Document:

Confidential

              	
                
                  Execution Copy

                

              

        
           

          

          CONFIDENTIAL TREATMENT REQUESTED

            UNDER 17 C.F.R. §§ 200.80(b)(4) and 240.24B-2

           

          

          
            Exhibit 10.67

          

        

         

        

      

      Factor B Development Collaboration, Option and License Agreement

       

        

      Among

      

      

      Ionis Pharmaceuticals, Inc.,

      

      

      And

      

      

      F. Hoffmann-La Roche Ltd

      

      

      And

      

      

      Hoffmann-La Roche Inc.

       

        

      
        
          

      

      
      
        Confidential

      

       

        

      FACTOR B DEVELOPMENT COLLABORATION, OPTION AND LICENSE AGREEMENT

      

      

      This FACTOR B DEVELOPMENT COLLABORATION, OPTION AND LICENSE AGREEMENT (the “Agreement”) is entered into as of the 9th day of October, 2018 (the “Effective Date”) by and among Ionis Pharmaceuticals,
            Inc., a Delaware corporation, having its principal place of business at 2855 Gazelle Court, Carlsbad, California 92010 (“Ionis”),

          and F. Hoffmann-La
            Roche Ltd, a Swiss corporation, having its principal place of business at Grenzacherstrasse 124, 4070 Basel, Switzerland (“Roche Basel”)

          and  Hoffmann-La Roche
            Inc.,  a New Jersey corporation, having its principal place of business at 150 Clove Road, Suite 8, Little Falls, New Jersey 07424 (“Roche

            US”; Roche Basel and Roche US are collectively referred to as “Roche”). Roche and Ionis each may be referred to herein
          individually as a “Party” or collectively as the “Parties”.

       

        

      RECITALS

      

      

      WHEREAS, Ionis has expertise in discovering
          and developing antisense drugs, and is developing the antisense drug IONIS-FB-LRx;

      

      

      WHEREAS, Roche has expertise in developing
          and commercializing drugs, and Roche is interested in developing and commercializing IONIS-FB-LRx;

      

      

      WHEREAS, Roche desires Ionis to develop
          IONIS-FB-LRx through completion of a phase 2 trial in the ophthalmological indication of geographic atrophy and an anticipated phase 2a trial in [***] and grant Roche
          an option to obtain an exclusive license to develop and commercialize such drug;

      

      

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

      

      

      ARTICLE 1.

      DEFINITIONS

      

      

      The terms used in this Agreement with initial letters capitalized, whether used in the singular or the plural, will have the meaning
          set forth in Appendix 1, or if not listed in Appendix 1, the meaning designated in places throughout the Agreement.

      

      

      ARTICLE 2.

      AGREEMENT OVERVIEW

      

      

      The intent of the Collaboration is for the Parties to develop IONIS-FB-LRx for (i) the treatment of geographic atrophy (“GA”), and (ii) potentially the treatment of [***] (“[***]”).  Ionis will Develop IONIS-FB-LRx through Completion of the Proposed Phase 2 Trials.  Roche will have an Option to obtain an exclusive license to further Develop, Manufacture, and Commercialize
          IONIS-FB-LRx.  Unless terminated earlier, the Option will be exercisable from any time the last patient specified in the most current version of the Development Plan
          (i.e. the initial Development Plan as modified by the JSC) has been enrolled in the Phase 2 GA Trial until the Option Deadline (the “Option
            Period”).  If Roche exercises its Option, Roche will be responsible for all further Development, Manufacturing and
          Commercializing activities related to the Products, except for any Phase 2 Trials then being conducted by Ionis under the Development Plan.  The

          purpose of this ARTICLE 2 is to provide a high-level overview of the roles, responsibilities, rights and obligations of each Party under this Agreement with regard to
          the Development and Commercialization of the Products, and therefore this ARTICLE 2 is qualified in its entirety by the more detailed provisions of this Agreement set
          forth below.

       

        

      
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      ARTICLE 3.

      DEVELOPMENT COLLABORATION FOR IONIS-FB-LRx

      

      

      
        
          	3.1.	
                  Development Activities for IONIS-FB-LRx.  The Parties will Develop IONIS-FB-LRx under a development plan agreed between the Parties or as may be amended by the JSC from time to time, which covers all Clinical Studies to be conducted
                      through completion of the Development activities necessary to obtain Approval of a Product in at least one (1) Indication (such plan, the “Development Plan”, and such program, the “Development Program”).  Each Party will use Commercially
                      Reasonable Efforts to conduct the Development activities assigned to such Party under, and in accordance with, the Development Plan; provided that
                      neither Roche nor Ionis will have any obligation to perform any activity that, after having consulted the JSC or the applicable JDC, it in good faith believes that continuing such activity would violate any Applicable Law, ethical
                      principles, or principles of scientific integrity.

                

        

      

      

      

      
        
          	

                	3.1.1.	
                  Development Plan.  As of the Effective Date, the Parties have agreed to an
                      initial Development Plan, which includes a clinical trial protocol synopsis for the Phase 2 GA Trial (the “GA Protocol”) and
                      a general outline for the Phase 2 [***] Trial.  Until the sooner of, the Development Plan is replaced by the IDCP under Section 8.1.1 or the JSC is
                      dissolved, the Development Plan will be updated at least annually by the JSC and the applicable JDC.  Subject to Section 4.1.1(b)(ii) below, any changes to
                      the Development Plan must be agreed to by the JSC and the applicable JDC.

                

        

      

      

      

      
        
          	

                	3.1.2.	
                  Proposed Phase 2 Trials.

                

        

      

      

      

      
        
          	 	(a)	
                  Phase 2 GA Trial.  Ionis will conduct the Phase 2 GA Trial under the GA
                      Protocol.  Ionis will use Commercially Reasonable Efforts to meet the timeline for the Phase 2 GA Trial as determined by the JSC and the applicable JDC, including to meet the Specific Performance Milestone Events in Appendix 2.  Ionis will keep Roche informed of the progress of such Phase 2 GA Trial through the JSC and applicable JDC.      

                

        

      

      

      

      
        
          	

                	(b)	
                  Phase 2 [***] Trial.  Ionis will conduct the Phase 2 [***] Trial under a
                      protocol to be finalized through the JSC and the applicable JDC.  Ionis will use Commercially Reasonable Efforts to meet the timeline for the Phase 2 [***] Trial as determined by the JSC and the applicable JDC, including to meet the
                      Specific Performance Milestone Events in Appendix 2. 
                      Ionis will keep Roche informed of the progress of such Phase 2 [***] through the JSC and applicable JDC.

                

        

      

      

      

      
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                	(c)	
                  Phase 2 Trial Data Package and Interim Data.  Promptly after conducting
                      interim data analysis related to either the Phase 2 GA Trial or the Phase 2 [***] Trial (if any), Ionis will provide to Roche a copy of its analyses and the underlying data sufficient for Roche to conduct a pharmacokinetics and/or
                      pharmacodynamics analysis, and ongoing safety data (which will be provided by Ionis to Roche on an ongoing basis). Once available to Ionis, Ionis will promptly deliver to Roche the Phase 2 Trial Data Package.

                

        

      

      

      

      
        
          	

                	3.1.3.	
                  Additional Development of IONIS-FB-LRx.  The Parties are discussing additional Development (clinical or non-clinical) of IONIS-FB-LRx and will continue such discussions in good faith prior to Option exercise.

                

        

      

      

      

      
        
          	

                	(a)	
                  If, before Option exercise, Ionis and Roche agree that Ionis will conduct an additional Phase 2 Trial or any additional earlier stage Clinical Study for the Product, then
                      the Parties will share the costs of such additional Phase 2 Trial and negotiate in good faith the design and reimbursement terms for such Clinical Study(ies), including a budget, payment schedule, an appropriate methodology to
                      allocate the costs of such Clinical Study(ies), and who will supply clinical-grade API and Finished Drug Product, and the JSC and the applicable JDC will revise the Development Plan to include a clinical trial protocol synopsis for
                      each such Clinical Study.

                

        

      

      

      

      
        
          	

                	(b)	
                  If, before Option exercise, Ionis (but not Roche) would like to conduct a phase 2b trial in [***] (the “Phase 2b [***] Trial”), then [***] such Phase 2b [***] Trial, and upon Initiation of a Registration-Directed Trial for [***] after Option exercise, Roche will pay to Ionis [***] within
                      [***] days after Initiation of a Registration-Directed Trial for [***] and Roche’s receipt of an invoice from Ionis. Initiation of the Registration-Directed Trial for [***] is at the sole discretion of Roche.  For clarity, no such
                      payment will be required if Roche does not provide the Option Exercise Notification. For clarity, the payment in this clause (b) is not applicable to clauses (a) or (c).

                

        

      

      

      

      
        
          	

                	(c)	
                  If Roche would like Ionis to conduct the Phase 2b [***] Trial but Ionis is unable or unwilling to conduct such trial, then Roche may undertake such Phase 2b [***] under
                      Ionis’ IND and Roche will pay [***] but may offset [***] of Roche’s reasonable costs incurred in running the Phase 2b [***] Trial before Option exercise against the next Post-Licensing Milestone Payment under Table 1 of Section 9.4 that becomes due.  Ionis will use Commercially Reasonable Efforts to comply with Roche’s reasonable requests for support regarding Regulatory Materials and interactions with Regulatory
                      Authorities and other activities required to conduct the Phase 2b [***] Trial under the Ionis IND.

                

        

      

      

      

      
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                	3.1.4.	
                  Attaching Plans to JSC Minutes.  The JSC will attach each revised
                      Development Plan to the meeting minutes of the JSC.

                

        

      

      

      

      
        
          	

                	3.1.5.	
                  Development Plan Costs. Before Option exercise, except as the Parties may
                      otherwise agree, Ionis will be responsible for all costs and expenses associated with the activities assigned to Ionis under the Development Plan, and Roche will be responsible for all costs and expenses associated with the activities
                      assigned to Roche under the Development Plan.  Before Option exercise, if the Parties mutually agree to a material change to the Development Program (e.g.,
                      add a new arm or increase the maximum number of study subjects) or a Regulatory Authority requires Ionis to change the Development Program (each an “Approved Change”), the Parties will share the Approved Change Costs (as defined below) as follows: 

                

        

      

      

      

      
        
          	

                	(a)	
                  If the Approved Change Costs are less than [***], then [***] will be responsible for the Approved Change Costs.

                

        

      

      

      

      
        
          	

                	(b)	
                  If the Approved Change Costs are [***]or higher and less than [***], then [***] will be responsible for the Approved Change Costs for the first [***] and [***] will be
                      responsible for the Approved Change Costs above [***].

                

        

      

      

      

      
        
          	

                	(c)	
                  If the Approved Change Costs are [***] or more, then each Party will be responsible for one half of the portion of the Approved Change Costs.  Each Party may credit any
                      amounts paid under Section 3.1.5(a) and Section 3.1.5(b) against amounts
                      payable under this Section 3.1.5(c).

                

        

      

      

      

      For clarity, the allocation of Approved Change Costs set forth in this Section

              3.1.5 will not apply to cost overruns associated with the Development Program that are not caused by Approved Changes.  For example, activities to improve recruitment rate (e.g., adding additional sites (other than due to the addition of a new arm or due to an increase in the maximum number of study subjects, or the addition of sites such that the total number of sites exceeds [***]) or
          increasing site payments), recruitment vendors, or costs resulting from a delay in study conduct, are cost overruns associated with the Development Program and are not Approved Changes.

      

      

      “Approved Change Costs”
          means [***] in each case with regard to clause (2) without considering the aggregate effect of all Approved Changes.

      

      

      
        
          	

                	3.1.6.	
                  Development Term.  The term for the conduct of the Development Program
                      under the Development Plan will begin on the date work began under such Development Plan and will end upon the earlier of (i) completion of all Development activities under such Development Plan to support Approval in at least one (1)
                      Indication in all Major Markets, (ii) the termination of such Development Program in accordance with Section 13.2.1, and (iii) mutual agreement of the
                      Parties to terminate the Development Program.

                

        

      

      

      

      
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          	3.2.	
                  Regulatory Matters. Before Option exercise and until Completion of the
                      Proposed Phase 2 Trials, Ionis will be responsible for all communications with Regulatory Authorities regarding a Product and will have final decision-making authority with respect to the matters set forth in this Section 3.2.

                

        

      

      

      

      
        
          	

                	3.2.1.	
                  Participation in Regulatory Meetings.  Ionis will provide Roche with as
                      much advance written notice as practicable of any meetings that Ionis has or plans to have with a Regulatory Authority regarding the Proposed Phase 2 Trials and any other Phase 2 Trial or earlier stage Clinical Study that the Parties
                      agree Ionis will conduct for a Product and will allow Roche (at Roche’s own expense) to participate in any such meetings as an observer.

                

        

      

      

      

      
        
          	

                	3.2.2.	
                  Regulatory Communications.  Ionis will provide Roche with copies of
                      documents and communications submitted to and received from Regulatory Authorities that materially impact the Development or Commercialization of a Product for Roche’s review and comment, and Ionis will consider in good faith
                      including any comments provided by Roche to such documents and communications.

                

        

      

      

      

      ARTICLE 4.

      COLLABORATION GOVERNANCE; MANUFACTURING AND COSTS

      

      

      
        
          	4.1.	
                  Collaboration Governance.

                

        

      

      

      

      
        
          	

                	4.1.1.	
                  Joint Steering Committee. Within thirty (30) days after the Effective
                      Date, the Parties will establish a joint steering committee (“JSC”) to govern the activities under the Development Plan. The
                      JSC will consist of three (3) representatives appointed by Ionis and three (3) representatives appointed by Roche. Each Party’s JSC representatives will be senior personnel empowered by such Party to make decisions related to clinical
                      development and regulatory strategy, and at least one of each Party’s members will have operational responsibility for such Party’s respective activities under the Development Plan. Each Party will be responsible for the costs and
                      expenses of its own employees or consultants attending JSC meetings.  The JSC will meet at least twice each Calendar Year but not more that four (4) times per Calendar Year. Ionis will have the right, but not the obligation, to
                      participate in the JSC after Option exercise.  If Ionis chooses not to participate, then Roche can dissolve the JSC.

