Disclosing Party’s Confidential Information it will, except where impracticable for necessary disclosures, give reasonable advance notice to the Disclosing Party of such disclosure requirement
                    and will use its reasonable efforts to secure confidential treatment of such Confidential Information required to be disclosed; (c) in communication with actual or potential lenders, investors, merger partners, acquirers, consultants,
                    or professional advisors on a need-to-know basis, in each case under confidentiality provisions no less restrictive than those of this Agreement; (d) to the extent such disclosure is required to comply with existing expressly stated
                    contractual obligations owed to such Party’s or its Affiliates’ licensor with respect to any intellectual property licensed to the other Party under this Agreement; or (e) as mutually agreed to in writing by the Parties.

              


         

        
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        	11.4.	
                Press Release; Publications; Disclosure of Agreement.

              


         

        	

              	11.4.1.	
                Appointment of a Communications Lead.  Prior to the Initiation of each Clinical Study under the Development Plan
                    for any Collaboration Program for which Biogen has not yet been granted a license under Section 4.1.1 with respect to a Product, the Neurology JSC shall appoint one of the Parties as the communications lead to take the lead role
                    in drafting, coordinating and facilitating the public disclosure of data and results arising from such Clinical Study (the “Communications Lead”); provided, however, that if a single Party is the IND-holder and sponsor of the Clinical Study, and is responsible for the conduct of the Clinical Study, then that Party shall automatically be deemed to be the
                    Communications Lead. The Communications Lead shall be responsible for drafting the initial publication and for coordinating and facilitating the disclosure activities for such Clinical Study as set forth in Sections 11.4.5 and 11.4.6;
                    provided, however, that if, after having worked together in good faith, the Communications Lead and the other Party cannot agree on a matter related to the public disclosure of data and results
                    arising from such a Clinical Study, then, subject to and without limiting Sections 11.4.5 and 11.4.6, (i) prior to the License Effective Date for such Collaboration Program, Ionis will have final decision-making
                    authority regarding such matter, and (ii) after the License Effective Date for such Collaboration Program, Biogen will have final decision-making authority regarding such matter.

              


         

        	

              	11.4.2.	
                Public Announcements.  On or promptly after the Effective Date, the Parties will jointly issue a public
                    announcement of the execution of this Agreement in form and substance mutually agreed by the Parties. Except to the extent required to comply with Applicable Law, regulation, rule or legal process or as otherwise permitted in accordance
                    with this Section 11.4, neither Party nor such Party’s Affiliates will make any public announcements, press releases or other public disclosures concerning this Agreement or the terms or the subject matter hereof without the
                    prior written consent of the other, which will not be unreasonably withheld, conditioned or delayed.

              


         

        	

              	11.4.3.	
                Use of Name.  Except as set forth in Section 11.4.11, neither Party will use the other Party’s name in a
                    press release or other publication without first obtaining the prior consent of the Party to be named.

              


         

        	

              	11.4.4.	
                Notice of Significant Events.  Each Party will immediately notify (and provide as much advance notice as possible,
                    but at a minimum two Business Days advance notice to) the other Party of any event materially related to a Product (including in such notice any disclosure of starting/stopping of a Clinical Study, clinical data or results, material
                    regulatory discussions, filings, Approval or Biogen’s sales projections) so the Parties may analyze the need for or desirability of publicly disclosing or reporting such event.

              


         

        
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              	11.4.5.	
                Prior to the License Effective Date.  Prior to the License Effective Date with respect to a Product, such Product
                    is the sole property of Ionis and, subject to any communication plan for such Product mutually agreed to by the Parties in accordance with Section 1.5.2(a) and to the provisions of this Section 11.4.5 and Section
                      11.4.7, Ionis will have the sole right to issue press releases, publish, present or otherwise disclose the progress and results regarding such Product to the public; which shall be consistent with its practice with its other
                    compounds and products; provided that with respect to any proposed press release or other similar public communication by Ionis disclosing regulatory discussions, the efficacy or safety data or clinical results related to such Product, (a) Ionis will submit such proposed communication to Biogen for review at least two Business Days in advance of such proposed public disclosure, (b)
                    Biogen will have the right to review and recommend changes to such communication, and (c) Ionis will in good faith consider any changes that are timely recommended by Biogen; and provided further that, if Biogen conducted or co-conducted a Clinical Study that is the subject of such public announcement, press release or other public disclosure, then any such public announcement, press
                    release or other public disclosure shall be jointly issued by the Parties (unless Biogen expressly waives in writing its right to jointly issue such public announcement, press release or other public disclosure). If Biogen desires to
                    make any public announcement, issue a press release or make any other public disclosure with respect to a Clinical Study that was conducted or co-conducted by Biogen prior to the date Biogen has been granted a license under Section
                      4.1.1 with respect to a Product, Biogen shall so notify Ionis and shall provide Ionis with a draft thereof at least two Business Days prior to the proposed publication thereof. Ionis may review and provide comments to Biogen and
                    the Parties shall discuss in good faith any such comments and seek to mutually agree on a final version of such proposed public announcement, press release or other public disclosure. Notwithstanding the foregoing, Ionis shall, pursuant
                    to this Section 11.4.5, retain final decision-making authority over (x) whether such proposed public announcement, press release or other public disclosure shall be issued or made, and (y) the content thereof, and in no event
                    shall Biogen issue any such public announcement, press release or other public disclosure under this Section 11.4.5 except in the final version approved by Ionis.

              


         

        
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              	11.4.6.	
                After the License Effective Date.  After the License Effective Date with respect to a Product, subject to the
                    provisions of this Section 11.4.6 and Section 11.4.7, Biogen will have the sole right to issue press releases, publish, present or otherwise disclose the progress and results regarding such Product to the public, which
                    shall be consistent with its practice with its other compounds and products; provided that with respect to any proposed press release or other similar public communication by Biogen disclosing
                    regulatory discussions, the efficacy or safety data or results related to such Product or Biogen’s sales projections, (a) Biogen will submit such proposed communication to Ionis for review at
                    least two Business Days in advance of such proposed public disclosure, (b) Ionis will have the right to review and recommend changes to such communication, and (c) Biogen will in good faith consider any changes that are timely
                    recommended by Ionis; and provided further that, if Ionis conducted or co-conducted a Clinical Study that is the subject of such public announcement,
                    press release or other public disclosure, then any such public announcement, press release or other public disclosure shall be jointly issued by the Parties (unless Ionis expressly waives in writing its right to jointly issue such
                    public announcement, press release or other public disclosure). If Ionis desires to make any public announcement, issue a press release or make any other public disclosure with respect to a Clinical Study that was conducted or
                    co-conducted by Ionis, Ionis shall so notify Biogen and shall provide Biogen with a draft thereof at least two Business Days prior to the proposed publication thereof. Biogen may review and provide comments to Ionis and the Parties
                    shall discuss in good faith any such comments and seek to mutually agree on a final version of such proposed public announcement, press release or other public disclosure. Notwithstanding the foregoing, Biogen shall, pursuant to this Section


                      11.4.6, retain final decision-making authority over  (i) whether such proposed public announcement, press release or other public disclosure shall be issued or made and (ii) the content thereof, and in no event shall Ionis issue
                    any such public announcement, press release or other public disclosure under this Section 11.4.6 except in the final version approved by Biogen.

              


         

        	

              	11.4.7.	
                Resolution of Disagreements Regarding Public Announcements.  If the Parties cannot mutually agree on the need for
                    or content of any press release, presentation or other public disclosure under Section 11.4.5 or Section 11.4.6 that is intended to be jointly issued, then either Party may promptly refer for resolution to a “C” level
                    executive of each Party (e.g., a Party’s Chief Operating Officer, Chief Executive Officer or Chief Business Officer) or to one of the Party’s Neurology JSC members. During the at least two Business Day advance review period described in
                    Section 11.4.5 or Section 11.4.6 (as applicable), such “C” level executives or Neurology JSC members will meet in person at a mutually acceptable time and location or by means of telephone or video conference to discuss
                    in good faith and attempt to resolve such dispute.

              


         

        
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              	11.4.8.	
                Scientific or Clinical Presentations for Products.  Regarding any proposed scientific publications or public
                    presentations related to summaries of results from any Clinical Studies generated by Ionis or Biogen for a Product, the Parties acknowledge that scientific lead time is a key element of the value of the Products under this Agreement and
                    further agree to use Commercially Reasonable Efforts to control public scientific disclosures of the results of the Development activities under this Agreement to prevent any potential adverse effect of any premature public disclosure
                    of such results. The Parties will establish a procedure for publication review and each Party will first submit to the other Party through the Joint Patent Committee an early draft of all such publications or presentations, whether they
                    are to be presented orally or in written form, at least [***] days prior to submission for publication including to facilitate the publication of any summaries of Clinical Studies data and results as required on the clinical trial
                    registry of each respective Party. Each Party will review such proposed publication in order to avoid the unauthorized disclosure of a Party’s Confidential Information and to preserve the patentability of inventions arising from the
                    Collaboration Programs. If, during such [***] day period, the other Party informs such Party that its proposed publication contains Confidential Information of the other Party, then such Party will delete such Confidential Information
                    from its proposed publication. In addition, if at any time during such [***] day period, the other Party informs such Party that its proposed publication discloses inventions made by either Party in the course of the Development under
                    this Agreement that have not yet been protected through the filing of a patent application, or the public disclosure of such proposed publication could be expected to have a material adverse effect on any Patent Rights or Know-How
                    solely owned or Controlled by such other Party, then such Party will either (a) delay such proposed publication for up to [***] days from the date the other Party informed such Party of its objection to the proposed publication, to
                    permit the timely preparation and first filing of patent application(s) on the information involved or (b) remove the identified disclosures prior to publication.  With respect to each Clinical Study, (i) if such Clinical Study is
                    Initiated prior to the date Biogen has been granted a license under Section 4.1.1 with respect to the applicable Product, Ionis shall determine authorship or attribution with respect to any proposed publications regarding the
                    results of such Clinical Study and (ii) if such Clinical Study is Initiated after the date Biogen has been granted a license under Section 4.1.1 with respect to the applicable Product, Biogen shall determine authorship or
                    attribution with respect to any proposed publications regarding the results of such Clinical Study, in each case ((i) and (ii)), by interpreting and applying the authorship and attribution principles of the International Committee of
                    Medical Journal Editors’ Recommendations for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, provided that (A) in
                    each case, the Party that has the right to determine attribution or authorship in accordance with this Section 11.4.8 shall consider in good faith any reasonable comments timely made by the other Party with respect thereto, (B)
                    any determination of authorship or attribution under this Section 11.4.8 shall be in compliance with the requirements of the applicable journal of the proposed publication and (C) the Party that does not have the right to
                    determine attribution or authorship in accordance with this Section 11.4.8 for any such proposed publication will have the right to have at least one author listed in such publication if such Party conducted or co-conducted such
                    Clinical Study.

              


         

        	

              	11.4.9.	
                SEC Filings.  Each Party will give the other Party a reasonable opportunity to review all material filings with the
                    SEC describing the terms of this Agreement prior to submission of such filings, and will give due consideration to any reasonable comments by the non-filing Party relating to such filing.

              


         

        	

              	11.4.10.	
                Subsequent Disclosure.  Notwithstanding the foregoing, to the extent information regarding this Agreement or the
                    Product has already been publicly disclosed, either Party (or its Affiliates) may subsequently disclose the same information to the public without the consent of the other Party.

              


         

        
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              	11.4.11.	
                Acknowledgment.  Each Party will acknowledge in any press release, public presentation or publication regarding the
                    Collaboration Programs or a Product, the other Party’s role in discovering and developing the Product or Discontinued Product, as applicable, that the Product is under license from Ionis and otherwise acknowledge the contributions from
                    the other Party, and each Party’s stock ticker symbol (e.g., Nasdaq: IONS, BIIB).

              


         

        	

              	(a)	
                Biogen understands and acknowledges the importance to Ionis of continuing to be associated with the drugs it discovers under the Collaboration Programs. As such, Biogen agrees that it will use reasonable efforts to prominently
                  acknowledge Ionis’ role in the discovery of a Product in any scientific, medical and other Product-related communications to the extent such communications address the research, discovery or commercialization of a Product, by prominently
                  including the words “Discovered by Ionis” or equivalent language (collectively, the “Ionis Attribution Language”) in any such
                  communications; provided, however, that Biogen shall have no obligation to include the Ionis Attribution Language in any of the following: (i)
                  communications or materials where such inclusion would be prohibited by Applicable Laws or applicable Third Party institutional, corporate or other policies; (ii) communications that Biogen does not control, such as publications with
                  non-Biogen lead authors; (iii) materials primarily focused on or directed to patients, or other materials where Biogen branding is not prominently featured; or (iv) abstracts or other communications with a word limitation, if Biogen
                  reasonably determines that such word limitation would preclude the inclusion of the Ionis Attribution Language; provided that in each case, Biogen will use reasonable efforts to have the Ionis
                  Attribution Language included in any such communication, consistent with the efforts that Biogen uses to have statements regarding its own contributions to the Product included in such communication.