                

        

      

      

      

      
        
          	

                	(a)	
                  Role of the JSC. Without limiting any of the foregoing, subject to Section 4.1.1(b), the JSC will perform the following functions, some or all of which may be addressed directly at any given JSC meeting:

                

        

      

      

      

      
        
          	

                	(i)	
                  Review and approve updates to the Development Plan with respect to the Proposed Phase 2 Trials as well as with respect to any Phase 2 Trial undertaken per Section 3.1.3
                      (including any material changes) as contemplated under Section 3.1;

                

        

      

      

      

      
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                	(ii)	
                  Review and approve regulatory filings regarding the Clinical Studies under the Development Plan with respect to the Proposed Phase 2 Trials as well as with respect to any
                      Phase 2 Trial undertaken per Section 3.1.3 in accordance with Section 3.2;

                

        

      

      

      

      
        
          	

                	(iii)	
                  Oversee the operation of any JDC regarding the Clinical Studies under the Development Plan with respect to the Proposed Phase 2 Trials as well as with respect to any
                      Phase 2 Trial undertaken per Section 3.1.3;

                

        

      

      

      

      
        
          	

                	(iv)	
                  Attempt to informally resolve any disputes that may arise between the Parties regarding the Proposed Phase 2 Trials as well as any Phase 2 Trial undertaken per Section 3.1.3; and

                

        

      

      

      

      
        
          	

                	(v)	
                  Such other review, approval and advisory responsibilities as may be assigned to the JSC by the Parties pursuant to this Agreement.

                

        

      

      

      

      
        
          	

                	(b)	
                  Decision Making.

                

        

      

      

      

      
        
          	

                	(i)	
                  Committee Decision Making. Decisions by the JSC will be made by unanimous
                      consent with each Party’s representatives having, collectively, one vote. At any given meeting of the JSC, a quorum will be deemed reached if a voting representative of each Party is present or participating in such meeting. No action
                      taken at any meeting of the 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 JSC has not reached unanimous
                      consensus.

                

        

      

      

      

      
        
          	

                	(ii)	
                  Implementation. Each Party will give due consideration to, and consider in
                      good faith, the recommendations and advice of the JSC regarding the conduct of the activities under the Development Plan. The JSC will endeavor in good faith to reach consensus on all decisions, however, if the JSC cannot unanimously agree on a matter to be decided by it within fifteen (15) Business Days, then the matter may be referred to the Executives for
                      resolution as set forth in Section 15.1.1. If the Executives cannot reach agreement, then (i) before Option exercise, Ionis will have the final
                      decision-making authority regarding the performance of activities under the Development Plan and whether to accept and how to implement the JSC’s recommendations with respect thereto, and (ii) after Option exercise, Roche will have
                      the final decision-making authority regarding the performance of activities under the Development Plan and whether to accept and how to implement the JSC’s recommendations with respect thereto, except with respect to decisions
                      regarding operational aspects of a Phase 2 Trial conducted by Ionis that has not yet Completed, which will be within Ionis’ final decision-making authority. In exercising its final decision-making authority under this Section 4.1.1(b)(ii), a Party will not increase the other Party’s costs or obligations under the Development Plan without such Party’s consent. Except as
                      otherwise expressly stated in this Agreement, the 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.

                

        

      

      

      

      
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                	4.1.2.	
                  Joint Development Committees.  Prior to the Initiation of the Phase 2 GA
                      Trial and the Phase 2 [***] Trial, as applicable, the Parties will establish a joint development committee (“JDC”) for the
                      Phase 2 GA Trial and a separate JDC for the Phase 2 [***] Trial.  Thereafter, if the Parties agree that Ionis will conduct any other Phase 2 Trial under the Development Plan, within thirty (30) days after such agreement, the Parties
                      will establish a separate JDC for such Phase 2 Trial.  Each JDC will consist of an equal number of representatives appointed by Ionis and Roche.  Each Party will be responsible for the costs and expenses of its own employees or
                      consultants attending JDC meetings.  Ionis will have the right, but not the obligation, to participate in each JDC after Option exercise.  If Ionis chooses not to participate, then Roche can dissolve the JDC. Each JDC will be
                      dissolved as soon as reasonably possible after the Completion of the applicable ongoing Phase 2 Trial over which such JDC has oversight.

                

        

      

      

      

      
        
          	

                	(a)	
                  Role of the JDCs.  Without limiting any of the foregoing, subject to Section 4.1.2(b), the applicable JDC will perform the following functions, some or all of which may be addressed directly at any given JDC meeting:

                

        

      

      

      

      
        
          	

                	(i)	
                  oversee the Parties’ activities regarding the applicable Phase 2 Trial under the Development Plan;

                

        

      

      

      

      
        
          	

                	(ii)	
                  oversee the formation and operation of any subcommittee of the JDC regarding the applicable Phase 2 Trial under the Development Plan;

                

        

      

      

      

      
        
          	

                	(iii)	
                  with respect to the JDC for the Phase 2 [***] Trial (or the JDC for any subsequent Phase 2 Trial that the Parties agree Ionis will conduct), discuss and agree upon the
                      proposed design and protocol(s) for the Phase 2 [***] Trial (or other Phase 2 Trial, if applicable) under the Development Plan and present such documents to the JSC for final approval; and

                

        

      

      

      

      
        
          	

                	(iv)	
                  such other review and advisory responsibilities as may be assigned to the applicable JDC by the Parties pursuant to this Agreement.

                

        

      

      

      

      
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                	(b)	
                  Decision Making.  Decisions by the applicable JDC will be made by
                      unanimous consent with each Party’s representatives having, collectively, one vote.  At any given meeting of the applicable JDC, a quorum will be deemed reached if a voting representative of each Party is present or participating in
                      such meeting.  No action taken at any meeting of the applicable JDC 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 applicable JDC has not reached unanimous consensus.  Each JDC will endeavor in good faith to reach consensus on all decisions over which it has oversight, however, if a JDC cannot unanimously agree on a matter to be decided by it within fifteen (15) Business Days, then the matter will be referred to the JSC for resolution in accordance with Section 4.1.1(b).

                

        

      

      

      

      
        
          	4.2.	
                  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 JSC and each JDC, and performing the activities listed in Schedule 4.2.

                

        

      

      

      

      
        
          	4.3.	
                  Records and Quality; Inspections; Materials Transfer.

                

        

      

      

      

      
        
          	

                	4.3.1.	
                  Records. Each Party will maintain records consistent with its own practice
                      of all Development and Commercial activities such Party performs under this Agreement and all results, data, inventions and developments made in the performance of such work. Such records will be in sufficient detail and in good
                      scientific manner appropriate for compliance reporting, effective auditing, patent and regulatory purposes. Upon prior written notice, a Party will provide the other Party with copies of all requested records, to the extent reasonably
                      required for the performance of a Party’s rights and obligations under this Agreement.

                

        

      

      

      

      
        
          	

                	4.3.2.	
                  Materials Transfer. To facilitate the activities under this Agreement,
                      either Party may provide to the other Party certain materials for use by the other Party in furtherance of the activities to be performed under this Agreement. Unless agreed otherwise between the Parties, all such materials will be
                      used by the receiving Party in accordance with the terms and conditions of this Agreement solely for purposes of exercising its rights and performing its obligations under this Agreement, and the receiving Party will not transfer such
                      materials to any Third Party unless expressly contemplated by this Agreement or upon the written consent of the supplying Party. Except as expressly set forth herein, SUCH MATERIALS ARE PROVIDED “AS IS” AND WITHOUT ANY REPRESENTATION
                      OR WARRANTY, EXPRESS OR IMPLIED, INCLUDING ANY IMPLIED WARRANTY OF MERCHANTABILITY OR OF FITNESS FOR ANY PARTICULAR PURPOSE OR ANY WARRANTY THAT THE USE OF THE MATERIALS WILL NOT INFRINGE OR VIOLATE ANY PATENT OR OTHER PROPRIETARY
                      RIGHTS OF ANY THIRD PARTY.

                

        

      

      

      

      
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                  	4.4.	
                          Manufacturing and Supply. Unless otherwise expressly agreed by the
                              JSC:

                        

                

              

            

            

          

          	

                	4.4.1.	
                  Supplies for Activities Before Option Exercise.  Ionis is solely
                      responsible for the manufacture and supply of API and Finished Drug Product to support the activities under the Development Plan through Completion of the Proposed Phase 2 Trials, including any costs associated with such manufacture
                      and supply.

                

        

      

      

      

      
        
          	

                	4.4.2.	
                  Supplies for Activities After Option Exercise.  After Option exercise,
                      Ionis will deliver to Roche, if Roche desires, any inventory of cGMP and non-cGMP API, cGMP and non-cGMP Finished Drug Product, and cGMP and non-cGMP packaged clinical trial material containing IONIS-FB-LRx in Ionis’ possession and that is not necessary to complete any then ongoing Phase 2 Trials being conducted by Ionis under the Development Plan [***] as set forth in Schedule 4.4.2.  After Option exercise, Roche is
                      responsible for the manufacture and supply of API and Finished Drug Product to support the activities under the Development Plan (except for any then-ongoing additional Phase 2 Trial being conducted by Ionis and any then-ongoing
                      Proposed Phase 2 Trials) and to Commercialize Product, including any costs associated with such manufacture and supply, and Ionis will, at Roche’s election either (i) assign to Roche contracts Ionis has with Third Party manufacturers
                      for the manufacture of such API or Finished Drug Product and will use commercially reasonable efforts to support Roche in qualifying such Third Party manufacturers, or (ii) transfer to Roche the Ionis Manufacturing and Analytical
                      Know-How in accordance with Section 7.2.2, subject to Section 7.2.3.  If,
                      prior to Option exercise, Roche elects to perform preliminary chemistry, manufacturing and controls work to evaluate the feasibility of manufacturing the Product or to determine whether to pursue either of the foregoing options
                      specified in this Section 4.4.2, Ionis will cooperate in good faith with Roche and will provide the materials and information requested by Roche necessary
                      to such evaluation. Each Party shall bear its own costs for such activities pursuant to the preceeding sentence.

                

        

      

      

      

      
        
          	4.5.	
                  Subcontracting.  Each Party may engage Third Party subcontractors to
                      perform certain of its obligations under this Agreement.  Any subcontractor engaged to perform a Party’s obligations under this Agreement will meet the qualifications typically required by such Party for the performance of work
                      similar in scope and complexity and will execute such Party’s standard nondisclosure agreement.  Any Party engaging a subcontractor hereunder will remain responsible for such activities.

                

        

      

      

      

      
        
          	4.6.	
                  Applicable Laws.  Each Party will perform its activities pursuant to this
                      Agreement in compliance with Applicable Law, including good laboratory and clinical practices and cGMP, in each case as applicable in the country, state, province, territory, and locale wherein such activities are conducted.

                

        

      

      

      

      
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      ARTICLE 5.

      EXCLUSIVITY COVENANTS

      

      

      
        
          	5.1.	
                  Exclusivity Covenants.  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 5.1.3:

                

        

      

      

      

      
        
          	

                	5.1.1.	
                  Before Option Exercise.  Before Option exercise, Ionis will work
                      exclusively within the collaboration described in the Agreement to conduct all discovery, research, development, manufacture or commercialization of an ASO that is designed to bind to the RNA that encodes Factor B in the Field.

                

        

      

      

      

      
        
          	

                	5.1.2.	
                  After Option Exercise.

                

        

      

      

      

      
        
          	

                	(a)	
                  After Option exercise, if Roche is Developing or Commercializing at least one Product under this Agreement, neither Ionis nor Roche independently or for or with any of
                      their respective Affiliates or any Third Party (including the grant of any license to any Third Party) will sell an ASO approved by a Regulatory Authority for marketing and sale that is designed to bind to the RNA that encodes Factor
                      B in the Field  until the Full Royalty Period ends in the first Major Market. After the end of the Full Royalty Period in the first Major Market, the exclusivity covenants set forth in this Section 5.1.2(a) will continue on a country-by-country basis in each country where the Full Royalty Period still applies [***].

                

        

      

      

      

      
        
          	

                	(b)	
                  The exclusivity covenants of Section 5.1.2(a) will not apply to [***] or [***], provided that Roche [***], or otherwise [***].

                

        

      

      

      

      
        
          	

                	5.1.3.	
                  Limitations and Exceptions to Ionis’ and Roche’s Exclusivity Covenants. Notwithstanding anything to the contrary in Section

                          5.1, the Parties and their Affiliates may perform the following activities:

                

        

      

      

      

      
        
          	

                	(a)	
                  all activities permitted or contemplated under this Agreement; and

                

        

      

      

      

      
        
          	

                	(b)	
                  with regard to Ionis and its Affiliates:

                

        

      

      

      

      
        
          	 	(i)	
                  any activities pursuant to the Prior Agreement;

                

        

      

      

      

      
        
          	

                	(ii)	
                  the granting of, or performance of obligations under, Permitted Licenses.

                

        

      

      

      

      
        
          	5.2.	
                  Effect of Exclusivity on Indications. Ionis and Roche are subject to
                      certain exclusivity covenants under Section 5.1; however, the
                      Parties acknowledge and agree that each Party (on its own or with a Third Party, or an Affiliate) may pursue products for the same Indication as a Product so long as such product is not an ASO designed to bind to the RNA that encodes Factor B.

                

           

          

        

      

      
        11

        
          

      

      
        Confidential

      

       

        

      ARTICLE 6.

      EXCLUSIVE OPTION

      

      

      
        
          	6.1.	
                  Option and Option Deadline.  Ionis hereby grants Roche an exclusive option
                      to obtain the license set forth in Section 7.1.1 (the “Option”). 

                      To obtain the license set forth in Section 7.1.1, Roche must exercise the Option by the [***] following Roche’s receipt of the Phase 2 Trial Data Package
                      from Ionis (the “Option Deadline”).  If, however, the Phase 2 GA Trial [***] and Roche is conducting the Phase 2b [***] Trial
                      under Section 3.1.3(c) or Ionis is conducting an additional Phase 2 Trial or any additional earlier stage Clinical Study for the Product under Section 3.1.3(a), then the Option Deadline will be extended until [***] after the Completion of the Phase 2b [***] Trial.

                

        

      

      

      

      
        
          	6.2.	
                  Option Exercise; Option Expiration.  During the Option Period, if, by the
                      Option Deadline, Roche (i) notifies Ionis in writing that it is exercising the Option (“Option Exercise Notification”), and
                      (ii) within [***] after the latest of (x) the Option Exercise Notification, (y) Roche’s receipt of an invoice from Ionis, and (z) expiration or termination of any applicable waiting period under the HSR Act or any other similar
                      Applicable Law, Roche timely pays Ionis the license fee set forth in Section 9.3, Ionis will, and hereby does, grant Roche the license set forth in Section 7.1.1.  Prior to the Option Deadline, Roche will have the full opportunity to conduct due diligence to evaluate whether to exercise the Option and Ionis
                      will cooperate with Roche and ensure that all necessary data and information, including clinical and manufacturing data and any available [***] analysis, are provided to Roche.  If, by the Option Deadline, Roche has not provided Ionis
                      the Option Exercise Notification, and within [***] after the latest of (1) providing the Option Exercise Notification, (2) receiving an invoice from Ionis for the license fee set forth in Section 9.3, and (3) expiration or termination of any applicable waiting period under the HSR Act or any other similar Applicable Law, has not paid Ionis the license fee set forth in Section 9.3, then Roche’s Option will expire.  If Roche’s Option expires, then Section 13.4.1
                      and Section 13.4.2 will apply.