              


         

        	

              	(b)	
                Ionis may include the Products (and identify Biogen as its partner for the Products) in Ionis’ drug pipeline.

              


         

        
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        ARTICLE 12

        MISCELLANEOUS

         

        	12.1.	
                Dispute Resolution.

              


         

        	

              	12.1.1.	
                Escalation.  In the event of any Dispute (other than a Setoff Dispute, which Setoff Dispute will be resolved
                    pursuant to Section 12.1.3, or dispute regarding the construction, validity or enforcement of either Party’s Patent Rights, which disputes will be resolved pursuant to Section 12.2), either Party may, within [***] days
                    after either Party notifies the other Party that the Dispute has not been resolved (provided that such notice cannot be given less than [***] days after the Dispute has arisen), make a written
                    request that the Dispute be referred for resolution to the Executive Vice President, Business Development of Biogen and the Chief Executive Officer of Ionis (the “Executives”). 


                    Within [***] days of either Party’s written request that the Dispute be referred to the Executives, the Executives will meet in person at a mutually acceptable time and location or by means of telephone or video conference to negotiate
                    a settlement of a Dispute.  Each Party may elect to have such Party’s Neurology JSC representatives participate in such meeting, if desired, provided that it provides the other Party with
                    reasonable advance notice of such intent so as to enable the other Party to have its Neurology JSC representatives also participate in such meeting, if desired.  If the Executives fail to resolve the Dispute within such [***] day
                    period, then the Dispute will be referred to mediation under Section 12.1.2.

              


         

        	

              	12.1.2.	
                Mediation.  If a Dispute subject to Section 12.1.1 cannot be resolved pursuant to Section 12.1.1,
                    or if neither Party timely makes the written request that the Dispute be referred to the Executives, the Parties will resolve any such Dispute in accordance with the dispute resolution procedures set forth in Schedule 12.1.2.

              


         

        	

              	12.1.3.	
                Setoff Disputes.  Setoff Disputes will be resolved in accordance with Section 10.4.4(b) and Schedule 10.4.4(b).

              


         

        	12.2.	
                Governing Law; Jurisdiction; Venue; Service of Process.

              


         

        	

              	12.2.1.	
                This Agreement and any Dispute will be governed by and construed and enforced in accordance with the laws of the State of Delaware, U.S.A., without reference to conflicts of laws principles.

              


         

        	

              	12.2.2.	
                Subject to the provisions of Section 12.1, each Party by its execution hereof, (a) hereby irrevocably submits to the exclusive jurisdiction of the United States District Court for the District of Delaware (or, if but only if
                  such court lacks, or will not exercise, subject matter jurisdiction over the entirety of a Dispute, the Court of Chancery of the State of Delaware, or, if but only if such court lacks, or will not exercise, subject matter jurisdiction
                  over the entirety of a Dispute, the Superior Court of the State of Delaware, with respect to the Dispute) for the purpose of any Dispute arising between the Parties in connection with this Agreement (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 courts, that venue in the above-named courts is improper, that its property is exempt or immune from attachment or execution, that any such Action brought in the above-named courts should
                  be dismissed on grounds of forum non conveniens, should be transferred or removed to any court other than the above-named courts, or should be stayed by reason of the pendency of some other
                  proceeding in any other court other than the above-named courts, or that this Agreement or the subject matter hereof may not be enforced in or by such courts and (c) hereby agrees not to commence any such Action other than before the
                  above-named courts.  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.

              


         

        
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              	12.2.3.	
                Each Party hereby agrees that service of process: (a) made in any manner permitted by Delaware law, or (b) made by overnight express courier service (signature required), prepaid, at its address specified pursuant to Section 12.8,
                  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.

              


         

        	12.3.	
                Remedies.  Notwithstanding anything to the contrary in this Agreement, each Party will be entitled to seek, in
                    addition to any other right or remedy it may have, at law or in equity, a temporary restraining order or a preliminary injunction, without the posting of any bond or other security, enjoining or restraining the other Party from any
                    violation or threatened violation of this Agreement, and the Parties agree that in the event of a threatened or actual material breach of this Agreement injunctive relief would be appropriate. Neither Party will be entitled to recover
                    any Losses relating to any matter arising under one provision of this Agreement to the extent that such Party has already recovered Losses with respect to such matter pursuant to other provisions of this Agreement (including recoveries
                    under Section 9.1 or Section 9.2, and the offsets under Section 6.8.3(c)).  Except for the offsets and credits explicitly set forth in Section 6.10, Section 6.8.3(b), Section 6.8.3(d) and
                    Section 10.4.4(b), neither Party will have the right to setoff any amount it is owed or believes it is owed against payments due or payable to the other Party under this Agreement.

              


         

        	12.4.	
                Assignment and Successors.  Neither this Agreement nor any obligation of a Party hereunder may be assigned by
                    either Party without the consent of the other, which will not be unreasonably withheld, delayed or conditioned, except that each Party may assign this Agreement and the rights, obligations and interests of such Party, in whole or in
                    part, without the other Party’s consent, to any of its Affiliates, to any purchaser of all or substantially all of its assets or all or substantially all of its assets to which this Agreement relates or to any successor corporation
                    resulting from any merger, consolidation, share exchange or other similar transaction; provided that if Biogen transfers or assigns this Agreement to [***] described in this Agreement, then
                    Biogen (or such Affiliate), will [***] Ionis under ARTICLE 6 for the [***] such that Ionis receives [***] assignment. In addition, Ionis may assign or transfer its rights to receive payments under this Agreement (but no
                    liabilities), without Biogen’s consent, to an Affiliate or to a Third Party in connection with a payment factoring transaction. Any purported assignment or transfer made in contravention of this Section 12.4 will be null and
                    void.

              


         

        The [***].

         

        To the extent Ionis utilizes a [***] in any year, Ionis will [***] to Biogen [***]. To assist Biogen in determining when a refund is due from Ionis pursuant to the foregoing sentence, beginning
          with the first Annual tax return for the year in which Biogen [***] payment under this Section 12.4, and each year thereafter (including, for clarity, all years in which Ionis utilizes a [***], supporting documentation for such [***].
          Notwithstanding the foregoing, if the [***].

         

        
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        	12.5.	
                Change of Control.

              


         

        	

              	12.5.1.	
                Pre-Existing Competitive Programs of an Acquirer.  If, at any time during the Agreement Term, a Change of Control
                    of a Party occurs involving a Person that, at the time of the execution of such Change of Control, is (A) developing or commercializing a (1) Competitive Product or (2) Competitive Indication Product within the Field (such pre-existing
                    Competitive Products and Competitive Indication Products, each, a “Pre-Existing Competitive Product”) or (B) is engaged in a Competitive Program or Competitive Indication
                    Program (such pre-existing Competitive Programs and Competitive Indication Programs, each, a “Pre-Existing Competitive Program,” and such Person being hereinafter referred to
                    as a “Competing Collaboration Acquirer”), then in each case ((A) and (B)):

              


         

        	

              	(a)	
                such Party shall promptly provide written notice to the other Party of such Change of Control;

              


         

        	

              	(b)	
                if such Change of Control involved Ionis, then Biogen may elect that some or all of the Biogen Reduced Participation and Information Obligations will apply to the Collaboration Programs to which the Pre-Existing Competitive Product or
                  Pre-Existing Competitive Program relate;

              


         

        	

              	(c)	
                such Party shall conduct activities pursuant to Section 12.6 to separate its Development activities under this Agreement from its development activities relating to any Pre-Existing Competitive Product(s) and Pre-Existing
                  Competitive Program(s); and

              


         

        	

              	(d)	
                the research, development, manufacture or commercialization of any Pre-Existing Competitive Product(s) by a Competing Collaboration Acquirer will not be a violation of such Party’s exclusivity covenants under Section 2.1.1 and
                  Section 12.5.2(a) will not apply to any such Pre-Existing Competitive Product or Pre-Existing Competitive Program; provided that the conditions of Section 12.5.1(a) and Section
                    12.5.1(c) are satisfied.

              


         

        	

              	12.5.2.	
                Acquired Competitive Programs; Acquired Associated Programs.

              


         

        	

              	(a)	
                If, at any time during the Agreement Term, either Party acquires a Third Party or a portion of the business of a Third Party (whether by merger, stock purchase or purchase of assets) that is, prior to such acquisition, engaged in
                  discovering, researching, developing or commercializing a Competitive Product within the Field or is engaged in a Competitive Program, in each case that would violate the provisions of ARTICLE 2 if conducted by such Party (such
                  acquired Competitive Product an “Acquired Competitive Product” and such acquired Competitive Program an “Acquired Competitive
                    Program”), then the limited continuation of the research, development, manufacture or commercialization of the Acquired Competitive Product(s) or Acquired Competitive Programs by the acquiring Party as permitted in this Section








                    12.5.2(a) in a manner that would have been in the ordinary course of business of such Third Party will not be a violation of such acquiring Party’s exclusivity covenants under Section 2.1.1; provided that following the closing of such acquisition, the conditions set forth in Sections 12.5.2(a)(i) through 12.5.2(a)(iv) are met:

              


         

        
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              	(i)	
                Such acquiring Party shall promptly provide written notice to the other Party of such acquisition;

              


         

        	

              	(ii)	
                Such acquiring Party shall use reasonable efforts to divest all such Acquired Competitive Products and Acquired Competitive Programs promptly following the closing of such acquisition, and in any event such Party shall complete such
                  divestment within [***] after the closing of such acquisition (the “Collaboration Divestiture Period”); provided that such
                  Collaboration Divestiture Period shall be extended, and such Party shall not be in breach of this Section 12.5.2(a) if, at the expiration thereof (and any extensions thereto), such Party provides competent evidence of reasonable
                  ongoing efforts to divest such Acquired Competitive Products and Acquired Competitive Programs; provided further that such Party shall cease all
                  development and commercialization activities with respect to all such Acquired Competitive Products and Acquired Competitive Programs if such Party has not completed such divestiture within [***] after the closing of such acquisition (it
                  being understood that such Party may thereafter continue its efforts to divest such asset);

              


         

        	

              	(iii)	
                During such divestiture period, the acquiring Party shall comply with Section 12.6 to separate its Development activities under this Agreement from its development activities relating to any Acquired Competitive Product or
                  Acquired Competitive Program; and

              


         

        	

              	(iv)	
                Neither Party nor its Affiliates may acquire a Competitive Product or a Competitive Program on a standalone basis.

              


         

        	

              	(b)	
                If Ionis is the acquiring Party of an Acquired Competitive Product or Acquired Competitive Program, then during the Collaboration Divestiture Period until Ionis [***], Biogen may elect that [***].

              


         

        	

              	(c)	
                In addition, without limiting Section 12.5.2(a)(iv), if at any time during the Agreement Term, (i) Ionis acquires a Third Party or a portion of the business of a Third Party (whether by merger, stock purchase or purchase of
                  assets) that is, prior to such acquisition, engaged (A) in [***] (an “Associated Product”) or any Competitive Indication Product, or (B) is engaged in [***] (an “Associated Program”) or a Competitive Indication Program, (ii) Ionis or an Ionis Affiliate [***] or (iii) Ionis or an Ionis Affiliate [***] then, in each case ((i) through (iii)) with respect to any Collaboration Program directed to the Collaboration Target to which the Associated Product, Associated Program, Competitive Product or Competitive Program is
                  directed and with respect to any Collaboration Program intended for the same indication as the Competitive Indication Product or the Competitive Indication Program, Biogen may elect that [***] and Ionis shall comply with the same
                  procedures as under Section 12.6 to separate its Development activities under this Agreement from its development activities relating to any such Associated Product, Associated Program, Competitive Product, Competitive Program,
                  Competitive Indication Product or Competitive Indication Program.

              


         

        
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        	12.6.	
                Protective Provisions.  At any time while (a) the Party involved in a Change of Control with a Competing
                    Collaboration Acquirer, (b) the Party with an Acquired Competitive Product or Acquired Competitive Program or (c) Ionis (in cases where Ionis otherwise has an Associated Product, Associated Program, Competitive Product, Competitive
                    Program, Competitive Indication Product or Competitive Indication Program) is conducting Development activities under this Agreement, then, in each case ((a) through (c)) such Party (as applicable under clause (a), (b) or (c)) must
                    separate such Development activities from its or its Affiliates’ other development activities relating to any such Competitive Product or Competitive Program, and, in the case of Ionis, from any such Associated Product, Associated
                    Program, Competitive Indication Product or Competitive Indication Program, as applicable (such other development activities, “Competing Development Activities”).  To that end,
                    and subject to the licenses granted to each Party (as applicable) under Section 4.3 or Section 4.4, any such Party will, and (if applicable) will cause the Competing Collaboration Acquirer to, (i) establish separate
                    teams to conduct Development activities under this Agreement and such Competing Development Activities, (ii) prevent any Confidential Information relating to the Development, Manufacture or Commercialization of any applicable Product
                    (including Know-How) from being disclosed to, or used by, individuals performing such Competing Development Activities and (iii) not use or reference in the development, manufacture or commercialization of the Competitive Product any
                    Know-How that is Confidential Information or conduct any activities Covered by any Patent Rights, in each case, Controlled by the Party involved in the Change of Control or the acquisition or its Affiliates prior to the effective date
                    of the Change of Control or the acquisition.

              


         

        	12.7.	
                Force Majeure.  No Party will be held responsible to the other Party nor be deemed to be in default under, or in
                    breach of any provision of, this Agreement for failure or delay in performing any obligation of this Agreement when such failure or delay is due to force majeure, and without the fault or negligence of the Party so failing or delaying.
                    For purposes of this Agreement, force majeure means a cause beyond the reasonable control of a Party, which may include acts of God; acts, regulations, or Laws of any government; war; terrorism; civil commotion; fire, flood, earthquake,
                    tornado, tsunami, explosion or storm; pandemic; epidemic and failure of public utilities or common carriers.  In such event the Party so failing or delaying will immediately notify the other Party of such inability and of the period for
                    which such inability is expected to continue. The Party giving such notice will be excused from such of its obligations under this Agreement as it is thereby disabled from performing for so long as it is so disabled for up to a maximum
                    of 90 days, after which time the Parties will negotiate in good faith any modifications of the terms of this Agreement that may be necessary to arrive at an equitable solution, unless the Party giving such notice has set out a
                    reasonable timeframe and plan to resolve the effects of such force majeure and executes such plan within such timeframe.  To the extent possible, each Party will use reasonable efforts to minimize the duration of any force majeure.

              


         

        
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        	12.8.	
                Notices.  Any notice or request required or permitted to be given under or in connection with this Agreement will
                    be deemed to have been sufficiently given if in writing and personally delivered or sent by certified mail (return receipt requested) electronic mail transmission (receipt verified), or overnight express courier service (signature
                    required), prepaid, to the Party for which such notice is intended, at the address set forth for such Party below:

              


         

        	
                If to Ionis, addressed to:

              	
                Ionis Pharmaceuticals, Inc.

                2855 Gazelle Court

                Carlsbad, CA  92010

                Attention:  Chief Executive Officer

                E-mail: [***]

              
	 	 
	
                with a copy to:

              	
                Ionis Pharmaceuticals, Inc.

                2855 Gazelle Court

                Carlsbad, CA  92010

                Attention:  General Counsel

                E-mail: [***]

              
	 	 
	
                If to Biogen, addressed to:

              	
                Biogen MA Inc.

                225 Binney Street

                Cambridge, MA  02142

                Attention:  Chief Legal Officer

                E-mail:  [***]

              
	 	 
	
                with a copy to:

              	
                Ropes & Gray LLP

                Prudential Tower

                800 Boylston Street

                Boston, MA  02199-3600

                Attention:  Hannah Freeman

                E-mail:  hannah.freeman@ropesgray.com

              


         

        or to such other address for such Party as it will have specified by like notice to the other Party; provided that notices of a change of address will
          be effective only upon receipt thereof.  If delivered personally or by electronic mail transmission, the date of delivery will be deemed to be the date on which such notice or request was given.  If sent by overnight express courier service, the
          date of delivery will be deemed to be the next Business Day after such notice or request was deposited with such service.  If sent by certified mail, the date of delivery will be deemed to be the third Business Day after such notice or request
          was deposited with the U.S. Postal Service.

         

        	12.9.	
                Export Clause.  Each Party acknowledges that the Laws and regulations of the United States restrict the export and
                    re-export of commodities and technical data of United States origin.  Each Party agrees that it will not export or re-export restricted commodities or the technical data of the other Party in any form without the appropriate United
                    States and foreign government licenses.

              


         

        
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        	12.10.	
                Waiver.  Neither Party may waive or release any of its rights or interests in this Agreement except in writing. 
                    The failure of either Party to assert a right hereunder or to insist upon compliance with any term or condition of this Agreement will not constitute a waiver of that right or excuse a similar subsequent failure to perform any such term
                    or condition.  No waiver by either Party of any condition or term in any one or more instances will be construed as a continuing waiver or subsequent waiver of such condition or term or of another condition or term.

              


         

        	12.11.	
                Severability.  If any provision hereof should be held invalid, illegal or unenforceable in any jurisdiction, then
                    the Parties will negotiate in good faith a valid, legal and enforceable substitute provision that most nearly reflects the original intent of the Parties and all other provisions hereof will remain in full force and effect in such
                    jurisdiction and will be liberally construed in order to carry out the intentions of the Parties hereto as nearly as may be possible. Such invalidity, illegality or unenforceability will not affect the validity, legality or
                    enforceability of such provision in any other jurisdiction.

              


         

        	12.12.	
                Entire Agreement.  This Agreement, together with the Schedules and Appendices hereto (including the [***] Letter), amends and restates the Original Agreement, sets forth all the covenants, promises, agreements, warranties, representations, conditions and understandings between the Parties with respect to the
                    subject matter hereof, fully supersedes the Original Agreement for the period commencing on the Amendment Date and continuing thereafter and supersedes and terminates all prior agreements and understanding between the Parties with
                    respect to the subject matter hereof.  Without limiting the foregoing, this Agreement supersedes that certain side letter between the Parties, dated as of October 9, 2015, relating to drug substance process development and
                    manufacturing, solely to the extent such side letter relates to Collaboration Programs under this Agreement.  For clarity, such side letter shall remain in full force and effect with respect to the Ionis/Biogen Additional Agreements. 
                    For the avoidance of doubt, this Agreement in no way supersedes, modifies or otherwise affects any of the Ionis/Biogen Additional Agreements, which will remain in full force and effect in accordance with each of their respective terms.
                    There are no covenants, promises, agreements, warranties, representations, conditions or understandings, either oral or written, between the Parties with respect to the subject matter hereof other than as set forth herein and therein. 
                    No subsequent alteration, amendment, change or addition to this Agreement will be binding upon the Parties hereto unless reduced to writing and signed by the respective authorized officers of the Parties.

              


         

        	12.13.	
                Independent Contractors.  Nothing herein will be construed to create any relationship of employer and employee,
                    agent and principal, partnership or joint venture between the Parties. Each Party is an independent contractor. Neither Party will assume, either directly or indirectly, any liability of or for the other Party.  Neither Party will have
                    the authority to bind or obligate the other Party and neither Party will represent that it has such authority.

              


         

        	12.14.	
                Interpretation.  Except as otherwise explicitly specified to the contrary, (a) references to a section, exhibit or
                    schedule means a section of, or schedule or exhibit to this Agreement, unless another agreement is specified, (b) the word “including” (in its various forms) means “including without limitation,” (c) the words “shall” and “will” have
                    the same meaning, (d) references to a particular statute or regulation include all rules and regulations thereunder and any predecessor or successor statute, rules or regulation, in each case as amended or otherwise modified from time
                    to time, (e) words in the singular or plural form include the plural and singular form, respectively, (f) references to a particular Person include such Person’s successors and assigns to the extent not prohibited by this Agreement, (g)
                    unless otherwise specified, “$” is in reference to United States dollars, and (h) the headings contained in this Agreement, in any exhibit or schedule to this Agreement and in the table of contents to this Agreement are for convenience
                    only and will not in any way affect the construction of or be taken into consideration in interpreting this Agreement.

              


         

        
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        	12.15.	
                Books and Records.  Any books and records to be maintained under this Agreement by a Party or its Affiliates or
                    Sublicensees will be maintained in accordance with U.S. Generally Accepted Accounting Principles (or any successor standard), consistently applied.

              


         

        	12.16.	
                Further Actions.  Each Party will execute, acknowledge and deliver such further instruments, and do all such other
                    acts, as may be necessary or appropriate in order to carry out the expressly stated purposes and the clear intent of this Agreement.

              


         

        	12.17.	
                Construction of Agreement.  The terms and provisions of this Agreement represent the results of negotiations
                    between the Parties and their representatives, each of which has been represented by counsel of its own choosing, and neither of which has acted under duress or compulsion, whether legal, economic or otherwise. Accordingly, the terms
                    and provisions of this Agreement will be interpreted and construed in accordance with their usual and customary meanings, and each of the Parties hereto hereby waives the application in connection with the interpretation and
                    construction of this Agreement of any rule of law to the effect that ambiguous or conflicting terms or provisions contained in this Agreement will be interpreted or construed against the Party whose attorney prepared the executed draft
                    or any earlier draft of this Agreement.

              


         

        	12.18.	
                Supremacy.  In the event of any express conflict or inconsistency between this Agreement and any Schedule or
                    Appendix hereto, the terms of this Agreement will apply.  The Parties understand and agree that the Schedules and Appendices hereto are not intended to be the final and complete embodiment of any terms or provisions of this Agreement,
                    and are to be updated from time to time during the Agreement Term, as appropriate and in accordance with the provisions of this Agreement.

              


         

        	12.19.	
                Counterparts.  This Agreement may be signed in counterparts, each of which will be deemed an original,
                    notwithstanding variations in format or file designation that may result from the electronic transmission, storage and printing of copies of this Agreement from separate computers or printers.  Facsimile signatures and signatures
                    transmitted via electronic mail in PDF format will be treated as original signatures.

              


         

        	12.20.	
                Compliance with Laws.  Each Party will, and will ensure that its Affiliates and Sublicensees will, comply with all
                    relevant Laws and regulations in exercising its rights and fulfilling its obligations under this Agreement.

              


         

        [SIGNATURE PAGE FOLLOWS]

         

        * - * - * - *

         

        
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        IN WITNESS WHEREOF, the Parties have caused this Agreement to be executed by their
            representatives thereunto duly authorized as of the Amendment Date.

         

        	
                BIOGEN MA INC.

              
	 
	
                By:/s/Anabella Villalobos

              
	
                Name: Anabella Villalobos

              
	
                Title: Senior Vice President, Biotherapeutics & Medicinal Sciences

              


        

        

        
          
            
              Signature Page to Amended and Restated Neurology Drug Discovery and Development

              Collaboration, Option and License Agreement

            

          

          
            


          
            CONFIDENTIAL

            EXECUTION VERSION

          

        

        IN WITNESS WHEREOF, the Parties have caused this Agreement to be executed by their
            representatives thereunto duly authorized as of the Amendment Date.

         

        	
                IONIS PHARMACEUTICALS, INC.

              
	 
	
                By:/s/Brett Monia

              
	
                Name:  Brett Monia

              
	
                Title: Chief Executive Officer

              


        

        

        
          
            
              
                Signature Page to Amended and Restated Neurology Drug Discovery and Development

                Collaboration, Option and License Agreement

              

            

          

          
            


          
            CONFIDENTIAL

            EXECUTION VERSION

          

        

        List of Appendices and Schedules

         

        Appendix 1 – Definitions

         

        Appendix 2 – Development Candidate Checklist

         

        Appendix 3 – Form of Side Letter

         

        Appendix 4 –[***] Letter

         

        Schedule 1.5.2(b) - Apportionment of Certain Milestone Payments and
            Biogen-Approved Costs

         

        Schedule 1.11.1 – Neurology JSC Governance

         

        Schedule 1.11.5 – Alliance Management Activities

         

        Schedule 4.6.3 – Ionis’ Fully Absorbed Cost of Goods Methodology

         

        Schedule 5.1.1 – Specific Performance Milestone Events

         

        Schedule 6.6.2(f) – Royalty Calculation Examples

         

        Schedule 6.6.2(g) – Allocation of Net Sales

         

        Schedule 6.8.1 – Certain Ionis In-License Agreements

         

        Schedule 8.2.4(a) – Ionis Core Technology Patents

         

        Schedule 8.2.4(b) – Ionis Manufacturing and Analytical Patents

         

        Schedule 8.2.4(c) – Ionis Product-Specific Patents

         

        Schedule 8.2.8 – Prior Agreements

         

        Schedule 10.4.4(b) – Advisory Panel Regarding Setoff Disputes

         

        Schedule 12.1.2 – Mediation

         

        
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        Appendix 1

         

        DEFINITIONS

         

        For purposes of this Agreement, the following capitalized terms will have the following meanings:

         

        “Accelerated Target” has the meaning set forth in Section 2.3.