                

        

      

      

      

      
        
          	6.3.	
                  HSR.  Each Party will (i) cooperate with the other Party in the
                      preparation, execution and filing of all documents that may be required pursuant to the HSR Act or any other Applicable Law, and (ii) observe all applicable waiting periods before consummating the Option exercise as set forth in Section 6.2.  Each Party will bear its own costs (including counsel or other expert fees) with respect to preparing, executing and filing such documents. 
                      Subject to the terms and conditions of this Agreement, each Party will use all reasonable efforts to take, or cause to be taken, all reasonable actions and to do, or cause to be done, all things necessary and appropriate to consummate
                      the exercise of the Option contemplated by Section 6.2 of this Agreement, should Roche choose to exercise the Option.  Notwithstanding anything to the
                      contrary contained in this Agreement, Roche will have the sole and exclusive right to determine, at its discretion but without any obligation whatsoever, whether it will have any obligation to take any actions in connection with, or
                      agree to, any demands for the license, sale divestiture or disposition of assets of Roche or its Affiliates or Ionis, asserted by the United States Federal Trade Commission, the Antitrust Division of the United States Department of
                      Justice or any other Regulatory Authority in connection with antitrust matters or international competition laws, or to defend through litigation any proceeding commenced by the Federal Trade Commission, the Antitrust Division of the
                      United States Department of Justice or other governmental authority in connection with the foregoing matters.

                

        

      

      

      

      
        12

        
          

      

      
        Confidential

      

       

        

      ARTICLE 7.

      LICENSE GRANTS

      

      

      
        
          	7.1.	
                  License Grants; Sublicense Rights.

                

        

      

      

      

      
        
          	

                	7.1.1.	
                  Development and Commercialization License Grant to Roche. Subject to the
                      terms of this Agreement, effective upon Roche’s exercise of the Option in accordance with this Agreement, Ionis grants to Roche a worldwide, exclusive, royalty-bearing, sublicensable (in accordance with Section 7.1.4 below) license under the Licensed Intellectual Property to Develop, Manufacture, have Manufactured (in accordance with Section 7.1.4 below), use, and Commercialize Products in the Field.

                

        

      

      

      

      
        
          	

                	7.1.2.	
                  Cross Licenses under Collaboration Intellectual Property.

                

        

      

      

      

      
        
          	

                	(a)	
                  Enabling Patent License from Roche to Ionis. Subject to the terms and
                      conditions of this Agreement (including Ionis’ exclusivity covenants under Section 5.1 and without limiting the license granted to Roche under Section 7.1.1), Roche hereby grants Ionis a fully-paid, royalty-free, irrevocable, worldwide, non-exclusive, sublicensable license under any Roche Collaboration
                      Intellectual Property (excluding any Product-Specific Patents) to research, develop, manufacture, have manufactured and commercialize products that include an ASO as an active pharmaceutical ingredient (other than a Product that is
                      being Developed or Commercialized by Roche, its Affiliates or Sublicensees under this Agreement or the HTT Research, Development, Option and License Agreement among the Parties dated April 8, 2013).

                

        

      

      

      

      
        
          	

                	(b)	
                  Enabling Patent License from Ionis to Roche. Subject to the terms and
                      conditions of this Agreement (including Roche’s exclusivity covenants under Section 5.1 and without limiting the license granted to Roche under Section 7.1.1), Ionis hereby grants Roche a fully-paid, royalty-free, irrevocable, worldwide, non-exclusive, sublicensable license under any Ionis Collaboration
                      Intellectual Property (excluding any Ionis Product-Specific Patents) to research, develop, manufacture, have manufactured and commercialize products that do not include an ASO as an active pharmaceutical ingredient.

                

        

      

      

      

      
        
          	

                	7.1.3.	
                  Amendment to the Existing Diagnostic Agreement.  After Option exercise,
                      Ionis and Roche will execute an amendment to the Existing Diagnostic Agreement on terms mutually agreed by Roche and Ionis, which amendment will include granting Roche a non-exclusive, sublicensable, worldwide license, with the right
                      to sublicense (through multiple tiers) under Patent Rights and/or Know-How Controlled by Ionis necessary or useful to research, develop , manufacture, have manufactured, and commercialize Factor B diagnostic products (including
                      diagnostic products and/or services to select patients who will use Products).

                

           

          

        

      

      
        13

        
          

      

      
        
          
            Confidential

             

            

          

          	

                	7.1.4.	
                  Sublicense Rights.

                

        

      

      

      

      
        
          	

                	(a)	
                  Subject to the terms of this Agreement, Roche will have the right to grant sublicenses under any license granted under Section 7.1.1 above:

                

        

      

      

      

      
        
          	

                	(i)	
                  under Ionis’ interest in Jointly Owned Collaboration IP to the extent it is exclusively licensed to Roche under this Agreement, the Ionis Core Technology Patents, Ionis
                      Product-Specific Patents, Ionis Collaboration Patents, Ionis Collaboration Know-How, and Ionis Know-How to an Affiliate of Roche or a Third Party; and

                

        

      

      

      

      
        
          	

                	(ii)	
                  under the Ionis Manufacturing and Analytical Patents and Ionis Manufacturing and Analytical Know-How solely to (y) an Affiliate of Roche or (z) a [***] (each, a “Licensed CMO”).

                

        

      

      

      

      
        
          	

                	(b)	
                  Requests to Grant Sublicenses to CMOs. If Roche provides Ionis with a
                      written request that Ionis grant a license under the Ionis Manufacturing and Analytical Patents and Ionis Manufacturing and Analytical Know-How to a CMO designated by Roche that is not a Licensed CMO, solely for such CMO to
                      manufacture Products for Roche, its Affiliate or Sublicensee in a manufacturing facility owned or operated by such CMO, [***].

                

        

      

      

      

      
        
          	

                	(c)	
                  Enforcing Sublicenses. Each sublicense by Roche under this Agreement will
                      be subject to, and consistent with, the terms of this Agreement.  Roche will be responsible to ensure compliance by its Sublicensees with the terms and conditions of this Agreement. If Ionis reasonably believes a Roche Sublicensee may
                      be violating the terms of this Agreement, then, within thirty (30) days after Ionis delivers a written request to Roche, Roche will provide Ionis a full and complete copy of the sublicense Roche entered with such Sublicensee.

                

        

      

      

      

      
        
          	

                	(d)	
                  Effect of Termination on Sublicenses. If this Agreement terminates for any
                      reason, any Sublicensee granted a sublicense by Roche to Develop or Commercialize Products 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 Roche; 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 Roche, 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 Roche. Roche 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.

                

        

      

      

      

      
        14

        
          

      

      
        
          
            Confidential

             

            

          

          	

                	7.1.5.	
                  No Implied Licenses. All rights in and to Licensed Intellectual Property
                      not expressly licensed to Roche under this Agreement are hereby retained by Ionis or its Affiliates. All rights in and to Roche Intellectual Property not expressly licensed or assigned to Ionis under this Agreement, are hereby
                      retained by Roche 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.

                

        

      

      

      

      
        
          	

                	7.1.6.	
                  License Conditions; Limitations. Subject to Section 9.10, any license granted under Section 7.1.1 and the sublicense rights under Section 7.1.4 is subject to and limited by (i) the Permitted Licenses, (ii) the Prior Agreement, and (iii), if any, the Additional Ionis In-License Agreements,
                      in each case to the extent the provisions of such obligations or agreements are specifically disclosed to Roche in writing (or via electronic data room).

                

        

      

      

      

      
        
          	

                	7.1.7.	
                  Trademarks for Products. After Option exercise, Roche is solely
                      responsible for all trademarks, trade dress, logos, slogans, designs, copyrights and domain names used on or in connection with Products licensed under Section 7.1.1.

                

        

      

      

      

      
        
          	7.2.	
                  Technology Transfer after Option Exercise. After Option exercise pursuant
                      to a technology transfer plan to be mutually agreed by Ionis and Roche, and subject to Section 7.2.3, Ionis will:

                

        

      

      

      

      
        
          	

                	7.2.1.	
                  Licensed Know-How – Generally. Deliver to Roche copies of Licensed
                      Know-How (other than the Ionis Manufacturing and Analytical Know-How) in the Field in Ionis’ possession not previously provided hereunder, for use solely in accordance with the license granted under Section 7.1.1 to Roche, together with all regulatory documentation (including drafts) related to any Phase 2 Trial Completed as of Option exercise. Following Option exercise, the
                      Parties will promptly agree on a plan to transfer to Roche (i) all regulatory documentation (including drafts) related to any Phase 2 Trial in progress as of Option exercise following the Completion of such Phase 2 Trial and (ii) any
                      other regulatory documentation regarding the Product in Ionis’ possession not previously provided to Roche.  To assist with the transfer of such Licensed Know-How, Ionis will make its personnel reasonably available to Roche during
                      normal business hours to transfer such Licensed Know-How under this Section 7.2.1.

                

        

      

      

      

      
        
          	

                	7.2.2.	
                  Ionis Manufacturing and Analytical Know-How. Deliver, at Roche’s election,
                      to one of either (i) Roche or (ii) a Licensed CMO solely to Manufacture API and Finished Drug Product on Roche’s behalf, copies of the Ionis Manufacturing and Analytical Know-How relating to Products in Ionis’ possession not
                      previously provided hereunder, which is necessary for the exercise by Roche, its Affiliates or a Third Party of the Manufacturing rights granted under Section 7.1.1.

                

        

      

      

      

      
        15

        
          

      

      
        
          
            Confidential

              

            

          

          	

                	7.2.3.	
                  Technology Transfer Costs. Perform the technology transfer activities
                      under this Section 7.2 for up to [***] FTE hours (free of charge to Roche) of Ionis’ time. Thereafter, if requested by Roche, Ionis will provide Roche with
                      a reasonable level of assistance in connection with such transfer, which Roche will reimburse Ionis for Ionis’ time incurred in providing such assistance at Ionis’ then-current FTE rate, and any of Ionis’ reasonable travel expenses
                      for travel requested by Roche, and any outside consultants’ costs and consultants’ reasonable travel expenses incurred by Ionis agreed in advance by Roche.

                

        

      

      

      

      ARTICLE 8.

      DEVELOPMENT, MANUFACTURING AND COMMERCIALIZATION

      

      

      
        
          	8.1.	
                  Roche Diligence.  After Option exercise, subject to the terms of this
                      Agreement, Roche is 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
                      Products, except with respect to any Phase 2 Trial being conducted by Ionis under the Development Plan that has not yet Completed by the time of Option exercise, which will remain the responsibility of Ionis until such Phase 2 Trial
                      has Completed.  Roche will use Commercially Reasonable Efforts to Develop, Manufacture and Commercialize Products, including to meet the timelines and milestones set forth in the Development Plan, the IDCP and the Specific Performance
                      Milestone Events.

                

        

      

      

      

      
        
          	

                	8.1.1.	
                  Replacement of Development Plan with the IDCP.  Prior to Initiation of the
                      first Registration-Directed Trial for a given Product, Roche will prepare a global integrated development and commercialization plan (“IDCP”) outlining key aspects for Developing such Product through Approval of at least one (1) Indication, and Roche’s worldwide strategy to launch and Commercialize such Product.  The IDCP will incorporate and
                      replace the Development Plan and will take the form of, and contain information consistent with, Roche’s Development and Commercialization plans for its similar products at similar stages of development or commercialization, including
                      Product Sales forecasts.  Once Roche has prepared such plan, Roche will update the IDCP consistent with Roche’s standard practice and provide such updates to Ionis at least Annually.

                

        

      

      

      

      
        
          	

                	8.1.2.	
                  Registration-Directed Trials. The Registration-Directed Trials will be
                      designed in accordance with the Registration-Directed Trial designs set forth in the applicable IDCP.  Roche will keep Ionis informed of the progress and status of each Registration-Directed Trial.  Roche will notify Ionis in writing
                      promptly after Roche completes each Registration-Directed Trial under the applicable IDCP.  Once the data generated under the statistical analysis plan for a Registration-Directed Trial is available to Roche, Roche will provide
                      promptly such data to Ionis.

                

        

      

      

      

      
        
          	

                	8.1.3.	
                  Investigator’s Brochure.  After Option exercise, in addition to the IDCP,
                      Roche 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 to Ionis Annually and upon any substantive change to
                      the safety or risk of the Products.

                

        

      

      

      

      
        16

        
          

      

      
        
          
            Confidential

          

           

          

          	

                	8.1.4.	
                  Participation in Regulatory Meetings.  Each Party will provide the other
                      Party with as much advance written notice as practicable of any meetings such Party has or plans to have with a Regulatory Authority regarding pre-approval or Approval matters for a Product and will allow the other Party (at such
                      other Party’s own expense) to participate in any such meetings as an observer. After Option exercise and upon transfer of the IND for IONIS-FB-LRx to
                      Roche, Roche will lead all interactions with Regulatory Authorities regarding IONIS-FB-LRx and Products.

                

        

      

      

      

      
        
          	

                	8.1.5.	
                  Regulatory Communications.  Each Party will provide the other Party with
                      copies of documents and communications submitted to and received from Regulatory Authorities that materially impact the Development or Commercialization of Products for the other Party’s review and comment, and the submitting Party
                      will consider in good faith including any comments provided by the reviewing Party to such documents and communications.

                

        

      

      

      

      
        
          	

                	8.1.6.	
                  Participation in Roche Clinical Development Team Meetings.  [***], Roche
                      will permit Ionis to participate in Roche’s key clinical development team meetings for Products (i.e., meetings that are likely to have a
                      material impact on the Development of the Product(s) (each such meeting, a “Key Meeting”), at Ionis’ reasonable request. 
                      Ionis’ and Roche’s respective designated clinical leaders will work together to come up with a schedule of such Key Meetings, giving Ionis as much advance written notice as practicable so that Ionis may, at Ionis’ expense, plan for
                      its participation in such meetings.

                

        

      

      

      

      
        
          	

                	8.1.7.	
                  Class Generic Claims.  If Roche intends to make any claims in a Product
                      label or regulatory filing that are class generic to ASOs or Ionis’ chemistry platform(s), Roche will provide such claims and regulatory filings to Ionis in advance and will consider in good faith any proposals and comments made by
                      Ionis.

                

        

      

      

      

      
        
          	8.2.	
                  IND; Global Safety Database.

                

        

      

      

      

      
        
          	

                	8.2.1.	
                  Transfer of the IONIS-FB-LRx IND to Roche; Global Safety Database Responsibilities. Until the Completion of the Proposed Phase 2 Trials and any other Phase 2 Trial conducted by Ionis under the Development Plan, Ionis will be the
                      holder of the IND for IONIS-FB-LRx. After Option exercise and upon Completion of the Proposed Phase 2 Trials and any other Phase 2 Trial conducted by Ionis
                      under the Development Plan, Ionis will transfer promptly the IND to Roche. Upon transfer of the IND to Roche and assumption by Roche of regulatory responsibilities under the IND, Roche will assume responsibility for the global safety
                      database related to IONIS-FB-LRx and Roche will be solely responsible for reporting to Regulatory Authorities in accordance with the Applicable Law for
                      expeditable adverse events and for periodic safety reporting relating to the safety of IONIS-FB-LRx and will furnish copies of such reports to Ionis.

                

        

      

      

      

      
        17

        
          

      

      
        
          
            Confidential

          

           

          

          	

                	8.2.2.	
                  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 non-clinical and clinical development and commercialization (the “Ionis Internal ASO Safety Database”). The
                      Ionis Internal ASO Safety Database is an internal database owned and maintained by Ionis to maximize Ionis’ and its partners’ understanding of Ionis’ compounds, and it is separate from, and not a substitute for, the global safety
                      database for which Roche will be responsible under Section 8.2.1 above. To maximize understanding of the safety profile and pharmacokinetics of Ionis
                      compounds, after Option exercise, Roche will cooperate in connection with populating the Ionis Internal ASO Safety Database. To the extent collected by Roche and in the form in which Roche uses/stores such information for its own
                      purposes, Roche will make available to Ionis 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 Roche (but Roche will make such information available to Ionis starting no later than thirty (30) days after Roche’s receipt of such information). In connection with any reported serious
                      adverse event for a Product, Roche will provide Ionis all serious adverse event reports, including initial, interim, follow-up, amended, and final reports. In addition, with respect to Products, Roche will make available to Ionis
                      copies of Annual safety updates filed with each IND and the safety sections of any final Clinical Study reports within thirty (30) days following the date such information is filed or is available to Roche, as applicable. Furthermore,
                      Roche will promptly make available to Ionis any supporting data and answer any follow-up questions reasonably requested by Ionis. All such information disclosed by Roche to Ionis will be Roche Confidential Information; provided, however, that Ionis may disclose any such Roche Confidential Information to (i) Ionis’ other partners pursuant to Section 8.2.2(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 Roche. Roche will contact Ionis’ Chief Medical Officer at Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, California 92010 (or at such other address/contact designated in writing by Ionis) for matters related
                      to the Ionis Internal ASO Safety Database. Roche will also cause its Affiliates and Sublicensees to comply with this Section 8.2.2(a).

                

        

      

      

      

      
        
          	 	(b)	
                  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 inform Roche of such
                      issues and, if requested, provide the data supporting Ionis’ conclusions.

                

           

          

        

      

      
        18

        
          

      

      
        Confidential

      

       

      
      ARTICLE 9.

      FINANCIAL PROVISIONS

       

        

      
        
          	9.1.	
                  Option Fee.  In partial consideration for Roche’s Option hereunder, within
                      ten (10) days following the Effective Date and receipt by Roche of an invoice from Ionis, Roche will pay Ionis an option fee of seventy-five million dollars (US$75,000,000).

                

        

      

      

      

      
        
          	9.2.	
                  Pre-Option Development Milestone.  In partial consideration for Roche’s
                      Option hereunder, Roche will pay Ionis a pre-option development milestone of [***] (the “Pre-Option Development Milestone Payment”),

                      which will be payable within [***] days after Roche receives from Ionis written notice that [***] (the “Pre-Option Development
                        Milestone Event”) and receipt by Roche of an invoice in such amount from Ionis.

                

        

      

      

      

      
        
          	9.3.	
                  License Fee.  Pursuant to Section 6.2, subsequent to Roche’s Option Exercise Notification, Roche will pay to Ionis a license fee of [***] within the timelines set forth in Section 6.2.

                

        

      

      

      

      
        
          	9.4.	
                  Milestone Payments for Achievement of Post-Licensing Milestone Events. As
                      further consideration for the licenses granted herein, Roche will pay to Ionis the applicable one-time milestone payments set forth in Table
                          1 below (each, a “Post-Licensing Milestone Payment”) when the corresponding milestone event listed in Table 1 (each, a “Post-Licensing
                        Milestone Event”) is first achieved by a Product for the specified Indication:

                

        

      

      

      

      	 	
              Table 1

            
	 	
              Post-Licensing Milestone

              Event

            	
              Post-Licensing Milestone

              Payment – Non-Rare

              Disease Indication

            	
              Post-Licensing Milestone

              Payment – Second Indication

            
	 	
              [***]

            	
              [***]

            	
              [***]

            
	 	
              [***]

            	
              [***]

            	
              [***]

            
	 	
              [***]

            	
              [***]

            	
              [***]

            
	 	
              [***]

            	
              [***]

            	
              [***]

            
	 	
              [***]

            	
              [***]

            	
              [***]

            
	 	
              [***]

            	
              [***]

            	
              [***]

            
	 	
              [***]

            	
              [***]

            	
              [***]

            
	 	
              Total Post-Licensing Milestone Payments

            	
              [***]

            	
              [***]

            

      

      

      
        19

        
          

      

      
        
          
            Confidential

             

            

          

          	9.5.	
                  Milestone Payments for First Achievement of Sales Milestone Event. Roche
                      will pay Ionis the applicable one-time milestone payments set forth in Table 2 below (each, a “Sales Milestone Payment”) after the first achievement of the corresponding event
                      listed in Table 2 (each, a “Sales Milestone Event”), by or on behalf of Roche or its Affiliates or Sublicensees.

                

        

      

      

      

      	 	
              Table 2

            
	 	
              Sales Milestone Event

            	
              Sales Milestone

              Payment

            
	 	
              [***] in worldwide Annual Net Sales of a Product

            	
              [***]

            
	 	
              [***] in worldwide Annual Net Sales of a Product

            	
              [***]

            
	 	
              [***] in worldwide Annual Net Sales of a Product

            	
              [***]

            
	 	
              Total Sales Milestone Payments

            	
              [***]

            

      
        
           

          

          	9.6.	
                  Limitations on Milestone Payments; Exceptions; Notice.

                

        

      

      

      

      
        
          	

                	9.6.1.	
                  Each milestone payment set forth in Table 1 and Table 2 above will be paid only once
                      upon the first achievement of the applicable Milestone Event, regardless of the number of Products subsequently achieving such Milestone Event or the number of times a given Product reaches such Milestone Event.

                

        

      

      

      

      
        
          	

                	9.6.2.	
                  If a particular Post-Licensing Milestone Event is not achieved because regulatory activities transpired such that achievement of such earlier Post-Licensing Milestone
                      Event was unnecessary or did not otherwise occur, then upon achievement of a later Post-Licensing Milestone Event the Post-Licensing Milestone Payment applicable to such earlier Post-Licensing Milestone Event will also be due.  For
                      example, if Roche proceeds directly to [***] without achieving the [***], then upon achieving the [***] Milestone Event, both the [***] and [***] Post-Licensing Milestone Payments will be due. For clarity, [***] or [***] in one region
                      does not trigger milestone payments in other regions.

                

        

      

      

      

      
        
          	

                	9.6.3.	
                  If a particular Milestone Event is achieved contemporaneously with or in connection with another Milestone Event, then both Milestone Events will be deemed achieved and
                      the milestone payments for both Milestone Events will be due.

                

        

      

      

      

      
        
          	

                	9.6.4.	
                  Each time a Milestone Event is achieved under Section 9.4 or Section 9.5, Roche will send to Ionis a written notice thereof promptly (but no later than ten (10) Business Days) following the date of achievement of such Milestone Event and such
                      payment will be due within thirty (30) days after the date such Milestone Event was achieved and receipt of an invoice by Roche from Ionis.

                

        

      

      

      

      
        20

        
          

      

      
        
          
            Confidential

             

            

          

          	9.7.	
                  Royalty Payments to Ionis.

                

        

      

      

      

      
        
          	

                	9.7.1.	
                  Roche Full Royalty. As partial consideration for the rights granted to
                      Roche hereunder, subject to the provisions of this Section 9.7.1 and Section 9.7.2,
                      Roche will pay to Ionis royalties on worldwide Annual Net Sales of Products sold by Roche, its Affiliates or Sublicensees, on a country-by-country and Product-by-Product basis, in each case in the amounts as follows in Table 3 below (the “Roche Full
                        Royalty”):

                

           

          

        

      

      	 	 	
              Table 3

            	 
	
              Royalty

              Tier

            	 	
              Worldwide Annual Net Sales of Products

            	
              Royalty

              Rate

            
	
              1

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

            	
              [***]%

            
	
              2

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

            	
              [***]%

            
	
              3

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

            	
              [***]%

            
	
              4

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

            	
              [***]%

            

      
        
           

          

          	

                	(a)	
                  For purposes of Table 3, Worldwide Annual Net Sales for a
                      particular Product will be calculated by [***].

                

        

      

      

      

      
        
          	

                	(b)	
                  Roche will pay Ionis royalties on Net Sales of Products arising from named patient and other similar programs under Applicable Laws, and Roche will provide reports and
                      payments to Ionis consistent with Section 9.11. 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 determining the Full Royalty Period. 

                

        

      

      

      

      
        
          	

                	9.7.2.	
                  Application of Royalty Rates. All royalties set forth under Section 9.7.1 are subject to the provisions of this Section 9.7.2, and are payable
                      as follows:

                

        

      

      

      

      
        
          	

                	(a)	
                  Full Royalty Period. Roche’s obligation to pay Ionis the Roche 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 latest of (i) the date of expiration of the last Valid Claim
                      within the Licensed Patents Covering such Product in the country in which such Product is used or sold, (ii) the date of expiration of 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 unless a [***] in such country, at which time in lieu of paying the Roche Full Royalty, Roche will pay Ionis the Roche Reduced
                      Royalty for such Product in such country in accordance with Section 9.7.2(b) (such royalty period, the “Full Royalty Period”).  For clarity, (X) Licensed Patents that are Jointly-Owned Collaboration Patents, and (Y) Roche Collaboration Patents, will count toward the
                      calculation of the Full Royalty Period in a particular country if the use or sale of a Product by an unauthorized Third Party in such country would infringe a Valid Claim of such Jointly-Owned Collaboration Patent or Roche
                      Collaboration Patent.

                

        

      

      

      

      
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                	(b)	
                  Reduced Royalty Period. Subject to Section 9.7.2(c), on a country-by-country and Product-by-Product basis, after the expiration of the Full Royalty Period in a country and until the end of the Reduced Royalty Period, in
                      lieu of the royalty rates set forth in Table 3 of Section 9.7.1,
                      Roche will pay Ionis royalty rates (the “Roche Reduced Royalty”) on Net Sales of Products in such country calculated on a
                      Calendar Quarter-by-Calendar Quarter basis by [***]; provided,

                        however, that the Roche Reduced Royalty rate in each country will in no event exceed the Reference Rate applicable under this Section 9.7. For
                      example, if peak Calendar Year Net Sales of Products during the Full Royalty Period were US$[***] and royalties paid for that same Calendar Year were US$[***] resulting in a [***], and if [***] and the [***], the applicable [***] in
                      such country would be [***]. Similarly, if the [***], then the applicable [***] in such country would be [***].

                

        

      

      

      

      Notwithstanding anything to the contrary in this subsection (b), if, during the Reduced Royalty Period for a Product, Ionis (on its
          own or with a Third Party) following marketing approval sells an ASO designed to bind to the RNA that encodes Factor B in the Field, then such Reduced Royalty Period will end and Roche’s worldwide license under Section 7.1.1 solely with respect to such Product will become fully paid-up and royalty-free.

      

      

      
        
          	

                	(c)	
                  Limitation on Aggregate Reduction for Roche Royalties.

                

        

      

      

      

      
        
          	

                	(i)	
                  In no event will the royalty reductions under Section 9.7.2(b) reduce the royalties payable
                      to Ionis on Net Sales of the applicable Product in any given period to an amount that is less than the [***].

                

        

      

      

      

      
        
          	

                	(ii)	
                  In no event will the aggregate royalty offsets under Section 9.10.3(b) reduce the royalties
                      payable to Ionis on Net Sales of a Product in the applicable country in any given period to an amount that is less than the greater of (i) [***], and (ii) [***] for such Product in such country in such period.

                

        

      

      

      

      
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                	(d)	
                  End of Royalty Obligation. On a country-by-country basis, other than
                      [***], Roche’s obligation to make royalty payments hereunder 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 [***] in such country and ending when the [***] is (i) with respect to Net Sales of Products
                      in Major Markets, [***], and (ii) [***].

                

        

      

      

      

      
        
          	

                	(e)	
                  Royalty Examples. Schedule 9.7.2(e) attached hereto contains examples of how royalties will be calculated under this Section 9.7.

                

        

      

      

      

      
        
          	

                	(f)	
                  Allocation of Net Sales. If, by reason of one or more royalty rate
                      adjustments under this Section 9.7.2, different royalty rates apply to Net Sales of Products from different countries, Roche will [***] such Net Sales
                      [***]. Schedule 9.7.2(f) attached hereto contains
                      examples of how Net Sales of Products from different countries at different royalty rates will be [***].

                

        

      

      

      

      
        
          	9.8.	
                  Apportionment of Compulsory Sublicensee Consideration. At such time as
                      Roche or any of its Affiliates or Sublicensees enters into a sublicense with a Compulsory Sublicensee, the Parties will discuss and mutually agree upon an adjustment of the royalty due to Ionis under Section 9.7 of this Agreement with respect to sales of Products by such Compulsory Sublicensee, with such adjustment calculated based on a [***].

                

        

      

      

      

      
        
          	9.9.	
                  Reverse Royalty Payments to Roche for Discontinued Products. If Ionis or
                      any of its Affiliates or Sublicensees Commercializes a Discontinued Product for which Roche has paid Ionis the license fee under Section 9.3, then following
                      the First Commercial Sale of such Discontinued Product by Ionis or its Affiliates or Sublicensees, Ionis will pay Roche a royalty of [***] of Annual worldwide net sales of such Discontinued Product (“Ionis Product Reverse Royalties”). Ionis will pay Roche such Ionis Product Reverse Royalties in accordance with the provisions governing payment of
                      royalties from Roche to Ionis in Sections 9.7.2, 9.10, 9.11, 9.12, 9.13,
                      and 9.14 (mutatis mutandis); provided, however, that Ionis’ obligation to pay Roche Ionis Product Reverse Royalties will expire once Ionis has paid Roche an amount equal to [***] for such Discontinued
                      Product under Section 9.4.

                

        

      

      

      

      
        
          	9.10.	
                  Third Party Payment Obligations.

                

        

      

      

      

      
        
          	 	9.10.1.	
                  In-License Agreements.

                

        

      

      

      

      
        
          	

                	(a)	
                  Ionis’ In-License Agreements between the Effective Date and the
                          Time of Option Exercise.  Before Ionis enters into an in-license agreement with a Third Party that would impact the Developing, Manufacturing and/or Commercializing of a Product, Ionis will consult with Roche and
                      discuss the terms and conditions of such license and seek Roche’s permission to enter into such license, which will not be unreasonably denied, conditioned or delayed. Before Roche exercises the Option, Ionis will provide to Roche a
                      final list of all agreements entered into after the Effective Date by Ionis with Third Party licensors or sellers under which Ionis licensed or acquired any Licensed Intellectual Property to be licensed to Roche under Section 7.1.1 (“Additional Ionis In-License Agreements”). 