         

        “Acceptance” means, with respect to an NDA, MAA or JNDA filed for a Product, (a) in the United States, the receipt of written notice from the FDA in
          accordance with 21 C.F.R. §314.101(a)(2) that such NDA is officially “filed,” (b) in the European Union, receipt by Biogen of written notice of acceptance by the EMA of such MAA for filing under the
          centralized European procedure in accordance with any feedback received from EU Regulatory Authorities; provided that if the centralized filing procedure is not used, then Acceptance will be determined
          upon the acceptance of such MAA by the applicable Regulatory Authority in a Major Market in the EU, (c) in any Major Market in Europe that is not a European Union country, receipt by Biogen of written notice of acceptance by the applicable
          Regulatory Authority of such MAA for filing in such country, and (d) in Japan, receipt by Biogen of written notice of acceptance of filing of such JNDA from the Koseisho (i.e., the Japanese Ministry of Health and Welfare, or any successor agency thereto).

         

        “Acquired Competitive Product” has the meaning set forth in Section 12.5.2(a).

         

        “Acquired Competitive Program” has the meaning set forth in Section 12.5.2(a).

         

        “Action” has the meaning set forth in Section 12.2.2.

         

        “Actual Biogen-Approved Costs” has the meaning set forth in Section 1.8.5.

         

        “Additional Core IP” means Third Party intellectual property that is necessary to [***]. For clarity, Additional Core IP does not include any
          Patent Rights claiming (or intellectual property related to) [***].

         

        “Additional Plan Costs” means [***].

         

        “Affiliate” of an entity means any corporation, firm, partnership or other entity which directly or indirectly through one or more intermediaries
          controls, is controlled by or is under common control with a Party to this Agreement. An entity will be deemed to control another entity if it (a) owns, directly or indirectly, at least 50% of the outstanding voting securities or capital stock
          (or such lesser percentage which is the maximum allowed to be owned by a foreign corporation in a particular jurisdiction) of such other entity, or has other comparable ownership interest with respect to any entity other than a corporation; or
          (b) has the power, whether pursuant to contract, ownership of securities or otherwise, to direct the management and policies of the entity. For clarity, Regulus Therapeutics Inc. will not be deemed an “Affiliate”
          of Ionis for the purposes of this Agreement under any circumstances.

         

        “Agreement” has the meaning set forth in the Preamble of this Agreement.

         

        “Agreement Term” has the meaning set forth in Section 10.1.

         

        
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        “Alliance Manager” has the meaning set forth in Section 1.11.5.

         

        “Amendment Date” has the meaning set forth in the Preamble of this Agreement.

         

        “ANDA” means an Abbreviated New Drug Application and all amendments and supplements thereto filed with the FDA, or the equivalent application filed with
          any equivalent agency or governmental authority outside the U.S. (including any supra-national agency such as the EMA in the EU).

         

        “Annual” means the period covering a Calendar Year or occurring once per Calendar Year, as the context requires.

         

        “API” means the bulk active pharmaceutical ingredient manufactured in accordance with cGMP for a Product.

         

        “Applicable Law” or “Law” means all applicable laws, statutes, rules, regulations and other
          pronouncements having the effect of law of any federal, national, multinational, state, provincial, county, city or other political subdivision, agency or other body, domestic or foreign, including any applicable rules, regulations, guidelines,
          or other requirements of the Regulatory Authorities that may be in effect from time to time.

         

        “Approval”
            means, with respect to a Product in any regulatory jurisdiction, approval from the applicable Regulatory Authority sufficient
              for the manufacture, distribution, use, marketing and sale of such Product in such jurisdiction in accordance with Applicable Laws. In jurisdictions where the applicable Regulatory Authority sets the pricing or reimbursement authorizations necessary for the general marketing and sale of such Product


            in the marketplace, Approval will not be deemed to have occurred if the final approval to market and sell such Product is
              being withheld because Biogen (or its Affiliate or Sublicensee) and the Regulatory Authority have not yet
              determined pricing or reimbursement even if all other approvals, licenses, registrations or authorizations necessary for marketing, sale or use of such Product in such jurisdiction have been
              obtained. “Approval” does not include authorization by a Regulatory Authority to conduct named patient, compassionate use or other similar activities.

         

        “ASO” means an Oligonucleotide compound, or analog, variant, mimic, or mimetic thereof, having a sequence that is at least six bases long and that
          modulates expression or splicing of a gene target via the binding, partially or wholly, of such compound to the RNA of such gene target, excluding any double-stranded Oligonucleotide compounds that are designed to act through the RNA-induced
          silencing complex.

         

        “Associated Product” has the meaning set forth in Section 12.5.2(c).

         

        “Associated Program” has the meaning set forth in Section 12.5.2(c).

         

        “Audit Report” has the meaning set forth in Section 6.10.

         

        “Bankruptcy Code” has the meaning set forth in Section 10.2.7(b).

         

        “Biogen” has the meaning set forth in the Preamble of this Agreement.

         

        
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        “Biogen Activities” means, under any Collaboration Program Research Plan or Development Plan, any and all research, pre-clinical and/or clinical activities that Biogen agrees to
          conduct; provided that Biogen will be deemed to have agreed to conduct any activities designated as Biogen Activities under any Collaboration Program Research Plan or Development Plan it approves.

         

        “Biogen-Approved Changes” means any changes (including number of subjects, duration of dosing, additional studies, additional endpoints, additional analysis, etc.) to the applicable
          Development Plan for a Product that are requested by either Party after the Parties have set the initial Cost Estimates for such Development Plan under Section 1.5.2(b), and (i) required by a Regulatory Authority or (ii) agreed to be paid
          for by Biogen.

         

        “Biogen-Approved Costs” has the meaning set forth in Section 1.8.

         

        “Biogen’s FTE Cost” means the FTE Rate applicable to Biogen, multiplied by the applicable number of FTEs.

         

        “Biogen Full Royalty” has the meaning set forth in Section 6.6.1.

         

        “Biogen Know-How” means any Know-How owned, used, developed by, or licensed to Biogen or its Affiliates, in each case to the extent Controlled by Biogen
          or its Affiliates on the Effective Date or at any time during the Agreement Term, but specifically excluding the Biogen Program Know-How.

         

        “Biogen Manufacturing Program Patent” has the meaning set forth in Section 4.8.5(a).

         

        “Biogen Patents” means any Patent Rights included in the Biogen Technology.

         

        “Biogen Product-Specific Patents” means all Product-Specific Patents owned, used, developed by, or licensed to
          Biogen or its Affiliates, in each case to the extent Controlled by Biogen or its Affiliates on the Effective Date or at any time during the Agreement Term.

         

        “Biogen Program Know-How” has the meaning set forth in Section 7.1.2.

         

        “Biogen Program Patents” has the meaning set forth in Section 7.1.2.

         

        “Biogen Program Technology” has the meaning set forth in Section 7.1.2.

         

        “Biogen-Prosecuted Patents” has the meaning set forth in Section 7.2.4.

         

        “Biogen Reduced Participation and Information Obligations” means solely with respect to the [***] (a) Biogen may [***], (b) Biogen will [***], (c) Biogen
          may [***] and (d) Biogen’s obligation [***], other than (i) reports required by Section 5.2.2, Section 6.9.1 and Section 10.4.3 (if applicable) (ii) upon Ionis’ reasonable request, information to the extent required to
          confirm Biogen’s compliance with its obligations under Section 5.1 and (iii) as reasonably required to permit Ionis to perform its obligations under this Agreement. The Biogen Reduced Participation and Information Obligations will not
          limit or diminish the scope of any licenses granted by Biogen to Ionis under this Agreement.

         

        
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        “Biogen Reduced Royalty” has the meaning set forth in Section 6.6.2(c).

         

        “Biogen Results” has the meaning set forth in Section 4.8.5(a).

         

        “Biogen Supported Pass-Through Costs” means [***].

         

        “Biogen Technology” means the Biogen Program Technology, Jointly-Owned Program Technology, Biogen Product-Specific Patents and any trademarks described in
          Section 4.1.5, owned, used, developed by, or licensed to Biogen or its Affiliates that is necessary or useful to Develop, register, Manufacture or Commercialize a Product.

         

         “Breaching Party” means the Party that is believed by the Non-Breaching Party to be in material breach of this Agreement.

         

        “Business Day” means any day other than a Saturday or Sunday on which banking institutions in New York, New York are open for business.

         

        “[***]” means [***], or any alternative splice variants, mutants, polymorphisms and fragments thereof.

         

        “Calendar Quarter” means a period of three consecutive months ending on the last day of March, June, September, or December, respectively, and will also
          include the period beginning on the Effective Date and ending on the last day of the Calendar Quarter in which the Effective Date falls.

         

        “Calendar Year” means a year beginning on January 1 (or, with respect to 2012, the Effective Date) and ending on December 31.

         

        “Carryover Development Candidate” has the meaning set forth in Section 1.7.4.

         

        “cGMP” means current Good Manufacturing Practices as specified in the United States Code of Federal Regulations, ICH Guideline Q7A, or equivalent Laws,
          rules, or regulations of an applicable Regulatory Authority at the time of manufacture.

         

        “Change of Control” means, with respect to a Party, (a) a merger or consolidation of such Party with a Third Party which results in the voting securities
          of such Party outstanding immediately prior thereto ceasing to represent at least 50% of the combined voting power of the surviving entity immediately after such merger or consolidation, (b) a transaction or series of related transactions in
          which a Third Party, together with its Affiliates, becomes the owner of 50% or more of the combined voting power of the outstanding securities of such Party, (c) the sale or other transfer to a Third Party of all or substantially all of such
          Party’s business to which the subject matter of this Agreement relates, or (d) the stockholders or equity holders of such Party will approve a plan of complete liquidation of such Party or an agreement for the sale or disposition by such Party of
          all or a substantial portion of such Party’s assets, other than pursuant to the transaction as described above or to an Affiliate. Notwithstanding the foregoing, the sale or issuance of shares in exchange for cash for purposes of a bona fide financing will not constitute a Change of Control.

         

        “Claims” has the meaning set forth in Section 9.1.

         

        
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        “Clinical Study” or “Clinical Studies” means a Phase 1 Trial, Phase 2 Trial, Phase 3 Trial or
          Phase 4 Trial, or such other study in humans that is conducted in accordance with good clinical practices and is designed to generate data in support or maintenance of an NDA, MAA or other similar marketing application.

         

        “Clinical Supplies” means API
            and Finished Drug Product for use in a Clinical Study.

         

        “CMC” means chemistry, manufacturing and controls.

         

        “CMO”
            means a Third Party contract manufacturer Manufacturing API, Clinical Supplies or Finished Drug Product for any purpose under this Agreement.

         

        “Collaboration Divestiture Period” has the meaning set forth in Section 12.5.2(a)(ii).

         

        “Collaboration Program” has
            the meaning set forth in Section 1.2.

         

        “Collaboration Program Research Plan” has the meaning set forth in Section 1.5.1(b).

         

        “Collaboration Target” means a
            gene target designated as a Collaboration Target pursuant to Section 1.4.

         

        “Collaborator IP” has the
            meaning set forth in Section 7.1.3(b).

         

        “Collaborator License” has the meaning set forth in Section 7.1.3(c).

         

        “Commercialize,” “Commercialization” or “Commercializing”
          means any and all activities directed to marketing, promoting, detailing, distributing, importing, having imported, exporting, having exported, selling or offering to sell a Product following receipt of Approval for such Product in the applicable
          country, including conducting pre-and post-Approval activities, including studies reasonably required to increase the market potential of such Product and studies to provide improved formulation and Product delivery, and launching and promoting
          such Product in each country.

         

        “Commercializing Party” means (a) Biogen, with respect to a Product that is being Developed and Commercialized by or on behalf of Biogen, its Affiliates
          or Sublicensees hereunder, and (b) Ionis, with respect to a Discontinued Product that is being Developed and Commercialized by or on behalf of Ionis, its Affiliates or Sublicensees hereunder.