                      Any payment obligations arising under any Additional Ionis In-License Agreements as they apply to Products that:

                

        

      

      

      

      
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                	(i)	
                  accrue before Option exercise will be paid by [***] as [***]; and

                

        

      

      

      

      
        
          	

                	(ii)	
                  accrue after Option exercise will be paid by [***] to [***] as [***], in which case Section 9.10.3
                      will apply.

                

        

      

      

      

      
        
          	

                	(b)	
                  Roche’s Existing In-License Agreements. Roche will be
                      solely responsible for any Third Party Obligations that become payable by Roche to Third Parties under any agreements or arrangements Roche has with such Third Parties as of the Effective Date, based on the Development or
                      Commercialization of a Product by Roche, its Affiliate or Sublicensee under this Agreement. Any such payment obligations will be paid by [***] to such Third Parties pursuant to the applicable agreement.

                

        

      

      

      

      
        
          	

                	9.10.2.	
                  New In-Licensed Product-Specific Patents.

                

        

      

      

      

      
        
          	

                	(a)	
                  On a Product-by-Product basis, after Option exercise, Roche or Ionis, as the case may be, will provide the other Party written notice of any additional Third Party Patent
                      Rights promptly after it has identified such Third Party Patent Rights as necessary to Develop or Commercialize a Product where such Third Party Patent Rights would be considered a Product-Specific Patent if either Party Controlled
                      such Patent Rights (“Additional Product-Specific Patents”), and Roche will have the first right, but not the obligation, to
                      negotiate with, and obtain a license from the Third Party Controlling such Additional Product-Specific Patents. If Roche obtains any such Additional Product-Specific Patents then any financial obligations under such Third Party
                      agreement will be paid solely by [***] to the Third Party.

                

        

      

      

      

      
        
          	

                	(b)	
                  If, however, Roche elects not to obtain such a license to such Additional Product-Specific Patents, Roche will so notify Ionis, and Ionis may obtain such a license to
                      such Additional Product-Specific Patents and Ionis will include such Additional Product-Specific Patents in the license granted to Roche under Section 7.1.1 provided that Roche agrees in writing to [***].

                

        

      

      

      

      
        
          	

                	9.10.3.	
                  Additional Core IP In-License Agreements.

                

        

      

      

      

      
        
          	

                	(a)	
                  Roche will promptly provide Ionis written notice of any [***] (“Additional

                        Core IP”) that Roche 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. For clarity,
                      Additional Core IP does not include any Patent Rights claiming (or intellectual property related to) [***]. If Ionis obtains such a Third Party license, Ionis will include such Additional Core IP in the license granted to Roche under
                      Section 7.1.1, and any financial obligations under such Third Party agreement will be paid solely by [***] as [***].

                

        

      

      

      

      
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                	(b)	
                  If, however, Ionis elects not to obtain such a license to such Third Party intellectual property, Ionis will so notify Roche, and Roche may obtain such a Third Party
                      license and, subject to Section 9.7.2(c)(ii), Roche may offset an amount equal to [***] of [***] paid by Roche under such Third Party license against any
                      [***] of this Agreement in such country for [***].

                

        

      

      

      

      
        
          	

                	(c)	
                  If Ionis does not agree with Roche that a license to such Third Party Patent Rights is necessary to [***], then Ionis will send written notice to such effect to Roche,
                      and the Parties will engage a mutually agreed 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 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 Roche is permitted to [***]. The costs of any Third Party expert engaged under this Section 9.10.3(c) will be paid by the Party against whom the
                      Third Party lawyer makes his or her determination.

                

        

      

      

      

      
        
          	9.11.	
                  Payments.

                

        

      

      

      

      
        
          	

                	9.11.1.	
                  Commencement. Beginning with the Calendar Quarter in which the First
                      Commercial Sale, named patient sale, compassionate use sale or other similar sales for a Product is made and for each Calendar Quarter thereafter, Roche will make royalty payments to Ionis under this Agreement within [***] following
                      the end of each such Calendar Quarter.

                

        

      

      

      

      
        
          	

                	9.11.2.	
                  Royalty Reporting. Each royalty payment will be accompanied by a report,
                      summarizing in writing for the relevant Calendar Quarter on a Product-by-Product basis the following information:

                

        

      

      

      

      
        
          	

                	(a)	
                  Sales in Swiss Francs on a country-by-country basis;

                

        

      

      

      

      
        
          	

                	(b)	
                  Net Sales in Swiss Francs on a country-by-country basis;

                

        

      

      

      

      
        
          	

                	(c)	
                  Total worldwide Net Sales in Swiss Francs;

                

        

      

      

      

      
        
          	

                	(d)	
                  Exchange rate used for the conversion of Net Sales from Swiss Francs to U.S. Dollars pursuant to Section

                          9.11.4;

                

        

      

      

      

      
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                	(e)	
                  Royalty rate pursuant to Section 9.7.1 and Section 9.7.2, as applicable; and

                

        

      

      

      

      
        
          	

                	(f)	
                  Total royalty payable in U.S. Dollars.

                

        

      

      

      

      In addition, Roche will include in each report under this Section
              9.11.2 information regarding any Net Sales of Products sold for named patient, compassionate use or other similar sales and any consideration received from any Compulsory Sublicensees.

      

      

      
        
          	

                	9.11.3.	
                  No Payments and Estimates. After first Approval, if no royalties or other
                      payments from Product sales are payable in respect of a given Calendar Quarter, Roche 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 (or any named patient sale, compassionate use sale or other similar sales of a Product) is made and for each Calendar Quarter thereafter, within ten
                      (10) Business Days following the end of each such Calendar Quarter, Roche will provide Ionis a [***] report estimating the total (A) Sales and Net Sales for Products projected for such Calendar Quarter, and (B) if available, the
                      amount of any consideration payable to Roche under sublicenses with Compulsory Sublicensees.

                

        

      

      

      

      
        
          	

                	9.11.4.	
                  Mode of Payment. All payments under this Agreement will be (i) payable in
                      full in U.S. Dollars, regardless of the country(ies) in which sales are made, (ii) made by wire transfer of immediately available funds to an account designated by Ionis in writing, and (iii) irrevocable and non-refundable. Any
                      corrections to calculations of royalty payments previously paid will be adjusted to the next royalty payment due. When calculating the Sales of a Product that occur in currencies other than U.S. Dollars, Roche will convert the amount
                      of such sales into Swiss Francs and then into U.S. Dollars using Roche’s then current internal foreign currency translation actually used on a consistent basis in preparing its audited financial statements (currently YTD average rate
                      as reported by Reuters).

                

        

      

      

      

      
        
          	

                	9.11.5.	
                  Records Retention. Commencing with the First Commercial Sale or named
                      patient sale of a Product, Roche 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 Roche hereunder.

                

        

      

      

      

      
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          	9.12.	
                  Audits. After the first Approval of a Product, during the remaining
                      Agreement Term and for a period of thirty-six (36) calendar months thereafter, at the request and expense of Ionis, Roche will permit an independent certified public accountant of internationally recognized standing appointed by
                      Ionis, at reasonable times and upon at least sixty (60) Business Days written notice, but in no case more than once per Calendar Year, 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 thirty-six (36) calendar months for those countries specifically requested by Ionis. No Calendar Year can
                      be audited more than once.  Any and all records of Roche examined by such independent certified public accountant will be deemed Roche’s Confidential Information. The independent certified public accountant will share all draft
                      reports with Roche before sharing the draft audit report with Ionis and before issuing the final document. Upon completion of the audit, the accounting firm will provide both Roche and Ionis with a written report disclosing whether
                      the calculation of Net Sales and royalty payments made by Roche are correct and the specific details concerning any discrepancies (“Audit

                        Report”). If any Audit Report  shows that Roche’s payments under this Agreement were less than the royalty amount that should have been paid, then Roche will make all payments required to be made by paying Ionis the
                      difference between such amounts to eliminate any discrepancy revealed by said inspection with the next royalty payment due, with interest calculated in accordance with Section

                          9.14. If any Audit Report shows that Roche’s payments under this Agreement were greater than the royalty amount that should have been paid, then [***] or [***]. Ionis will pay all fees charged by such accountant
                      pursuant to the audit, except that, if the audit determines that any additional amounts payable by Roche for an audited period exceed [***] of
                      the amount actually paid for such audited period, then, in addition to paying Ionis any unpaid amounts discovered in such audit, Roche will pay the fees and expenses charged by such accountant.

                

        

      

      

      

      
        
          	9.13.	
                  Taxes.

                

        

      

      

      

      
        
          	 	9.13.1.	
                  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.

                

        

      

      

      

      
        
          	

                	9.13.2.	
                  Withholding Tax. 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 to secure an exemption from, or a reduction in, any withholding taxes, the Parties will provide such
                      documentation to the extent they are able to do so. In accordance with the procedures set forth in Section 12.3, the receiving Party will also indemnify the
                      paying Party for any tax, interest or penalties imposed on the paying Party if the paying Party improperly reduces or eliminates withholding tax based upon representations made by the receiving Party.

                

        

      

      

      

      
        
          	

                	9.13.3.	
                  Tax Cooperation. At least fifteen (15) days prior to the date a given
                      payment is due under this Agreement, the non-paying Party will provide the paying Party with any and all tax forms that may be reasonably necessary for the paying Party to lawfully not withhold tax or to withhold tax at a reduced rate
                      with respect to such payment under an applicable bilateral income tax treaty. Following the paying Party’s timely receipt of such tax forms from the non-paying Party, the paying Party 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. The non-paying Party will provide any such tax forms to the paying Party 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 9.13.

                

           

          

        

      

      
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      The provisions of this Section 9.13 are to be read in
          conjunction with the provisions of Section 15.4 below.

      

      

      
        
          	9.14.	
                  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 (i) one month LIBOR rate in effect on the date that such payment would have been first due plus two
                      percentage points (2%) or (ii) the maximum rate permissible under applicable law.

                

        

      

      

      

      ARTICLE 10.

      INTELLECTUAL PROPERTY

      

      

      
        
          	10.1.	
                  Ownership.

                

        

      

      

      

      
        
          	

                	10.1.1.	
                  Ionis Intellectual Property and Roche Intellectual Property. As between
                      the Parties, Ionis will own and retain all of its rights, title and interest in and to the Licensed Know-How and Licensed Patents and Roche will own and retain all of its rights, title and interest in and to the Roche Know-How and
                      Roche Patents, subject to any assignments, rights or licenses expressly granted by one Party to the other Party under this Agreement.

                

        

      

      

      

      
        
          	

                	10.1.2.	
                  Agreement Intellectual Property. Each Party will promptly disclose to the
                      other Party in writing, and will cause its Affiliates to so disclose, the discovery, development, or creation of any invention made solely or jointly by the Parties in connection with the performance of obligations 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
                      Collaboration Intellectual Property 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.

                

        

      

      

      

      
        
          	

                	10.1.3.	
                  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, and will cooperate with respect to the activities set forth in this ARTICLE 10.  Ionis’ obligation to
                      participate in the JPC will terminate upon the date Ionis is no longer obligated to participate in the JSC.  Thereafter, Ionis will have the right, but not the obligation, to participate in JPC meetings. If Ionis chooses not to
                      participate, then Roche can dissolve the JPC. The JPC determines the invention classification for each invention arising under this Agreement. The classifications are (i) Ionis Product-Specific Patents, (ii) Ionis Collaboration
                      Patents, (iii) Roche Collaboration Patents, (iv) Jointly-Owned Collaboration Patents, (v) Ionis Core Technology Patents, and (vi) Ionis Manufacturing and Analytical Patents. The JPC will endeavor to separate the claims within such
                      Patent Rights into separate and distinct patent applications corresponding with the categories described in this Section 10.1.3(a) to the extent possible
                      without diminishing the patentability of the inventions.

                

        

      

      

      

      
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                	(b)	
                  A strategy will be discussed with regard to (x) prosecution and maintenance, defense and enforcement of (A) Ionis Product-Specific Patents, (B) Ionis Collaboration
                      Patents, (C) Roche Collaboration Patents, and (D) Jointly-Owned Collaboration Patents licensed to Roche under Section 7.1.1 in connection with a Product,
                      (y) defense against allegations of infringement of Third Party Patent Rights, and (z) licenses to Third Party Patent Rights or Know-How (including whether to obtain any licenses under any such Third-Party Patent Rights or Know-How,
                      and whether there are any known Third Party Obligations applicable to a particular Product), in each case to the extent such matter would be reasonably likely to have a material impact on the Agreement or the licenses granted
                      hereunder, which strategy will be considered in good faith by the Party entitled to prosecute, enforce and defend such Patent Rights hereunder, but will not be binding on such Party.  Notwithstanding the above, subject to the
                      provisions of Section 9.10, Roche will have final say as to whether to obtain any licenses under Third-Party Patent Rights or Know-How.

                

        

      

      

      

      
        
          	

                	(c)	
                  In addition, the JPC will be responsible for the determination of inventorship. The determination of inventorship will be in accordance with United States patent laws and
                      therefore will determine if the invention is solely or jointly owned by the relevant Party or Parties. In case of a dispute in the JPC (or otherwise between Ionis and Roche) over inventorship or classification, if the JPC cannot
                      resolve such dispute, even after seeking the JSC’s input, 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.

                

        

      

      

      

      
        
          	

                	(d)	
                  The JPC will comprise an equal number of members from each Party. The JPC 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 10. The JPC will determine by unanimous consent the JPC operating procedures at its first meeting. To the
                      extent reasonably requested by either Party, the JPC will solicit the involvement of more senior members of their respective legal departments with respect to critical issues. Each Party’s representatives on the JPC 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.

                

        

      

      

      

      
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          	10.2.	
                  Prosecution and Maintenance of Patents.

                

        

      

      

      

      
        
          	

                	10.2.1.	
                  Patent Filings. The Party responsible for Prosecution and Maintenance of
                      any Patent Rights as set forth in Section 10.2.2 and Section 10.2.3 will
                      endeavor to obtain patent protection for a 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.

                

        

      

      

      

      
        
          	

                	10.2.2.	
                  Licensed Patents and Roche Patents.

                

        

      

      

      

      
        
          	

                	(a)	
                  Licensed Patents.

                

        

      

      

      

      
        
          	

                	(i)	
                  Ionis Core and Manufacturing Patents. Ionis will at all times control and
                      be responsible for all aspects of (i) the Ionis Core Technology Patents, and (ii) the Ionis Manufacturing and Analytical Patents.

                

        

      

      

      

      
        
          	

                	(ii)	
                  Ionis Product-Specific Patents.