         

        “Commercially Reasonable Efforts” means the carrying out of discovery, research, development or commercialization activities using good-faith commercially
          reasonable and diligent efforts that the applicable Party would reasonably devote to a compound or product of similar market potential or profit potential at a similar stage in development or product life resulting from its own research efforts,
          based on conditions then prevailing and taking into account, without limitation, issues of safety and efficacy, Regulatory Authority-approved labeling, product profile, the competitiveness of alternative products in the marketplace, the likely
          timing of the product’s entry into the market, the patent and other proprietary position, the likelihood of Approval and other relevant scientific, technical and commercial factors. Without limiting any of the foregoing, Commercially Reasonable
          Efforts as it applies to Biogen’s Development or Commercialization of a Product hereunder includes the use of Commercially Reasonable Efforts to perform the “General Activities” described in Schedule 5.1.1, and Commercially Reasonable Efforts as it applies to Ionis’ Development of a Product hereunder includes use of Commercially Reasonable Efforts to adhere to the activities and
          timelines set forth in each Collaboration Program Research Plan and Development Plan.

         

        
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        “Communications Lead” has the meaning set forth in Section 11.4.1.

         

        “Competing Collaboration Acquirer” has the meaning set forth in Section 12.5.1.

         

        “Competing Development Activities” has the meaning set forth in Section 12.6.

         

        “Competitive Indication Product” means any product intended for use in the same indication as any Development Candidate or Product.

         

        “Competitive Indication Program” means any internal research program for which a budget has been established or to which research personnel have been
          assigned, with the goal of discovering and developing a Competitive Indication Product for which drug discovery activities have been initiated.

         

        “Competitive Infringement” has the meaning set forth in Section 7.5.1.

         

        “Competitive Product” means any ASO that is designed to bind to or directly modulate the RNA that encodes a High Interest
          Target or a Collaboration Target, other than a Product that is being pursued under this Agreement.

         

        “Competitive Program” means any internal research program for which a budget has been established or to which research personnel have been assigned, with
          the goal of discovering and developing a Competitive Product for which drug discovery activities have been initiated.

         

        “Complete,” “Completed,” or “Completion”
          means, with respect to a Clinical Study, the point in time at which the primary database lock for such study has occurred and, if such study has a statistical analysis plan, the data generated based on that primary database lock under the
          statistical analysis plan for such study are available.

         

        “Compound” means on a Collaboration Program-by-Collaboration Program basis, any ASO that is designed to bind to the RNA that encodes the applicable
          Collaboration Target, where such ASO is discovered by Ionis prior to or in the performance of the Collaboration Program Research Plan, including each Development Candidate under such Collaboration Program.

         

        “Confidential Information” has the meaning set forth in Section 11.1. “Confidential Information” does not
          include information that:

         

        	

              	(a)	
                was in the lawful knowledge and possession of the Receiving Party or its Affiliates prior to the time it was disclosed to, or learned by, the Receiving Party or its Affiliates, or was otherwise developed independently by the Receiving
                  Party or its Affiliates, as evidenced by written records kept in the ordinary course of business, or other documentary proof of actual use by the Receiving Party or its Affiliates;

              


         

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

              


         

        	

              	(c)	
                became generally available to the public or otherwise part of the public domain after its disclosure and other than through any act or omission of the Receiving Party or its Affiliates in breach of this Agreement; or

              


         

        	

              	(d)	
                was disclosed to the Receiving Party or its Affiliates, other than under an obligation of confidentiality, by a Third Party who had no obligation to the Disclosing Party or its Affiliates not to disclose such information to others.

              


         

        “Conflicting Patent Right” has the meaning set forth in Section 7.2.4(d).

         

        “Control” or “Controlled” means possession of the ability to grant a license or sublicense
          hereunder without violating the terms of any agreement with any Third Party; provided, however, that if a Party has a right to grant a license or sublicense, with
          respect to an item of intellectual property to the other Party only upon payment of compensation (including milestones or royalties) to a Third Party (“Third Party Compensation”) (other
          than Ionis Supported Pass-Through Costs in the case of Ionis, and other than Biogen Supported Pass-Through Costs in the case of Biogen), then the first Party will be deemed to have “Control” of the
          relevant item of intellectual property only if the other Party agrees to bear the cost of such Third Party Compensation. Notwithstanding anything to the contrary under this Agreement, with respect to any Third Party that becomes an Affiliate of a
          Party after the Effective Date (including a Third Party acquirer), no intellectual property of such Third Party will be included in the licenses granted hereunder by virtue of such Third Party becoming an Affiliate of such Party.

         

        “Cost Estimate” has the meaning set forth in Section 1.5.2(b).

         

        “Cover,” “Covered” or “Covering”
          means, with respect to a patent, that, but for rights granted to a Person under such patent, the act of making, using or selling by such Person would infringe a Valid Claim included in such patent, or in the case of a patent that is a patent
          application, would infringe a Valid Claim in such patent application if it were to issue as a patent.

         

        “CTD” has the meaning set forth in Section 4.6.

         

        “Deficiency Notice” has the meaning set forth in Section 3.1.2.

         

        “Develop,” “Developing” or “Development”
          means with respect to a Product, any and all discovery, characterization, or preclinical (including IND-Enabling Toxicology Studies), clinical, or regulatory activity with respect to the Product to seek Approval (including the submission of all
          necessary filings with applicable Regulatory Authorities to support such preclinical and clinical activities and Approval), including human clinical trials conducted after Approval of the Product to seek Approval for additional indications for
          the Product.

         

        
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        “Development Candidate” means a Compound that is reasonably determined by Ionis’ RMC in accordance with Ionis’ standard procedures for designating
          development candidates [***] as ready to start IND-Enabling Toxicology Studies. The checklist Ionis uses as of the Effective Date when reviewing potential development candidates for approval is attached hereto as Appendix 2.

         

        “Development Candidate Data Package” means, with respect to a [***], the [***]; provided that such package
          contains the [***]. The checklist Ionis uses as of the Effective Date when reviewing potential development candidates for approval is attached hereto as Appendix 2.

         

        “Development Plan” has the meaning set forth in Section 1.5.2(a).

         

        “Diagnostic Option” has the meaning set forth in Section 3.2.1.

         

        “Disclosing Party” has the meaning set forth in Section 11.1.

         

        “Discontinued Product” means a Product that is the subject of a termination under this Agreement.

         

        “Dispositive Disagreement Condition” has the meaning set forth in Section 1.3.2.

         

        “Dispute” means any dispute arising between the Parties relating to, arising out of or in any way connected with this Agreement or any term or condition
          hereof, or the performance by either Party of its obligations hereunder, whether before or after termination of this Agreement that cannot be resolved by the Parties.

         

        “DMPK Agreement” means the DMPK Research, Development, Option and License Agreement between the Parties dated June 27, 2012, as amended and/or restated
          from time to time.

         

        “DOJ” has the meaning set forth in Section 3.1.4(a).

         

        “Drug Development Program” means the aggregate drug development activities related to each Development Candidate through [***] under a Collaboration
          Program in accordance with the applicable Development Plan for all Collaboration Programs under this Agreement.

         

        “Drug Discovery Program” means the aggregate drug discovery activities including drug screening, identification, characterization, optimization and other
          necessary activities according to the applicable Collaboration Program Research Plans to achieve Target Sanction status, and then identify a Development Candidate for all Collaboration Programs under this Agreement.

         

        “Drug Discovery Term” has the meaning set forth in Section 1.7.1.

         

        “Effective Date” has the meaning set forth in the Recitals of this Agreement.

         

        “EMA” means the European Medicines Agency and any successor entity thereto.

         

        
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        “Enabled Core Program Patents” means Program Patents Controlled by a Party or any of its Affiliates on the Effective Date or during the Agreement Term
          claiming (a) methods of dosing (frequency, duration, concentration, volume, etc.) generally applicable to Oligonucleotides to achieve optimal tissue distribution or enhance other properties of an Oligonucleotide; (b) methods of determining an
          effective human dose based on animal data that are generally applicable to Oligonucleotides; (c) methods of determining an effective dose based on actual or modeled pharmacokinetic data generally applicable to Oligonucleotides; (d) methods of
          identifying or optimizing predictive biomarkers for diseases; (e) observations about a disease based on data from a natural history study; (f) proprietary disease models; or (g) methods of using radio-labeled ligands with Oligonucleotides in
          animals.

         

        “Estimated Lock Date” has the meaning set forth in Section 3.1.1.

         

        “Estimated Biogen-Approved Costs” means Ionis’ good faith estimate of the Biogen-Approved Costs it will incur during the applicable Measurement Period.

         

        “European Union” or “EU” means each and every country or territory that is officially part of
          the European Union.

         

        “Excluded Payments” means (a) royalty or profit sharing payments, or any other type of payment based on periodic sales of a Product; (b) payments made in
          consideration of Ionis’ or Ionis’ Affiliate’s equity or debt securities at fair market value; (c) payments made to pay for or reimburse Ionis or Ionis’ Affiliate for the fully-burdened cost of research and development; (d) payments made to pay
          for or reimburse Ionis or Ionis’ Affiliate for the cost of prosecuting, maintaining or defending Patent Rights; and (e) payments made to Ionis or Ionis’ Affiliate to pass-through to a Third Party in satisfaction of a payment obligation Ionis or
          Ionis’ Affiliate has to such Third Party.

         

        “Executives” has the meaning set forth in Section 12.1.1.

         

        “FDA” means the United States Food and Drug Administration and any successor entity thereto.

         

        “Field” means, except as may be limited under Section 4.1.4, any prophylactic or therapeutic use or form of administration for any indication.

         

        “Finished Drug Product” means any drug product containing API as an active ingredient in finished bulk form for the Development or Commercialization by a
          Party under this Agreement.

         

        “First Commercial Sale” means with respect to a Product, the first sale of such Product by Biogen, its Affiliate or its Sublicensee to a Third Party in a
          particular country after Approval of the Product has been obtained in such country.

         

        “Follow-On Agreement” has the meaning set forth in Section 2.1.2.

         

        “Follow-On Compound” means, with respect to a given Compound for a given Collaboration Target, any ASO (other than the Development Candidate for such
          Collaboration Target) that is designed to bind to the RNA that encodes such Collaboration Target discovered by or on behalf of Ionis following the License Effective Date for the applicable Collaboration
          Program.

         

        “Follow-On Interest Notice” has the meaning set forth in Section 2.1.2(a).

         

        
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        “Follow-On Negotiation Notice”
            has the meaning set forth in Section 2.1.2.

         

        “FTC” has the meaning set forth in Section 3.1.4(a).

         

        “FTE” means a total of 47 weeks or 1880 hours per year of work on the Development, Manufacturing or Commercialization of a Product carried out by
          employees of a Party having the appropriate relevant expertise to conduct such activities.

         

        “FTE Costs” has the meaning set forth in Section 1.8.

         

        “FTE Rate” means $[***] for the Calendar Year 2012. The FTE Rate will be increased each Calendar Year thereafter by the [***].

         

        “Full Royalty Period” has the meaning set forth in Section 6.6.2(a).

         

        “Fully Absorbed Cost of Goods” means the costs incurred by Ionis as determined using the methodology set forth in Schedule







              4.6.3 fairly applied and as employed on a consistent basis throughout Ionis’ operations.

         

        “Gene-Editing Product” means an Oligonucleotide that, when introduced into a cell of an organism, (a) is stably integrated within the genome or stable
          episome of the cell of such organism or (b) causes (or is perceived to cause) a permanent change in the genome of the cell of such organism.

         

        “Generic Product” means, with respect to a particular Product, one or more Third Party product(s) (a) having the
          same active pharmaceutical ingredient as such Product and for which in the U.S. an ANDA has been filed naming such Product as the reference listed drug or outside of the U.S., an equivalent process where bioequivalence to such Product has been
          asserted, and (b) such Third Party product(s) when taken in the aggregate have a market share (measured in number of prescriptions with the numerator of such fractional share being such Third Party product(s) taken in the aggregate, and the
          denominator being the total of such Third Party product(s) taken in the aggregate plus such Product taken in the aggregate, as provided by IMS) during the applicable Calendar Quarter in such country of at least [***]%.

         

        “GLP” means the then-current good laboratory practice standards promulgated or endorsed by the FDA as defined in 21 C.F.R. Part 58, and comparable foreign
          regulatory standards.

         

        “High Interest Target” has the meaning set forth in Section 1.3.1.  For clarity, at any given time, if a gene target is not on the High Interest Target List at such time, then
          such gene target is not a High Interest Target.

         

        “High Interest Target Development Candidate” means an ASO that is discovered by or on behalf of Ionis and designed to bind to the RNA that encodes a High Interest Target that is
          reasonably determined by Ionis’ RMC to be a development candidate in accordance with Ionis’ standard procedures for designating development candidates.