                

        

      

      

      

      (1)          Before Option Exercise. Before Option exercise, subject to Section 10.2.3 and Section 10.2.4, at Ionis’ expense, Ionis will control and be responsible for Prosecuting and Maintaining the Ionis Product-Specific Patents.

      

      

      (2)         After Option Exercise. After Option exercise, subject to Section 10.2.3 and Section 10.2.4, at Roche’s expense, so long as the applicable license to Roche under Section 7.1.1
          is in effect, Roche will control and be responsible for all aspects of the Prosecution and Maintenance of all Ionis Product-Specific Patents (including any Jointly-Owned Collaboration Patents that are also Product-Specific Patents) Covering
          Products and will either (i) use commercially reasonably efforts to Prosecute and Maintain such Patent Rights or (ii) offer to assign Roche’s entire right, title and interest in such Patent Rights to Ionis, in which case following any such
          assignment all licenses granted in this Agreement by Ionis to Roche under such Patent Rights will become non-exclusive and the exclusivity covenants under Section 5.1 will no longer apply to such Patent Rights.

      

      

      
        
          	

                	(b)	
                  Roche Patents and Roche Collaboration Patents. Roche will control and be
                      responsible for all aspects of the Prosecution and Maintenance of all Roche Patents and Roche Collaboration Patents, subject to Section 10.2.3 and Section 10.2.4.

                

        

      

      

      

      
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                	10.2.3.	
                  Jointly-Owned Collaboration Patents. The Parties will decide through the
                      JPC the appropriate Party to control and be responsible for Prosecuting and Maintaining all Jointly-Owned Collaboration Patents not provided for above.

                

        

      

      

      

      
        
          	

                	10.2.4.	
                  Other Matters Pertaining to Prosecution and Maintenance of Patents.

                

        

      

      

      

      
        
          	

                	(a)	
                  Each Party will keep the other Party informed through the JPC as to material developments with respect to the Prosecution and Maintenance of the Product-Specific Patents
                      or Jointly-Owned Collaboration Patents for which such Party has responsibility for Prosecution and Maintenance pursuant to Section 10.2.2 or this Section 10.2.4, including by providing copies of material data as it arises, any office actions or office action responses or other correspondence that such
                      Party provides to or receives from any patent office, including notice of all interferences, reissues, re-examinations, oppositions or requests for patent term extensions, and all patent-related filings, and by providing the other
                      Party the timely opportunity to have reasonable input into the strategic aspects of such Prosecution and Maintenance.

                

        

      

      

      

      
        
          	

                	(b)	
                  If Roche elects (i) not to file and prosecute patent applications for the Jointly-Owned Collaboration Patents or Ionis Product-Specific Patents that have been licensed to
                      Roche under this Agreement for which Roche has responsibility for Prosecution and Maintenance pursuant to Section 10.2.2 or Section 10.2.3 (“Roche-Prosecuted Patents”) in a particular country, (ii)
                      not to continue the prosecution (including any interferences, oppositions, reissue proceedings, re-examinations, and patent term extensions, adjustments, and restorations) or maintenance of any Roche-Prosecuted Patent in a particular
                      country, or (iii) not to file and prosecute patent applications for the Roche-Prosecuted Patent in a particular country following a written request from Ionis to file and prosecute in such country, then Roche will so notify Ionis
                      promptly in writing of its intention in good 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 Ionis will have the right, but not the
                      obligation, to file, prosecute, maintain, enforce, or otherwise pursue such Roche-Prosecuted Patent in the applicable country at its own expense with counsel of its own choice. In such case, Roche will cooperate with Ionis to file
                      for, or continue to Prosecute and Maintain or enforce, or otherwise pursue such Roche-Prosecuted Patent in such country. Notwithstanding anything to the contrary in this Agreement, if Ionis assumes responsibility for the Prosecution
                      and Maintenance of any such Roche-Prosecuted Patent under this Section 10.2.4(b), Ionis will have no obligation to notify Roche if Ionis intends to abandon
                      such Roche-Prosecuted Patent. The analogous situation will apply mutatis mutandis with regard to Patent Rights (excluding Ionis Core Technology
                      Patents and Ionis Manufacturing and Analytical Patents) for which Ionis has responsibility for Prosecution and Maintenance pursuant to Section 10.2.2 or Section 10.2.3.

                

        

      

      

      

      
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                	(c)	
                  The Parties, through the JPC, will cooperate in good faith to determine if and when any divisional or continuation applications will be filed with respect to any
                      Jointly-Owned Collaboration Patents or Product-Specific Patents, and where a divisional or continuation patent application filing would be practical and reasonable, then such a divisional or continuation filing will be made.

                

        

      

      

      

      
        
          	

                	(d)	
                  If the Party responsible for Prosecution and Maintenance pursuant to Section 10.2.3 intends
                      to abandon such Jointly-Owned Collaboration Patent without first filing a continuation or substitution, then such Party will notify the other Party of such intention at least sixty (60) days before such Jointly-Owned Collaboration
                      Patent will become abandoned, and such other Party will have the right, but not the obligation, to assume responsibility for the Prosecution and Maintenance thereof at its own expense (subject to Section 10.3.1) 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 interest in and to such Jointly-Owned Collaboration Patents. If a Party assumes responsibility for the Prosecution and Maintenance of any such
                      Jointly-Owned Collaboration Patents under this Section 10.2.4(d), such Party will have no obligation to notify the other Party of any intention of such
                      Party to abandon such Jointly-Owned Collaboration Patents.

                

        

      

      

      

      
        
          	

                	(e)	
                  In addition, the Parties will consult, through the JPC, 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.

                

        

      

      

      

      
        
          	10.3.	
                  Patent Costs.

                

        

      

      

      

      
        
          	

                	10.3.1.	
                  Jointly-Owned Collaboration Patents. Unless the Parties agree otherwise,
                      Ionis and Roche will share equally the Patent Costs associated with the Prosecution and Maintenance of Jointly-Owned Collaboration Patents; provided
                        that, either Party may decline to pay its share of costs for filing, prosecuting and maintaining any Jointly-Owned Collaboration 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 interest in and to such Jointly-Owned Collaboration Patents.

                

        

      

      

      

      
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                	10.3.2.	
                  Licensed Patents and Roche Patents. Except as set forth in Section 10.2.4 and Section 10.3.1, 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 10.2; provided, however, that after Option exercise, Roche will be solely responsible for Patent Costs arising
                      from the Prosecution and Maintenance of the Ionis Product-Specific Patents; provided that, Roche may decline to pay for filing, prosecuting and
                      maintaining any such Ionis Product-Specific Patents in a particular country or particular countries, in which case all licenses granted in this Agreement by Ionis to Roche under such Patent Rights will become non-exclusive and the
                      exclusivity covenants under Section 5.1 will no longer apply to such Patent Rights.

                

        

      

      

      

      
        
          	10.4.	
                  Defense of Claims Brought by Third Parties.

                

        

      

      

      

      
        
          	

                	10.4.1.	
                  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 Option exercise at its sole cost and expense and (b)  Roche will have the first right, but not the
                      obligation, to defend against any such Proceeding initiated after Option exercise 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 10.4, and the Lead Party will keep the other Party apprised of the progress of such Proceeding. If the Lead Party elects not to defend against a Proceeding, then the Lead
                      Party will so notify the other Party in writing within sixty (60) 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 10.4. Each Party will provide the other Party with prompt written notice of the commencement of any such Proceeding under this Section
                          10.4, 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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                	10.4.2.	
                  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, Ionis will have the first right, but not the obligation, to defend
                      against and settle such Proceeding at its sole cost and expense. Roche 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 Roche 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 10.4.2, and Ionis will promptly furnish Roche with a copy of each communication relating to the
                      alleged infringement received by Ionis.

                

        

      

      

      

      
        
          	

                	10.4.3.	
                  Interplay Between Enforcement of IP and Defense of Third Party Claims.  
                      Notwithstanding the provisions of Section 10.4.1 and Section 10.4.2, to the
                      extent that a Party’s defense against a Third Party claim of infringement under this Section 10.4 involves (i) the enforcement of the other Party’s Know-How
                      or Patent Rights, or (ii) 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

                          10.5 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
                          10.5, 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

                          10.5, to enforce such Know-How or Patent Rights or defend such invalidity claim).

                

        

      

      

      

      
        
          	10.5.	
                  Enforcement of Patents Against Competitive Infringement.

                

        

      

      

      

      
        
          	

                	10.5.1.	
                  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 obligation of confidentiality with respect to any Product-Specific Patents by reason of the development,
                      manufacture, use or commercialization of a product directed against the RNA that encodes Factor B 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 10.5.7 below, such written notice will be given within ten (10) Business Days.

                

        

      

      

      

      
        
          	

                	10.5.2.	
                  Before Option Exercise. For any Competitive Infringement occurring after
                      the Effective Date but before Option exercise, 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 Roche will have the
                      right to be represented in that action by counsel of its own choice at its own expense, however, Ionis will have the sole right to control such
                      litigation.  Ionis will provide Roche with prompt written notice of the commencement of any such Proceeding, and Ionis will keep Roche apprised of the progress of such Proceeding.  If Ionis fails to initiate a Proceeding within a
                      period of ninety (90) days after receipt of written notice of such Competitive Infringement (subject to a ninety (90)-day extension to conclude negotiations, which extension will apply only if Ionis has commenced good faith
                      negotiations with an alleged infringer for elimination of such Competitive Infringement within such ninety (90)-day period), Roche 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 10.5.2 to the extent involving any Ionis Core Technology Patents or Ionis Manufacturing and Analytical Patents.

                

        

      

      

      

      
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                	10.5.3.	
                  After Option Exercise.  For any Competitive Infringement with respect to a
                      Product (except for a Discontinued Product) occurring after Option exercise, so long as part of such Proceeding Roche also enforces any Patent Rights Controlled by Roche being infringed that Cover a Product, then Roche 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, Roche will have the right to control such litigation.  If Roche fails to initiate a Proceeding
                      within a period of ninety (90) days after receipt of written notice of such Competitive Infringement (subject to a 90-day extension to conclude negotiations, if Roche has commenced good faith negotiations with an alleged infringer for
                      elimination of such Competitive Infringement within such ninety (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 Roche
                      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 10.5.3 to the extent involving any Ionis Core Technology Patents or Ionis Manufacturing and Analytical Patents.

                

        

      

      

      

      
        
          	

                	10.5.4.	
                  Joinder.

                

        

      

      

      

      
        
          	

                	(a)	
                  If a Party initiates a Proceeding in accordance with this Section 10.5, 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

                          10.5.5, the costs and expenses of each Party incurred pursuant to this Section 10.5.4(a) will be borne by the Party initiating such
                      Proceeding.

                

        

      

      

      

      
        
          	

                	(b)	
                  If one Party initiates a Proceeding in accordance with this Section 10.5, 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.

                

        

      

      

      

      
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                	10.5.5.	
                  Share of Recoveries. Any damages or other monetary awards recovered with
                      respect to a Proceeding brought pursuant to this Section 10.5 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); then

                

        

      

      

      

      
        
          	

                	(b)	
                  any remaining proceeds constituting direct or actual damages for acts of infringement occurring before Roche’s exercise of the Option will be (i) [***]; or (ii) [***];
                      then

                

        

      

      

      

      
        
          	

                	(c)	
                  any remaining proceeds constituting direct or actual damages for acts of infringement occurring after Roche’s exercise of the Option will be treated [***], and [***];
                      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.

                

        

      

      

      

      
        
          	

                	10.5.6.	
                  Settlement. Notwithstanding anything to the contrary under this ARTICLE 10, neither Party may enter a settlement, consent judgment or other voluntary final disposition of a suit under this ARTICLE 10 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.

                

        

      

      

      

      
        
          	

                	10.5.7.	
                  35 U.S.C. § 271(e)(2) Infringement. Notwithstanding anything to the
                      contrary in this Section 10.5, solely with respect to Licensed Patents, for a Competitive Infringement under 35 U.S.C. § 271(e)(2), the time period set
                      forth in Section 10.5.2 during which a Party will have the initial right to bring a Proceeding will be shortened to a total of twenty-five (25) days, so
                      that, to the extent the other Party has the right, pursuant to such Section 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 twenty-five (25) days after such first Party’s receipt of written notice of such Competitive Infringement.

                

        

      

      

      

      
        
          	10.6.	
                  Other Infringement.

                

        

      

      

      

      
        
          	

                	10.6.1.	
                  Jointly-Owned Collaboration Patents. With respect to the infringement of a
                      Jointly-Owned Collaboration 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 10.6.1 will be shared as follows: (i) 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); (ii) any remaining proceeds constituting direct damages will be [***] and will retain the remainder of such proceeds, and (iii) any
                      remaining proceeds constituting punitive or treble damages will be allocated as follows: (A) if the Parties jointly initiate a Proceeding pursuant to this Section
                          10.6.1, [***] of such proceeds; and (B) if only one Party initiates the Proceeding pursuant to this Section 10.6.1, such Party will receive
                      [***] of such proceeds and the other Party will receive [***] of such proceeds.

                

        

      

      

      

      
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                	10.6.2.	
                  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.

                

        

      

      

      

      
        
          	

                	10.6.3.	
                  Patents Solely Owned by Roche. Roche will retain all rights to pursue an
                      infringement of any Patent Right solely owned by Roche which is other than a Competitive Infringement and Roche will retain all recoveries with respect thereto.

                

        

      

      

      

      
        
          	10.7.	
                  Patent Listing.

                

        

      

      

      

      
        
          	

                	10.7.1.	
                  Roche’s Obligations. Roche 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 JPC, to evaluate and identify all applicable Patent
                      Rights, and Roche will have the right to review, where reasonable, original records relating to any invention for which Patent Rights are being considered by the JPC for any such listing. Notwithstanding the preceding sentence, Roche
                      will retain final decision-making authority as to the listing of all applicable Patent Rights for a Product that are not Ionis Core Technology Patents or Ionis Manufacturing and Analytical Patents, regardless of which Party owns such
                      Patent Rights.

                

        

      

      

      

      
        
          	

                	10.7.2.	
                  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 JPC, 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 JPC 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.

                

        

      

      

      

      
        
          	10.8.	
                  Joint Research Agreement under the Leahy-Smith America Invents Act. If a
                      Party intends to invoke its rights under 35 U.S.C. § 102(c) of the Leahy-Smith America Invents Act, it will notify the other Party and neither Party will make an election under such provision when exercising its rights under this ARTICLE 10 without the prior written consent of the other Party (such consent not to be unreasonably withheld, conditioned or delayed), and the Parties will use
                      reasonable efforts to cooperate and coordinate their activities with such 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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          	10.9.	
                  Obligations to Third Parties. Notwithstanding any of the foregoing, each
                      Party’s rights and obligations with respect to Licensed Intellectual Property under this ARTICLE 10 will be subject to the Third Party rights and
                      obligations under any (i) Third Party agreements for Additional Product-Specific Patents, the restrictions and obligations of which Roche has agreed to under Section
                          9.10.2(b), (ii) the Prior Agreement, and (iii) Additional 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 Roche hereunder and this Agreement purports to grant any such rights to Roche, Ionis will act in such regard with respect to such
                      Patent Rights at Roche’s direction.