         

        “High Interest Target List” has the meaning set forth in Section 1.3.1.

         

        
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        “HSR Act” means the Hart-Scott-Rodino Antitrust Improvements Act of 1976, as amended, and the rules and regulations promulgated thereunder.

         

        “HSR Clearance” means all applicable waiting periods under the HSR Act with respect to the transactions contemplated under this Agreement have expired or
          have been terminated.

         

        “HSR Clearance Date” means the earliest date on which the Parties have actual knowledge that all applicable waiting periods under the HSR Act with respect to the transactions
          contemplated under this Agreement have expired or have been terminated.

         

        “HSR Filing” means filings by Biogen and Ionis with the United States Federal Trade Commission and the Antitrust Division of the United States Department
          of Justice of a Notification and Report Form for Certain Mergers and Acquisitions (as that term is defined in the HSR Act) with respect to the matters set forth in this Agreement, together with all required documentary attachments thereto.

         

        “HSR Termination Royalty” has the meaning set forth in Section 10.2.3(b)(ii).

         

        “Incremental Tax Cost” has the meaning set forth in Section 12.4.

         

        “IND” means an Investigational New Drug Application (as defined in the Food, Drug and Cosmetic Act, as amended) filed with the FDA or its foreign
          counterparts.

         

        “IND-Enabling Toxicology Studies” means the pharmacokinetic and toxicology studies required to meet the requirements for filing an IND.

         

        “Indemnitee” has the meaning set forth in Section 9.3.

         

        “Initiation” or “Initiate” means, with respect to any IND-Enabling Toxicology Study, dosing of
          the first animal subject in such IND-Enabling Toxicology Study and, with respect to any Clinical Study, dosing of the first human subject in such Clinical Study.

         

        “Integrated Development Plan” or “IDP” has the meaning set forth in Section 5.1.2.

         

        “Ionis” has the meaning set forth in the Preamble of this Agreement.

         

        “Ionis Attribution Language” has the meaning set forth in Section 11.4.11.

         

        “Ionis/Biogen Additional Agreement” means (a) each of the Ionis/Biogen Preexisting Development Agreements, (b) the Neurology II Agreement, (c) the Research Collaboration, Option and License
            Agreement between the Parties dated December 19, 2017, and (d) the New Strategic Neurology Drug Discovery and Development Collaboration, Option and License Agreement between the Parties dated April 19, 2018, in each case ((a)-(d)), as amended
            or restated from time to time.

         

        “Ionis/Biogen Preexisting Development Agreements” means the SMN Agreement and the DMPK Agreement.

         

        
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        “Ionis Breach Event” has the meaning set forth in Section 10.4.4(a).

         

        “Ionis Core Technology Patents” means all Patent Rights owned, used, developed by, or licensed to Ionis or its Affiliates, in each case to the extent
          Controlled by Ionis or its Affiliates on the Effective Date or at any time during the Agreement Term, claiming subject matter generally applicable to ASOs, other than Ionis Product-Specific Patents or Ionis Manufacturing and Analytical Patents. A list of Ionis Core Technology Patents as of the Effective Date is set forth on Schedule 8.2.4(a) attached hereto.

         

        “Ionis In-License Agreements” has the meaning set forth in Section 6.8.1(a).

         

        “Ionis Internal ASO Safety Database” has the meaning set forth in Section 5.2.2.

         

        “Ionis Know-How” means any Know-How, including any Jointly-Owned Program Know-How and Ionis Program Know-How, owned, used, developed by, or licensed to
          Ionis or its Affiliates, in each case to the extent Controlled by Ionis or its Affiliates on the Effective Date or at any time during the Agreement Term. Ionis Know-How does not include the Ionis Manufacturing and Analytical Know-How.

         

        “Ionis Manufacturing and Analytical Know-How” means Know-How, including Jointly-Owned Program Know-How, that relates to the synthesis or analysis of a
          Product regardless of sequence or chemical modification, owned, used, developed by, or licensed to Ionis or its Affiliates, in each case to the extent Controlled by Ionis or its Affiliates on the Effective Date or at any time during the Agreement
          Term. Ionis Manufacturing and Analytical Know-How does not include the Ionis Know-How.

         

        “Ionis Manufacturing and Analytical Patents” means Patent Rights, including Jointly-Owned Program Patents, that claim methods and materials used in the
          synthesis or analysis of a Product regardless of sequence or chemical modification, owned, used, developed by, or licensed to Ionis or its Affiliates, in each case to the extent Controlled by Ionis or its Affiliates on the Effective Date or at
          any time during the Agreement Term. A list of Ionis Manufacturing and Analytical Patents as of the Effective Date is set
            forth on Schedule 8.2.4(b) attached hereto. Ionis Manufacturing and
          Analytical Patents do not include the Ionis Product-Specific Patents or the Ionis Core Technology Patents.

         

        “Ionis Platform Technology” has the meaning set forth in Section 8.2.4.

         

        “Ionis Product-Specific Patents” means all Product-Specific Patents, in each case to the extent Controlled by
          Ionis or its Affiliates on the Effective Date or at any time during the Agreement Term. A list of Ionis Product-Specific Patents as of the Effective Date is set forth on Schedule 8.2.4(c) attached
            hereto.

         

        “Ionis Program Know-How” has the meaning set forth in Section 7.1.2.

         

        “Ionis Program Patents” has the meaning set forth in Section 7.1.2.

         

        “Ionis Program Technology” has the meaning set forth in Section 7.1.2.

         

        
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        “Ionis Results” has the meaning set forth in Section 4.8.5(a).

         

        “Ionis Supported Pass-Through Costs” means [***].

         

        “Japan NDA” or “JNDA” means the Japanese equivalent of an NDA







          filed with the Koseisho (i.e., the Japanese Ministry of Health and Welfare, or any successor agency thereto).

         

        “JNDA Approval” means the Approval of a JNDA by the Koseisho (i.e., the Japanese Ministry of Health and Welfare, or any successor agency thereto) for the applicable Product in Japan.

         

        “Joint Patent Committee” or “JPC” has the meaning set forth in Section 7.1.3(a).

         

        “Jointly-Owned Program Know-How” has the meaning set forth in Section 7.1.2.

         

        “Jointly-Owned Program Patents” has the meaning set forth in Section 7.1.2.

         

        “Jointly-Owned Program Technology” has the meaning set forth in Section 7.1.2.

         

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

         

        “Lead Party” has the meaning set forth in Section 7.4.1.

         

        “License Effective Date” means, on an Option-by-Option and Collaboration Program-by-Collaboration Program basis, the date on which Biogen notifies Ionis
          in writing that it wishes to exercise the Option and pays to Ionis the applicable license fee set forth in Section 6.3 (in the event Biogen wishes to exercise its Option for a Collaboration Program).

         

        “Licensed Know-How” means Ionis Manufacturing and Analytical Know-How, and Ionis Know-How. For clarity, Licensed Know-How does not include any Know-How
          covering formulation technology or delivery devices.

         

        “Licensed Patents” means the Ionis Product-Specific Patents, Ionis Core Technology Patents, Ionis Manufacturing and Analytical Patents and Ionis’ interest
          in Jointly-Owned Program Patents. For clarity, Licensed Patents do not include any Patent Rights claiming formulation technology or delivery devices unless such Patent Rights are included in the Jointly-Owned Program Patents.

         

        “Licensed Technology” means, on a Product-by-Product basis, any and all Licensed Patents, Licensed Know-How, and any trademarks described in Section
            4.1.5, to the extent necessary or useful to Develop, register, Manufacture or Commercialize such Product.  Licensed Technology does not include any technology in-licensed by Ionis from [***] under the [***].

         

        “Losses” has the meaning set forth in Section 9.1.

         

        
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        “MAA”
            means, with respect to a particular Product, a marketing authorization application filed with the EMA or other European Regulatory Authority after completion of Clinical Studies to obtain Approval for such Product under the centralized
              European filing procedure or, if the centralized EMA filing procedure is not used, filed using the applicable procedures in any European Union country or
              other country in Europe.

         

        “MAA Approval” means, with respect to a particular Product, the
          Approval of an MAA by the EMA for such Product in any European Union country or other country in Europe.

         

        “Major Market” means any of the following countries: the United States, Japan, the United Kingdom, Germany, France, Italy and Spain.

         

        “Manufacture” or “Manufactured” or “Manufacturing”
          means any activity involved in or relating to the manufacturing, quality control testing (including in-process, release and stability testing), releasing or packaging, for pre-clinical and clinical purposes, of API or a Product in finished form.

         

        “Manufacturing Process Development Terms” means Section 4.1.2(c)(ii), Section 4.3.1(a), Section 4.3.1(c), Section 4.4, Section 4.5, Section
            4.7.2 and Section 4.8.5 of this Agreement.

         

        “Measurement Period” has the meaning set forth in Section 1.8.3 or Section 1.8.4, as applicable.

         

        “Milestone Event” means a Pre-Licensing Milestone Event or a Post-Licensing Milestone Event, as the case may be.

         

        “Minimum Third Party Payments” means [***].

         

        “NDA” means a New Drug Application filed with the
            FDA after completion of Clinical Studies to obtain Approval for a Product in the United States.

         

        “NDA Approval” means the Approval of an NDA by the FDA for a Product in the U.S.

         

        “Negotiation Period” has the
            meaning set forth in Section 2.1.2.

         

        “Net Sales” means the gross amount billed or invoiced on sales of a Product by Biogen, its Affiliates and Sublicensees, less the following:

         

        (a)             customary trade, quantity, or cash discounts to non-affiliated brokers
          or agents to the extent actually allowed and taken;

         

        (b)             amounts repaid or credited by reason of rejection or return;

         

        (c)           to the extent separately stated on purchase orders, invoices, or other documents of sale,
          any taxes or other governmental charges levied on the production, sale, transportation, delivery, or use of such Product which is paid by or on behalf of Biogen; and

         

        
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        (d)             outbound transportation costs prepaid or allowed and costs of insurance in transit.

         

        In any transfers of a Product between Biogen, its Affiliates and Sublicensees, Net Sales are calculated based on the final sale of such Product to an independent Third Party.  If
          Biogen, its Affilate or a Sublicensee receives non-monetary consideration for a Product, Net Sales are calculated based on the fair market value of that consideration.  If Biogen, its Affiliates or Sublicensees uses or disposes of a Product in
          the provision of a commercial service, the Product is sold and the Net Sales are calculated based on the sales price of the Product to an independent Third Party during the same royalty period or, in the absence of sales, on the fair market value
          of the Product as determined by the Parties in good faith. Net Sales shall not include any transfers of supplies of the applicable Product for (i) use in clinical trials, pre-clinical studies or other research or development activities, or (ii) a
          bona fide charitable purpose, or (iii) a commercially reasonable sampling program.

         

        With respect to Net Sales as it applies to royalties payable by Ionis, the Parties agree that any reasonable definition of “net sales” that is (x) customarily used in pharmaceutical industry technology licensing or collaboration contracts and
          (y) consistent with GAAP or International Financial Reporting Standards and is subsequently agreed to by Ionis (or a Third Party acquirer or assignee) and Ionis’ Sublicensee or commercialization partner in an arms-length transaction under a
          particular sublicense or commercialization agreement will replace the definition of Net Sales in this Agreement and will be used in calculating the royalty payment to Biogen on sales of products sold pursuant to such agreement. If Ionis uses such
          an alternate definition of “net sales” in a particular sublicense, (A) Ionis will include such “net sales” definition in the applicable royalty reports to assist Biogen with verifying royalty payments and (B) if such definition is not consistent
          with GAAP or International Financial Reporting Standards, upon Biogen’s request, Ionis will reconcile the royalties calculated under such definition with GAAP or International Financial Reporting Standards.

         

        “Neurology II Agreement” means the Second Amended and Restated Strategic Neurology Drug Discovery and Development Collaboration, Option and License Agreement between the Parties
            dated October 17, 2018.

         

        “Neurology JSC” has the meaning set forth in Section 1.11.1.

         

        “New Third Party Licenses” has the meaning set forth in Section 8.3.2.

         

        “Non-Breaching Party” means the Party that believes the Breaching Party is in material breach of this Agreement.

         

        “[***] Indications” means therapeutic uses that are not designed to treat [***] diseases or [***] diseases.

         

        “Oligonucleotide” means a synthetic compound that comprises or consists of at least five linked nucleosides (including any analog, variant, mimic, or
          mimetic thereof). For clarity, the [***] of Oligonucleotides [***].  Oligonucleotides [***].  Oligonucleotides may be single-stranded or multi-stranded.

         

        
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        “Option” has the meaning set forth in Section 3.1.3.