                

        

      

      

      

      
        
          	10.10.	
                  Additional Right and Exceptions. Notwithstanding any provision of this ARTICLE 10, but subject to Section 10.4.3,  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. If Ionis determines, in Ionis’ sole discretion, not to enforce any Ionis Core Technology Patents or Ionis Manufacturing and Analytical Patents and does not permit Roche to so enforce such Patent Rights, then the Parties
                      will mutually agree on an appropriate adjustment (if any) of the future consideration payable by Roche under this Agreement to reflect any adverse impact Ionis’ failure to enforce such Patent Rights has on Products.

                

        

      

      

      

      
        
          	10.11.	
                  Patent Term Extension. The Parties will cooperate with each other in gaining patent term extension wherever applicable to a Product, including European supplementary protection certificates and pediatric
                      exclusivity. After exercising the Option, Roche will determine which Ionis Product-Specific Patents and Jointly Owned Collaboration Patents that are also Product-Specific Patents will be extended and what extensions will be sought.

                

        

      

      

      

      
        
          	10.12.	
                  No Challenge. If, during the Agreement Term, solely with respect to rights
                      to the Ionis Product-Specific Patents that are included (or, prior to Option exercise, are eligible to be included) in a license granted to Roche under Section 7.1.1,
                      Roche, its Affiliates or Sublicensees, in any country, (a) commence or otherwise voluntarily determine to participate in (other than 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) any action or proceeding, challenging or denying the enforceability or validity of any claim within an issued patent or patent application within such Ionis
                      Product-Specific Patents, or (b) direct, support or actively assist any other Person (other than 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) 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 Ionis Product-Specific Patents, then
                      unless, within thirty (30) days after written notice from Ionis, Roche rescinds any actions brought by Roche, its Affiliates, or Sublicensees, Ionis may, to the extent permitted under Applicable Law, terminate this Agreement and the
                      provisions of Section 13.4.1 and Section 13.4.2 will apply; [***].

                

           

          

        

      

      
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      ARTICLE 11.

      REPRESENTATIONS AND WARRANTIES

      

      

      
        
          	11.1.	
                  Representations and Warranties of Both Parties. Each Party hereby
                      represents and warrants to the other Party, as of the Effective Date, that:

                

        

      

      

      

      
        
          	

                	11.1.1.	
                  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;

                

        

      

      

      

      
        
          	

                	11.1.2.	
                  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;

                

        

      

      

      

      
        
          	

                	11.1.3.	
                  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;

                

        

      

      

      

      
        
          	

                	11.1.4.	
                  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 to the best of its knowledge and belief violate any law or regulation of any court, governmental body or administrative or other agency having jurisdiction over such
                      Party;

                

        

      

      

      

      
        
          	

                	11.1.5.	
                  to the best of its knowledge and belief, other than with respect to the HSR Act, 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

                

        

      

      

      

      
        
          	

                	11.1.6.	
                  it has not employed (and, to the best of its knowledge and belief, 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 Non-Clinical Studies or Clinical Studies of a Product and its activities under the Development Plan.

                

        

      

      

      

      
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          	11.2.	
                  Representations and Warranties of Ionis. Ionis hereby represents and
                      warrants to Roche, as of the Effective Date, that:

                

        

      

      

      

      
        
          	

                	11.2.1.	
                  To the best of its knowledge and belief, there are no additional licenses under any intellectual property owned or Controlled by Ionis or its Affiliates as of the
                      Effective Date that would be required in order for Roche to further Develop and Commercialize a Product existing on the Effective Date.

                

        

      

      

      

      
        
          	

                	11.2.2.	
                  The Licensed Intellectual Property 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 Products existing on the Effective Date in the Field. Ionis has not previously assigned, transferred, conveyed or otherwise encumbered its right, title and interest in the
                      Licensed Intellectual Property in a manner that conflicts with any rights granted to Roche hereunder.

                

        

      

      

      

      
        
          	

                	11.2.3.	
                  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 Licensed Intellectual Property 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 Licensed Intellectual Property that would impact activities
                      under this Agreement.

                

        

      

      

      

      
        
          	

                	11.2.4.	
                  Schedule 11.2.4(a), Schedule 11.2.4(b)
                      and Schedule 11.2.4(c) set forth true, correct and
                      complete lists of all Ionis Core Technology Patents, Ionis Manufacturing and Analytical Patents, and Ionis Product-Specific Patents that apply to Products as of the Effective Date, 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 Roche under this Agreement.

                

        

      

      

      

      
        
          	

                	11.2.5.	
                  (a) There is no fact or circumstance known by Ionis that would cause Ionis to reasonably conclude that any Licensed 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 Licensed Patent is not properly identified on each patent, (c) all official fees, maintenance fees and annuities for the
                      Licensed Patents have been paid and all administrative procedures with governmental agencies have been completed, (d) none of the Ionis Product-Specific Patents that would be licensed by Ionis to Roche upon Option exercise under this
                      Agreement is currently involved in any interference, reissue, re-examination, cancellation or opposition proceeding and neither Ionis, nor any of its Affiliates, has received any written notice from any person, or has knowledge, of
                      such actual or threatened proceeding, and (e) to the best of Ionis’ knowledge and belief, Roche’s practice of the inventions claimed in the Ionis Product-Specific Patents in the performance of the Development Plan contemplated as of
                      the Effective Date will not [***].

                

        

      

      

      

      
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                	11.2.6.	
                  Schedule 11.2.6 is a complete and accurate list of the one Prior Agreement, which is the only agreement that creates Third Party Obligations that affect the rights granted by Ionis to Roche under this Agreement. 
                      Ionis is not in default of such Prior Agreement, and the applicable Third Party, to the best knowledge of Ionis, has no grounds upon which to claim that Ionis is in default that would affect the rights granted by Ionis to Roche under
                      this Agreement. To the best knowledge of Ionis, the applicable Third Party is not in default with respect to a material obligation under such Prior Agreement that would adversely impact activities under this Agreement.

                

        

      

      

      

      
        
          	

                	11.2.7.	
                  Ionis has all rights necessary to grant the option and licenses contained in this Agreement, and has the ability to work exclusively with Roche as set forth in this
                      Agreement, including the covenants granted in Section 5.1.

                

        

      

      

      

      
        
          	11.3.	
                  Ionis Covenants. Ionis hereby covenants to Roche that, except as expressly
                      permitted under this Agreement:

                

        

      

      

      

      
        
          	

                	11.3.1.	
                  Ionis will promptly amend Schedule 11.2.4(a), Schedule 11.2.4(b) and Schedule 11.2.4(c) and submit such amended Schedules to Roche 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.

                

        

      

      

      

      
        
          	

                	11.3.2.	
                  during the Agreement Term, Ionis will maintain and not breach (i) the Prior Agreement, (ii) any Additional Ionis In-License Agreements (if any), and (iii) any agreements
                      with Third Parties entered into after the Option exercise (including Third Party agreements for Additional Product-Specific Patents described in Section 9.10.2(b)
                      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 Roche for a Product under this Agreement (collectively (i), (ii), and (iii),
                      “New Third Party Licenses”);

                

        

      

      

      

      
        
          	

                	11.3.3.	
                  Ionis will promptly notify Roche 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 Roche
                      to cure such breach on Ionis’ behalf upon Roche’s request;

                

        

      

      

      

      
        
          	

                	11.3.4.	
                  Ionis will not amend, modify or terminate any New Third Party License in a manner that would adversely affect Roche’s rights hereunder without first obtaining Roche’s
                      written consent, which consent may be withheld in Roche’s sole discretion;

                

        

      

      

      

      
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                	11.3.5.	
                  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 Roche under this Agreement;

                

        

      

      

      

      
        
          	

                	11.3.6.	
                  Ionis will cause its Affiliates, licensees and sublicensees to comply with the terms of Section 5.1;

                

        

      

      

      

      
        
          	

                	11.3.7.	
                  all employees and contractors of Ionis performing Development activities hereunder on behalf of Ionis will be obligated to assign all right, title and interest in and to
                      any inventions (or grant a license to Ionis or an option to obtain such a license) developed by them, whether or not patentable, to Ionis or such Affiliate, respectively, as the sole owner thereof; and

                

        

      

      

      

      
        
          	

                	11.3.8.	
                  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 Roche to further Develop, Manufacture or Commercialize a Product, and Roche has exercised its Option and the license granted to Roche under this Agreement is in effect, Ionis will make such technology available to Roche on
                      commercially reasonable terms.

                

        

      

      

      

      
        
          	11.4.	
                  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. ROCHE AND IONIS UNDERSTAND THAT PRODUCTS ARE THE SUBJECT OF ONGOING RESEARCH AND DEVELOPMENT
                        AND THAT NEITHER PARTY CAN ASSURE THE SAFETY, USEFULNESS OR COMMERCIAL OR TECHNICAL VIABILITY OF THE PRODUCTS.

                

        

      

      

      

      ARTICLE 12.

      INDEMNIFICATION; INSURANCE

      

      

      
        
          	12.1.	
                  Indemnification by Roche. Roche 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:

                

        

      

      

      

      
        
          	

                	12.1.1.	
                  the gross negligence or willful misconduct of Roche, its Affiliates or Sublicensees and its or
                      their respective directors, officers, employees and agents, in connection with Roche’s performance of its obligations or exercise of its rights under this Agreement;

                

        

      

      

      

      
        
          	

                	12.1.2.	
                  any breach of any representation or warranty or express covenant made by Roche under ARTICLE 11
                      or any other provision under this Agreement;

                

        

      

      

      

      
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                	12.1.3.	
                  the Development or Manufacturing activities that are conducted by or on behalf of Roche 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

                

        

      

      

      

      
        
          	

                	12.1.4.	
                  the Commercialization of a Product by or on behalf of Roche 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 12.2.

      

      

      
        
          	12.2.	
                  Indemnification by Ionis. Ionis will indemnify, defend and hold harmless
                      Roche 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:

                

        

      

      

      

      
        
          	

                	12.2.1.	
                  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;

                

        

      

      

      

      
        
          	

                	12.2.2.	
                  any breach of any representation or warranty or express covenant made by Ionis under ARTICLE 11
                      or any other provision under this Agreement;

                

        

      

      

      

      
        
          	

                	12.2.3.	
                  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 Roche pursuant to this Agreement);
                      or

                

        

      

      

      

      
        
          	

                	12.2.4.	
                  any development, manufacturing or commercialization activities that are conducted by or on behalf
                      of Ionis or its Affiliates or Sublicensees with respect to a Product or 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 Roche or its Affiliates, licensees, Sublicensees or contractors and its or their
          respective directors, officers, employees and agents or other circumstance for which Roche has an indemnity obligation pursuant to Section 12.1.

      

      

      
        
          	12.3.	
                  Procedure. If a Person entitled to indemnification under Section 12.1 or Section 12.2 (an “Indemnitee”) seeks such indemnification, such Indemnitee will (i) inform the indemnifying Party in writing of a Claim as soon as reasonably practicable after such Indemnitee
                      receives notice of such Claim, (ii) 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 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), (iii) cooperate as reasonably requested (at the expense of the indemnifying Party) in the defense of the Claim, and (iv) undertake reasonable steps to mitigate any
                      Losses with respect to the Claim. The provisions of Section 10.4 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 12.1 or Section 12.2, as the case may be, for Claims settled or compromised by the Indemnitee without the indemnifying Party’s prior written consent.

                

        

      

      

      

      
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          	12.4.	
                  Insurance.

                

        

      

      

      

      
        
          	

                	12.4.1.	
                  Ionis’ Insurance Obligations. Ionis will maintain, at its cost, reasonable
                      insurance against liability and other risks associated with its activities contemplated by this Agreement (including product liability for a Discontinued Product), including but not limited to its indemnification obligations herein,
                      in such amounts and on such terms as are customary for prudent practices for biotech companies of similar size and with similar resources in the pharmaceutical industry for the activities to be conducted by it under this Agreement
                      taking into account the scope of development of products. Ionis will maintain such insurance throughout the Agreement Term and for five (5) years thereafter, and Ionis will furnish to Roche evidence of any insurance required under
                      this Section 12.4.1, upon request.

                

        

      

      

      

      
        
          	

                	12.4.2.	
                  Roche’s Insurance Obligations. Roche hereby represents and warrants to
                      Ionis that it will maintain, at its cost, reasonable insurance or self-insure against liability and other risks associated with its activities contemplated by this Agreement (including product liability), including but not limited to
                      its indemnification obligations herein, in such amounts and on such terms as are customary for prudent practices for large companies in the pharmaceutical industry for the activities to be conducted by Roche under this Agreement.
                      Roche will maintain such self-insurance throughout the Agreement Term and for five years thereafter, and will furnish to Ionis evidence of such insurance, upon request.

                

        

      

      

      

      
        
          	12.5.	
                  LIMITATION OF CONSEQUENTIAL DAMAGES. EXCEPT FOR (a) CLAIMS OF A THIRD PARTY THAT ARE SUBJECT TO INDEMNIFICATION UNDER THIS ARTICLE

                          12, (b) CLAIMS ARISING OUT OF A PARTY’S WILLFUL MISCONDUCT OF THIS AGREEMENT, (c) A PARTY’S BREACH OF ARTICLE 5, (d) A BREACH OF SECTION 13.4.1(b) BY ROCHE OR ITS AFFILIATES OR (e) 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, 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.

                

        

      

      

      

      
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      ARTICLE 13.

      TERM; TERMINATION

      

      

      
        
          	13.1.	
                  Agreement Term; Expiration. This Agreement is effective as of the
                      Effective Date and, unless earlier terminated pursuant to the other provisions of this ARTICLE 13, will continue in full force and effect until this
                      Agreement expires as follows:

                

        

      

      

      

      
        
          	

                	13.1.1.	
                  on a country-by-country and Product-by-Product basis, on the date of expiration of all payment obligations by the Commercializing Party under this Agreement with respect
                      to such Product (or such Discontinued Product) in such country; and

                

        

      

      

      

      
        
          	

                	13.1.2.	
                  in its entirety upon the expiration of all payment obligations under this Agreement with respect to the last Product (or last Discontinued Product) in all countries
                      pursuant to Section 13.1.1; and

                

        

      

      

      

      
        
          	

                	13.1.3.	
                  where Roche has not provided Ionis a written notice stating Roche is exercising its Option under Section

                          6.1 by the Option Deadline.

                

        

      

      

      

      The period from the Effective Date until the date of expiration of this Agreement pursuant to this Section 13.1 is the “Agreement Term”. On a Product-by-Product basis, if with respect to
          a particular Product this Agreement expires (i.e., is not terminated early) under Section 13.1.1
          or Section 13.1.2 in a particular country, then, effective upon such expiration, Ionis will and hereby does grant to Roche a fully paid-up and irrevocable
          non-exclusive, sublicensable license under the Licensed Intellectual Property to Manufacture, Develop and Commercialize the Product that is the subject of such expiration in such country.