         

        “Option Acceleration Deadline” has the meaning set forth in Section 1.5.2(d).

         

        “Option Acceleration Notice” has the meaning set forth in Section 1.5.2(d).

         

        “Option Deadline” has the meaning set forth in Section 3.1.3.

         

        “Option Period” means, with respect to a Collaboration Program, the period beginning on the Effective Date and ending on the expiration or earlier
          termination of the Option with respect to such Collaboration Program.

         

        “Original Agreement” has the meaning set forth in the Recitals of this Agreement.

         

        “Panel Decision” has the meaning set forth in Section 10.4.4(b).

         

        “Party” or “Parties” means Biogen and Ionis individually or collectively.

         

        “Patent Costs” means the reasonable fees and expenses paid to outside legal counsel, and filing, maintenance and other reasonable out-of-pocket expenses
          paid to Third Parties, incurred in connection with the Prosecution and Maintenance of Patent Rights.

         

        “Patent Rights” means (a) patents, patent applications and similar government-issued rights protecting inventions in any country or jurisdiction however
          denominated, (b) all priority applications, divisionals, continuations, substitutions, continuations-in-part of and similar applications claiming priority to any of the foregoing, and (c) all patents and similar government-issued rights
          protecting inventions issuing on any of the foregoing applications, together with all registrations, reissues, renewals, re-examinations, confirmations, supplementary protection certificates, and extensions of any of (a), (b) or (c).

         

        “Permitted Licenses” means (a) licenses granted by Ionis before or after the Effective Date to any Third Party under the Ionis Core Technology Patents,
          the Ionis Manufacturing and Analytical Patents, or the Ionis Manufacturing and Analytical Know-How (but not under the Ionis Product-Specific Patents) to (i) use Oligonucleotides (or supply Oligonucleotides to end users) solely to conduct
          pre-clinical research, or (ii) enable such Third Party to manufacture or formulate Oligonucleotides, where (A) such Third Party is primarily engaged in providing contract manufacturing or services and is not primarily engaged in drug discovery,
          development or commercialization of therapeutics; and (B) Ionis does not assist such Third Party to identify, discover or make a Compound or Product; and (b) material transfer agreements with academic collaborators or non-profit institutions
          solely to conduct noncommercial research.

         

        “Person” will 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.

         

        “Pharmacovigilance Agreement” has the meaning set forth in Section 5.2.1.

         

        
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        “Phase 1 Trial” means the first clinical study in human beings Initiated by Ionis under the applicable Development Plan pursuant to an IND that has been
          filed with a Regulatory Authority in a Major Market or Canada. If Biogen exercises the Option before Ionis Initiates such a Phase 1 Trial, then the definition of “Phase 1 Trial” means the first clinical
          study of the applicable Development Candidate in human beings Initiated by Biogen, its Affiliate or its Sublicensee.

         

        “Phase 1 Trial Design” means, with respect to a Collaboration Program, the Phase 1 Trial design set forth in the applicable Development Plan, which may be
          amended from time to time during the Agreement Term as mutually agreed in writing by the Parties (in consultation with the Neurology JSC).

         

        “Phase 2 Trial” means, with respect to a Product, a Clinical Study that is intended to explore the feasibility, safety, dose ranging or efficacy of such
          Product, that is prospectively designed to generate sufficient data (if successful) to commence a Phase 3 Trial (or foreign equivalent) of such Product, as further defined in 21 C.F.R. 312.21(b) or the corresponding regulation in jurisdictions
          other than the United States.

         

        “Phase 3 Trial” means, with respect to a Product, a pivotal Clinical Study in humans performed to gain evidence with statistical significance of the
          efficacy of such Product in a target population, and to obtain expanded evidence of safety for such Product that is needed to evaluate the overall benefit-risk relationship of such Product, to form the basis for approval of an NDA by a Regulatory
          Authority and to provide an adequate basis for physician labeling, as described in 21 C.F.R. 312.21(c), as amended from time to time, or the corresponding regulation in jurisdictions other than the United States.

         

        “Phase 4 Trial” means, with respect to a Product, (a) any Clinical Study conducted to satisfy a requirement of a Regulatory Authority in order to maintain
          a Regulatory Approval for such Product or (b) any Clinical Study conducted after the first Regulatory Approval in the same disease state for which such Product received Regulatory Approval other than for purposes of obtaining Regulatory Approval.

         

        “PoC Data Package” means, with respect to a Product, [***], (d) copies of all filings submitted to Regulatory Authorities regarding such Product, (e) a
          summary of the patent status relating to such Product, and (f) a summary of any Third Party Obligations Ionis believes relate to the Product.

         

        “PoC Trial” means, with respect to a Collaboration Program, the first phase 2a Clinical Study in human patients with a pharmacokinetic or target reduction
          endpoint or other therapeutic or physiological endpoint.

         

        “PoC Trial Completion Notice” has the meaning set forth in Section 3.1.2.

         

        “PoC Trial Design” means the PoC Trial design set forth in each Development Plan, which may be amended from time to time during the Agreement Term as
          mutually agreed in writing by the Parties (in consultation with the Neurology JSC).

         

        “Post-Licensing Milestone Event” has the meaning set forth in Section 6.4.

         

        
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        “Pre-Clinical Studies” means in vitro and in vivo studies of a
          Product, not in humans, including those studies conducted in whole animals and other test systems, designed to determine the toxicity, bioavailability, and pharmacokinetics of such Product and whether such Product has a desired effect.

         

        “Pre-Existing Competitive Product” has the meaning set forth in Section 12.5.1.

         

        “Pre-Existing Competitive Program” has the meaning set forth in Section 12.5.1.

         

        “Pre-Licensing Milestone Event” has the meaning set forth in Section 6.2.

         

        “Prior Agreements” means the agreements listed on Schedule 8.2.8 attached
          hereto.

         

        “Proceeding” means an action, suit or proceeding.

         

        “Product” means, on a Collaboration Program-by-Collaboration Program basis, a finished drug product containing a Compound as an active pharmaceutical
          ingredient.

         

        “Product-Specific Patents” means Patent Rights Controlled by a Party or any of its Affiliates on or after the Effective Date, including any Program
          Patents, claiming (a) the specific composition of matter of a Product, or (b) methods of using a Product as a prophylactic
            or therapeutic; provided, however, that Patent Rights Controlled by Ionis







          or any of its Affiliates that (i) include claims that are directed to subject matter applicable to ASOs in general, or (ii) include an ASO, the sequence of which targets the RNA that encodes a Collaboration Target and the RNA of a gene that does not encode a Collaboration Target,
            will not be considered Product-Specific Patents, and in the case of (i) and (ii), such Patent Rights will be considered Ionis Core Technology Patents.

         

        “Program Patents” has the meaning set forth in Section 7.1.2.

         

        “Prosecution and Maintenance” or “Prosecute and Maintain” means, with regard to a Patent
          Right, the preparing, filing, prosecuting and maintenance of such Patent Right, as well as handling re-examinations, reissues, and requests for patent term extensions with respect to such Patent Right, together with the conduct of interferences,
          the defense of oppositions and other similar proceedings with respect to the particular Patent Right. For clarification, “Prosecution and Maintenance” or “Prosecute and Maintain” will not include any other enforcement actions taken with respect to a Patent Right.

         

        “Receiving Party” has the
            meaning set forth in Section 11.1.

         

        “Reduced Royalty Period” has the meaning set forth in Section 6.6.2(e).

         

        “Regulatory Approval” means the approval necessary for the commercial manufacture, distribution, marketing, promotion, offer for sale, use, import,
          export, and sale of a pharmaceutical product in a jurisdiction regulated by a Regulatory Authority.

         

        “Regulatory Authority” means any governmental authority, including the FDA, EMA or Koseisho (i.e., the
          Japanese Ministry of Health and Welfare, or any successor agency thereto), that has responsibility for granting any licenses or approvals or granting pricing or reimbursement approvals necessary for the marketing and sale of a Product in any
          country.

         

        
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        “Regulatory Materials” means, with respect to a Product, any regulatory submissions, notifications, registrations, approvals and/or other filings and
          correspondence made to or with a Regulatory Authority in any country or jurisdiction, and any other records required by Applicable Law to be maintained that may be necessary or useful to develop, manufacture, market, sell or otherwise
          commercialize such Product in any such country or jurisdiction.

         

        “Replacement Limit” has the meaning set forth in Section 1.3.3.

         

        “Research” means conducting the research activities with Compounds as set forth in each Collaboration Program Research Plan, including pre-clinical
          research and lead optimization, but specifically excluding Development and Commercialization. When used as a verb, “Researching” means to engage in Research.

         

        “Results” has the meaning set forth in Section 4.8.5(a).

         

        “Reverse Royalties” has the meaning set forth in Section 6.7.1.

         

        “RMC” means Ionis’ Research Management Committee, or any successor committee.

         

        “ROFN Period” has the meaning set forth in Section 2.1.2.

         

        “ROFN Termination Event” has
            the meaning set forth in Section 2.1.2.

         

        “Royalty Quotient” has the meaning set forth in Section 6.6.2(c).

         

        “Service Provider” means the Third Party(ies) conducting the original and revised studies under the applicable Development Plan.

         

        “Setoff Amount” has the meaning set forth in Section 10.4.4(b).

         

        “Setoff Dispute” has the meaning set forth in Section 10.4.4(b).

         

        “Setoff Dispute Notice” has the meaning set forth in Section 10.4.4(b).

         

        “SMN Agreement” means the Development, Option and License Agreement between the Parties dated January 3, 2012, as amended and/or restated from time to
          time.

         

        “Specific Performance Milestone Event” has the meaning set forth in Section 5.1.1.

         

        “Step-In Party” has the meaning set forth in Section 7.4.1.

         

        “Sublicensee” means a Third Party to whom a Party or its Affiliates or Sublicensees has granted a sublicense or license under any Licensed Technology or
          Biogen Technology, as the case may be, licensed to such Party in accordance with the terms of this Agreement.

         

        
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        “Subsequent Deal” has the meaning set forth in Section 10.2.3(b)(i).

         

        “Substitution Limit” has the meaning set forth in Section 1.4.2.

         

        “Superior Patent Right” has the meaning set forth in Section 7.2.4(d).

         

        “Target Related Biogen Program Claim” has the meaning set forth in Section 4.3.3(a).

         

        “Target Related Ionis Program Claim” has the meaning set forth in Section 4.3.2(a).

         

        “Target Sanction” means when the therapeutic potential of a Collaboration Target has been demonstrated in pre-clinical disease models and such
          Collaboration Target has received approval by Ionis’ RMC to expend resources to identify a human Development Candidate, all in accordance with Ionis’ standard processes.

         

        “[***]” means the [***].

         

        “[***] Letter” means that certain [***].

         

        “Third Party” means a Person or entity other than the Parties or their respective Affiliates.

         

        “Third Party Obligations” means any financial and non-financial encumbrances, obligations, restrictions, or limitations imposed by an agreement between
          Ionis and a Third Party (including the Ionis In-License Agreements) that relate to a Product or a Collaboration Target, including field or territory restrictions, covenants, milestone payments, diligence obligations, sublicense revenue,
          royalties, or other payments.

         

        “Transition Services” has the meaning set forth in Section 10.4.5(b).

         

        “Trial Court” has the meaning set forth in Section 10.4.4(b).

         

        “Trial Master File” has the meaning set forth in Section 4.8.4.

         

        “Trial Master File Deficiency Notice” has the meaning set forth in Section 4.8.4.

         

        “United States” or “U.S.” means the fifty states of the United States of America and all of
          its territories and possessions and the District of Columbia.

         

        “Valid Claim” means a claim (a) of any issued, unexpired United States or foreign Patent Right, which will not, in the country of issuance, have been
          donated to the public, disclaimed, nor held invalid or unenforceable by a court of competent jurisdiction in an unappealed or unappealable decision, or (b) of any United States or foreign patent application within a Patent Right, which will not,
          in the country in question, have been cancelled, withdrawn, abandoned nor been pending for more than seven years, not including in calculating such seven-year period of time in which such application is in interference or opposition or similar
          proceedings or time in which a decision of an examiner is being appealed. Notwithstanding the foregoing, on a country-by-country basis, a patent application pending for more than seven years will not be considered to have any Valid Claim for
          purposes of this Agreement unless and until a patent meeting the criteria set forth in clause (a) above with respect to such application issues.

         

        
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        Appendix 2

         

        Development Candidate Checklist

         

        [***]

         

        

        
          120

          
            


        

         
          	


        

         

          

        Appendix 3

         

        Form of Side Letter

         

        	
                [Date]

              
	 
	
                Ionis Pharmaceuticals, Inc.

              
	
                2855 Gazelle Court

              
	
                Carlsbad, CA 92010

              
	
                Attention:  Chief Executive Officer

              
	
                E-mail: [***]

              


        

        

        Re:  Establishment of Cost Estimates and Milestone Payments

         

        Dear [Chief Executive Officer]:

         

        Reference is hereby made to that certain Amended and Restated Neurology Drug Discovery and Development Collaboration, Option and License Agreement by and between Ionis and Biogen dated _________
          ___, [2020] (the “Neurology I Agreement”), as supplemented and/or amended to date.  Any capitalized terms not defined herein will have the meaning set forth in the Neurology I Agreement.

         

        This letter memorializes the Cost Estimates and corresponding milestone payments set forth on the exhibit attached hereto as Exhibit A for the Collaboration Program and Development
          Candidate specified on Exhibit A, which Cost Estimates and corresponding milestone payments have been agreed by the Neurology JSC in accordance with Section 1.5.2(b) of the Neurology I Agreement. Exhibit A hereto
          supersedes and replaces any previously approved Cost Estimates and corresponding milestone payments for the Collaboration Program and Development Candidate set forth on Exhibit A.

         

        Please indicate your concurrence with the accuracy of Exhibit A as agreed to by the Neurology JSC by executing a copy of this letter and returning it to Biogen. This letter may be
          executed in counterparts, each of which will be deemed an original, notwithstanding variations in format or file designation which may result from electronic transmission, store and printing of copies of this letter from separate computers or
          printers.  Facsimile signatures and signatures transmitted via electronic mail in PDF format will be treated as original signatures.

        

        

        [The remainder of this page is intentionally left blank.]

         

        

        
          
            225 Binney Street, Cambridge, MA 02142 • Phone 781-464-2000 • www.biogen.com

          

          
            


        

        	 	
                Sincerely,

              
	 	 
	 	
                [VP of Corporate Development]

              
	 	
                Vice President, Corporate Development

              
	 	
                Biogen MA Inc.

              


        

        

        	
                CONFIRMED ON BEHALF OF IONIS PHARMACEUTICALS, INC.:

              
	 
	
                By:

              
	 
	
                Name:

              
	 
	
                Title:

              
	 
	
                Date:

              


         

        	
                Cc:

              	
                Ionis Pharmaceuticals, Inc.

              
	 	
                2855 Gazelle Court

              
	 	
                Carlsbad, CA 92010

              
	 	
                Attention:  General Counsel

              
	 	
                Email: [***]

              


        

        

        
          
            225 Binney Street, Cambridge, MA 02142 • Phone 781-464-2000 • www.biogen.com

          

          
            


        

        Exhibit A

         

        	
                Collaboration Program:

              	

              	 


        

        

        	
                Development Candidate:

              	

              	 


        

        

        [***]

         

            

        
          
            


        

        
          	


        

        

        

        	
                [Date]

              
	 
	
                Ionis Pharmaceuticals, Inc.

              
	
                2855 Gazelle Court

              
	
                Carlsbad, CA 92010

              
	
                Attention:  Chief Executive Officer

              
	
                E-mail: [***]

              


        

        

        Re:  Establishment of Biogen-Approved Costs

         

        Dear [Chief Executive Officer]:

         

        Reference is hereby made to that certain Amended and Restated Neurology Drug Discovery
            and Development Collaboration, Option and License Agreement by and between Ionis and Biogen dated _________ ___, [2020] (the “Neurology I Agreement”),
              as supplemented and/or amended to date.  Any capitalized terms not defined herein will have the meaning set forth in the Neurology I Agreement.

         

        This letter memorializes certain Biogen-Approved Costs set forth on the exhibit attached hereto as Exhibit A for the Collaboration Program and Development Candidate specified on Exhibit A, which Biogen-Approved Costs have been mutually agreed by the Parties (including, if applicable, through the Neurology JSC) in accordance with Section 1.8 of the Neurology I Agreement.

         

        Please indicate your concurrence with the accuracy of Exhibit A as agreed to by the Parties by executing a copy of this letter and returning it to Biogen. This letter may be executed in counterparts, each of which will be deemed an original, notwithstanding
            variations in format or file designation which may result from electronic transmission, store and printing of copies of this letter from separate computers or printers.  Facsimile signatures and signatures transmitted via electronic mail in PDF
            format will be treated as original signatures.

        

        

        [The remainder of this page is intentionally left blank.]

        

        

        
          
            225 Binney Street, Cambridge, MA 02142 • Phone 781-464-2000 • www.biogen.com

          

          
            


        

        	 	
                Sincerely,

              
	 	 
	 	
                [VP of Corporate Development]

              
	 	
                Vice President, Corporate Development

              
	 	
                Biogen MA Inc.

              


        

        

        
          CONFIRMED ON BEHALF OF IONIS PHARMACEUTICALS, INC.:

        

        

        

        	
                By:

              	 	 
	 	 	 
	
                Name:

              	 	 
	 	 	 
	
                Title:

              	 	 
	 	 	 
	
                Date:

              	 	 


         

        	
                Cc:

              	
                Ionis Pharmaceuticals, Inc.

              
	 	
                2855 Gazelle Court

              
	 	
                Carlsbad, CA 92010

              
	 	
                Attention:  General Counsel

              
	 	
                E-mail: [***]

              


        

        

        
          
            225 Binney Street, Cambridge, MA 02142 • Phone 781-464-2000 • www.biogen.com

          

          
            


        

        Exhibit A

         

        	
                Collaboration Program:

              	 	 


        

        

        	
                Development Candidate:

              	 	 


        

        

         

        	 	
                [***]

              	 	
                Biogen-Approved Costs

              	 	
                Apportionment of 

                Biogen-Approved Costs 

                under Section 1.8.1

                 [***]

              
	 	 	 	 	 	 
	 	 	 	 	 	 
	 	 	 	 	 	 


        

        

        
          
            225 Binney Street, Cambridge, MA 02142 • Phone 781-464-2000 • www.biogen.com

          

          
            


        

        
        Appendix 4

         

        [***] Letter

            

         

        (See attached)

         

        
          - 127-

          
            


        

        Schedule 1.5.2(b)

         

        Apportionment of Certain Milestone Payments and Biogen-Approved Costs

         

        [***]

         

        
          - 128-

          
            


        

        Schedule 1.11.1

         

        Neurology JSC Governance

         

        	

              	(a)	
                The Neurology JSC will determine the Neurology JSC operating procedures, including frequency of meetings (at least quarterly), location of meetings, and responsibilities for agendas and minutes. The Neurology JSC will codify these
                  operating procedures in the written minutes of the first meeting.

              


         

        	

              	(b)	
                The Neurology JSC may hold meetings in person or by audio or video conference as determined by the Neurology JSC; but at least two meetings per year will be in person (one held at Ionis’ facilities, and the other held at Biogen’s
                  facilities in the U.S.). Alliance Managers will attend Neurology JSC meetings as participating non-members. In addition, upon prior approval of the other Party, each Party may invite its employees or consultants to attend Neurology JSC
                  meetings, including any subject matter expert(s) with valuable knowledge of Collaboration Targets or the diseases associated with such Collaboration Targets.

              


         

        	

              	(c)	
                The co-chairs will be responsible for ensuring that activities occur as set forth in this Agreement, including ensuring that Neurology JSC meetings occur, Neurology JSC recommendations are properly reflected in the minutes, and any
                  dispute is given prompt attention and resolved in accordance with Section 1.11.3, Section 7.1.3 and Section 12.1, as applicable.

              


         

        	

              	(d)	
                The Neurology JSC members from the same Party will collectively have one vote. The Neurology JSC will strive to make recommendations with approval of both Ionis members and Biogen members, and record such recommendations in the minutes
                  of the applicable Neurology JSC meeting.

              


         

        	

              	(e)	
                The Neurology JSC may form subcommittees and working groups as it determines in order to carry out its activities under this Agreement, all of which will dissolve when the Neurology JSC dissolves.

              


         

        
          - 129-

          
            


        

        Schedule 1.11.5

        

        

        Alliance Management Activities

         

        Each Alliance Manager is responsible for:

         

        	

              	(a)	
                Promoting the overall health of the relationship between the Parties;

              


         

        	

              	(b)	
                Developing a mutually agreed alliance launch plan covering any activities and systems that the Parties need to implement within the first 100 days after the Effective Date to support the Collaboration Programs;

              


         

        	

              	(c)	
                Organizing Neurology JSC meetings, including agendas, drafting minutes, and publishing final minutes;

              


         

        	

              	(d)	
                Supporting the co-chairs of the Neurology JSC with organization of meetings, information exchange, meeting minutes, and facilitating dispute resolution as necessary;

              


         

        	

              	(e)	
                Preparing status and progress reports on the above as determined necessary by the Neurology JSC;

              


         

        	

              	(f)	
                Ensuring compliance in maintaining the Ionis Internal ASO Safety Database as outlined in Section 5.2;

              


         

        	

              	(g)	
                Ensuring proper approval of publications prior to submission as required in Section 11.4; and

              


         

        	

              	(h)	
                Understanding and communicating the components contained in the relationship-management document provided by Ionis to Biogen, to assist Biogen in understanding and complying with the contractual obligations under the Ionis In-License
                  Agreements after the License Effective Date with respect to a Collaboration Program.

              


         

        
          - 130-

          
            


        

        Schedule 4.6.3

        

        

        Ionis’ Fully Absorbed Cost of Goods Methodology

        Cost Estimate of API Cost per Kilogram

        (OOO’s)

        

        

        [***]

        

        

        
          - 131-

          
            


        

        Schedule 5.1.1

         

        Biogen’s Development and Commercialization Activities

         

        [***]

         

        
          - 132-

          
            


        

        Schedule 6.6.2(f)

         

        Royalty Calculation Examples

         

        [***]

        

        

        
          - 133-

          
            


        

        Schedule 6.6.2(g)

         

        Allocation of Net Sales

         

        [***]

         

        
          - 134-

          
            


        

        Schedule 6.8.1

        

        

        Certain Ionis In-License Agreements

         

        (Relevant to the Collaboration Programs and High Interest Targets as of the Effective Date)

         

        [***]

        

        

        
          - 135-

          
            


        

        Schedule 8.2.4(a)

         

        Ionis Core Technology Patents

         

        [***]

         

        
          - 136-

          
            


        

        Schedule 8.2.4(b)

         

        Ionis Manufacturing and Analytical Patents

         

        [***]

         

        
          - 137-

          
            


        

        Schedule 8.2.4(c)

         

        Ionis Product-Specific Patents

         

        [***]

         

        

        
          - 138-

          
            


        

        Schedule 8.2.8

         

        Prior Agreements

         

        [***]

         

        
          - 139-

          
            


        

        Schedule 10.4.4(b)

        

        

        Advisory Panel Regarding Setoff Disputes

         

        [***]

         

        
          - 140-

          
            


        

        Schedule 10.4.5

         

        Transition Services

        

        

        [***]

         

        
          - 141-

          
            


        

        Schedule 12.1.2

        

        

        Mediation

         

        	1.	
                Mediation.

              


         

        1.1            If a Dispute cannot be resolved pursuant to Section 12.1.1 of the Agreement (Escalation), the Parties agree to
          try in good faith to resolve any such Dispute by non-binding mediation administered by the American Arbitration Association (the “AAA”) in accordance with its Commercial Mediation
          Procedures then in effect (the “Procedures”), as modified by this Section 1.1 of this Schedule 12.1.2.  The mediation will be
          conducted by a single mediator appointed by agreement of the Parties, within 15 days after either Party notifies the other Party of its intention to mediate such Dispute, or failing such agreement, appointed by the AAA in accordance with the
          Procedures; provided that in either case the mediator will be a retired Delaware state or federal judge.  Unless otherwise mutually agreed upon by the Parties, the mediation proceedings will be conducted
          in Dover, Delaware. The Parties agree that they will share equally the costs and expenses of the mediation; provided that each Party will bear its own attorneys’ fees and associated costs and expenses. 
          The mediation conference will be held within [***] days after appointment of the mediator, and will last no more than two consecutive days unless otherwise mutually agreed upon by the Parties.  Any resolution of a Dispute by mediation pursuant to
          this Section 1.1 of these mediation procedures will be in writing and signed by duly authorized representatives of both Parties.

         

        1.2           If the Parties cannot resolve a Dispute in accordance with Section 1.1 of this Schedule 12.1.2, then such Dispute will be resolved by the Parties in accordance with Section 12.2 of the Agreement (Governing Law; Jurisdiction; Venue; Service of Process).

         

         

        

        
          - 142-