      

      

      
        
          	13.2.	
                  Termination of the Agreement.

                

        

      

      

      

      
        
          	

                	13.2.1.	
                  Roche’s Termination for Convenience. After payment by Roche of the option  fee under Section 9.1, subject to Section 13.4.1 below, Roche may terminate this Agreement in its entirety or in part on a country-by-country or Product-by-Product basis for convenience by
                      providing (i) ninety (90) days’ written notice to Ionis of such termination if the Product has not been sold commercially, or (ii) one hundred eighty (180) days’ written notice to Ionis of such termination if the Product has been sold
                      commercially. 

                

        

      

      

      

      
        
          	

                	13.2.2.	
                  Termination for Material Breach.

                

        

      

      

      

      
        
          	

                	(a)	
                  Roche’s Right to Terminate. If Roche believes that Ionis is in material
                      breach of this Agreement (other than with respect to a failure to use Commercially Reasonable Efforts under Section 3.1, which is governed by Section 13.2.3 below), then Roche may deliver notice of such material breach to Ionis. If the breach is curable, Ionis will have sixty (60) days to cure such
                      breach. If Ionis fails to cure such breach within the sixty (60)-day period, or if the breach is not subject to cure, Roche may terminate this Agreement by providing written notice to Ionis.

                

        

      

      

      

      
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                	(b)	
                  Ionis’ Right to Terminate. If Ionis believes that Roche is in material
                      breach of this Agreement (other than with respect to a failure to use Commercially Reasonable Efforts under Section 3.1 or Section 8.1, which is governed by Section 13.2.3 below), then Ionis may deliver notice of such material
                      breach to Roche. If the breach is curable, Roche will have sixty (60) 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 thirty (30) days
                      following such notice). If Roche fails to cure such breach within the sixty (60)-day or thirty (30)-day period, as applicable, or if the breach is not subject to cure, Ionis may terminate this Agreement by providing written notice to
                      Roche.

                

        

      

      

      

      
        
          	 	13.2.3.	
                  Remedies for Failure to Use Commercially Reasonable Efforts.

                

        

      

      

      

      
        
          	

                	(a)	
                  If Ionis, in Roche’s reasonable determination, fails to use Commercially Reasonable Efforts to conduct the activities Ionis agreed to perform under Section 3.1 prior to Option exercise, Roche will notify Ionis and, within thirty (30) days thereafter, Ionis and Roche 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 for such activities in Section 3.1. Following such a meeting, if Ionis fails to use Commercially Reasonable Efforts as contemplated by Section

                          3.1, then subject to Section 13.2.4 below, Roche will have the right, at its sole discretion, to (i) terminate this Agreement, or (ii) prior
                      to Option exercise, Roche may elect to trigger the alternative remedy provisions of Section 13.3 below, which such election is Roche’s sole and exclusive
                      remedy if Ionis fails to use Commercially Reasonable Efforts in the activities contemplated in Section 3.1 prior to Option exercise.

                    

                

        

      

      

      

      
        
          	

                	(b)	
                  If Roche, in Ionis’ reasonable determination, fails to use Commercially Reasonable Efforts under Section

                          3.1 or Section 8.1 above, Ionis will notify Roche and, within thirty (30) days thereafter, Ionis and Roche 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 Roche’s use of Commercially Reasonable Efforts under Section 3.1 or Section 8.1. Following such a meeting, if Roche fails to use Commercially Reasonable Efforts as contemplated by
                      Section 3.1  or Section 8.1, then subject to Section 13.2.4 below, Ionis will have the right, at its sole discretion, to terminate this  Agreement.

                

        

      

      

      

      
        
          	 	13.2.4.	
                  Disputes Regarding Material Breach. Notwithstanding the foregoing, if the
                      Breaching Party in Section 13.2.2 or Section 13.2.3 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 sixty (60)-day period, the Non-Breaching Party will not have the
                      right to terminate this Agreement in accordance with Section 13.2.2 or Section 13.2.3,
                      or trigger the alternative remedy provisions of Section 13.3, as applicable, unless and until it has been determined in accordance with Section 15.1 that this Agreement was materially breached by the Breaching Party and the Breaching Party fails to cure such breach within thirty (30) days
                      following such determination. During the pendency of such dispute, all the terms 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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          	 	13.2.5.	
                  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 is served with an involuntary petition against it, filed in any insolvency proceeding, and such petition is not dismissed within ninety (90) days after
                      the filing thereof; or if the other Party is a party to any dissolution or liquidation; or if the other Party makes 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.

                

        

      

      

      

      
        
          	13.3.	
                  Alternative Remedy to Termination Available to Roche Prior to Option Exercise.
                      If Roche elects, pursuant to Section 13.2.3(a)(ii),  to exercise the alternative remedy provisions of this Section 13.3 in lieu of terminating this Agreement by providing written notice of such election to Ionis in accordance with Section
                          13.2.3(a), then this Agreement will continue in full force and effect with the following modifications:

                

        

      

      

      

      
        
          	

                	(a)	
                  Ionis will have no further obligations under the Development Plan, and Roche is responsible for the continued Development and Commercialization of IONIS-FB-LRx (including meeting all remaining performance obligations under Section 8.1);

                

        

      

      

      

      
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                	(b)	
                  effective as of the date of Roche’s notice to Ionis electing the alternative remedy provisions of this Section

                          13.3, Roche will be deemed for all purposes of this Agreement to have exercised the Option;

                

        

      

      

      

      
        
          	

                	(c)	
                  Roche will have and Ionis grants, the exclusive license under Section 7.1.1;

                

        

      

      

      

      
        
          	

                	(d)	
                  Ionis will perform its obligations under Section 7.2, assign and transfer the IND for
                      IONIS-FB-LRx to Roche, and transfer, at Roche’s request, any Phase 2 Trials then-being administered by Ionis, all within ninety (90) days after Roche
                      electing to exercise its alternative remedies under this Section 13.3; and

                

        

      

      

      

      
        
          	

                	(e)	
                  the financial provisions of ARTICLE 9 will be modified as follows:

                

        

      

      

      

      
        
          	

                	(i)	
                  Roche will [***]; and

                

        

      

      

      

      
        
          	

                	(ii)	
                  [***], Roche will [***], and the license fee set forth in Section 9.3 will be [***].

                

        

      

      

      

      The milestone provisions of Section 9.4
          and Section 9.5 and the royalty provisions of Section 9.7 will [***].

      

      

      
        
          	13.4.	
                  Consequences of Termination or Expiration of the Agreement.

                

        

      

      

      

      
        
          	 	13.4.1.	
                  In General. If this Agreement is terminated by a Party in accordance with
                      Section 10.12 or this ARTICLE 13 in its entirety or on a country-by-country or
                      Product-by-Product basis at any time and for any reason, the following terms will apply to any such termination:

                

        

      

      

      

      
        
          	

                	(a)	
                  Return of Information and Materials. After termination of the Agreement,
                      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 that are the subject of such termination.
                      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)	
                  License Termination. Upon termination but not expiration of the Agreement,
                      except for the licenses granted under Section 7.1.2 or, if applicable, Section 13.1,
                      any licenses granted by Ionis to Roche under this Agreement will terminate and Roche, its Affiliates and Sublicensees will cease selling all Products that are the subject of such termination, unless Ionis elects to have Roche continue
                      to sell the applicable Product(s) as part of the Transition Activities under Section 13.4.2(i).

                

        

      

      

      

      
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                	(c)	
                  Exclusivity Covenants. Upon termination of this Agreement for any reason
                      or expiration of this Agreement, neither Party will have any further obligations under Section 5.1 of this Agreement.

                

        

      

      

      

      
        
          	

                	(d)	
                  Development Plan. Upon termination of this Agreement for any reason or
                      expiration of this Agreement, neither Party will have any further obligations under the Development Plan or IDCP.

                

        

      

      

      

      
        
          	

                	(e)	
                  Accrued Rights. Termination of this Agreement for any reason or expiration of this Agreement will be without prejudice to any rights or financial compensation that will have accrued to the benefit of a Party
                      prior to such termination. Such termination will not relieve a Party from obligations that are expressly indicated to survive the termination of this Agreement. For purposes of clarification, milestone payments under ARTICLE 9 accrue as of the date the applicable Milestone Event is achieved even if the payment is not due at that time.

                

        

      

      

      

      
        
          	

                	(f)	
                  Survival. The following provisions of this Agreement will survive the
                      expiration or termination of this Agreement: Section 7.1.2 (Cross Licenses under Collaboration Intellectual Property); Section 7.1.4(d) (Effect of Termination on Sublicenses), Section 7.2 (Technology Transfer) (but only to the
                      extent necessary to satisfy the requirements of Section 13.4.2), Section 9.9
                      (Reverse Royalty Payments to Roche for a Discontinued Product), Section 9.11.5 (Records Retention), Section 9.12 (Audits), Section 10.1.1 (Ionis Intellectual Property and Roche Intellectual Property), Section 10.1.2 (Agreement Intellectual Property), Section 10.4.2 (Discontinued Product), Section 11.4 (Disclaimer), ARTICLE 12 (Indemnification; Insurance), Section 13.1 (Agreement Term; Expiration), Section 13.4 (Consequences of Expiration
                      or Termination of the Agreement), ARTICLE 14 (Confidentiality), ARTICLE 15
                      (Miscellaneous) and Appendix 1 (Definitions) (to the extent definitions are embodied in the foregoing listed Articles and
                      Sections).

                

        

      

      

      

      
        
          	

                	13.4.2.	
                  Special Consequences of Expiration or Termination of the Agreement. If (A)
                      this Agreement expires due to the expiration of Roche’s Option under Section 6.2, (B) Roche terminates the Agreement under Section 13.2.1 (Roche’s Termination for Convenience), or (C) Ionis terminates this Agreement under Section 10.12
                      (No Challenge), Section 13.2.2(b) (Ionis’ Right to Terminate) or Section 13.2.3(b)
                      (Remedies for Failure to Use Commercially Reasonable Efforts), then, [***] the following additional terms will also apply:

                

        

      

      

      

      
        
          	

                	(a)	
                  License to Ionis for Discontinued Products. Roche will
                      and hereby does grant to Ionis a sublicensable, worldwide, exclusive license or sublicense, as the case may be, under all Roche Collaboration Intellectual Property created pursuant to activities under this Agreement (excluding
                      Companion Diagnostic IP) as of the date of such reversion that Covers Discontinued Products solely as necessary to Develop, make, have made, use, sell, offer for sale, have sold, import and otherwise Commercialize such Discontinued
                      Products in the Field;

                

        

      

      

      

      
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                	(b)	
                  License to Ionis for Companion Diagnostic Products.
                      Roche will make available to Ionis, on commercially reasonable terms, (i) any Discontinued Product-specific diagnostic products and/or services offered by Roche as of the date of such reversion to patients who use the Discontinued
                      Product (each, a “Companion Diagnostic Product”) and (ii) any Patent Rights and Know-How Covering such Companion Diagnostic
                      Products (such intellectual property, “Companion Diagnostic IP”) Controlled by Roche as of the date of such reversion that is
                      necessary to Develop or continue to Commercialize such Companion Diagnostic Products;

                

        

      

      

      

      
        
          	

                	(c)	
                  Know-How Transfer. Within ninety (90) days following
                      the date of termination, Roche will transfer to Ionis for use with respect to the Development and Commercialization of Discontinued Products, copies of any Collaboration Know-How data, results, and regulatory information, and to the
                      extent solely related to the Discontinued Products, pricing and market access strategy information, health economic study information, material communications with payors, filings, and files in the possession of Roche as of the date
                      of such reversion that relate to such Discontinued Products and are necessary for the Development of such Discontinued Products, and any other information or material specified in Section 7.2;

                

        

      

      

      

      
        
          	

                	(d)	
                  Regulatory Materials. Within ninety (90) days
                      following the date of the termination, Roche will assign, and hereby does assign, to Ionis all of Roche’s right, title and interest in and to all Regulatory Materials for the Discontinued Product, including any IND, orphan drug
                      designation and marketing authorizations that relate to the applicable Discontinued Product;

                

        

      

      

      

      
        
          	

                	(e)	
                  Trademarks. Roche will license to Ionis any trademarks
                      that are specific to Discontinued Products solely for use with such Discontinued Products; provided, however, that in no event will Roche have
                      any obligation to license to Ionis any trademarks used by Roche both in connection with a Product and in connection with the sale of any other product or service, including any Roche- or Roche-formative marks, company logos, or
                      trademarks of its Affiliates or Sublicensees;

                

        

      

      

      

      
        
          	

                	(f)	
                  Prosecution and Maintenance. Ionis will control and be
                      responsible at its sole cost for all aspects of the Prosecution and Maintenance of all Jointly-Owned Collaboration Patents, and Roche will provide Ionis with (and will instruct its counsel to provide Ionis with) all of the information
                      and records in Roche’s and its counsel’s possession related to the Prosecution and Maintenance of such Jointly-Owned Collaboration Patents;

                

        

      

      

      

      
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                	(g)	
                  Stocks of API and Finished Drug Product. Ionis will
                      have the right to purchase from Roche any or all of the inventory of API and/or Finished Drug Product for such Discontinued Product held by Roche as of the effective date of termination (that are not committed to be supplied to any
                      Third Party or Sublicensee, in the ordinary course of business, as of the effective date of termination), if any, at a price equal to [***] to acquire or manufacture such inventory. Ionis will notify Roche within forty-five (45) days
                      after the effective date of termination whether Ionis elects to exercise such right;

                

        

      

      

      

      
        
          	

                	(h)	
                  Manufacturing Technology Transfer. If Roche or Roche’s
                      CMO is manufacturing API and/or Finished Drug Product as of the termination triggering this provision, Ionis may request Roche to conduct (or cause to be conducted by Roche’s CMO) a technology transfer to Ionis (or Ionis’ designated
                      Third Party supplier) of any technology, information and data reasonably related to Roche’s or such CMO’s manufacturing and supply of API and/or Finished Drug Product for such Discontinued Product, and if so requested, Roche will
                      conduct (or cause to be conducted by Roche’s CMO) such a technology transfer, and Ionis will [***], and Roche will (or will cause Roche’s CMO to) continue to (i) provide reasonable support and cooperation with Ionis’ regulatory
                      filings and interactions with Regulatory Authorities related to Roche’s or such CMO’s API and/or Finished Drug Product manufacturing (including any required inspections), and (ii) supply (or cause to be supplied by Roche’s CMO) API
                      and/or Finished Drug Product to Ionis, at a price equal to [***] to enable Ionis to identify and contract with a suitable Third Party API and/or Finished Drug Product manufacturer; and

                

        

      

      

      

      
        
          	

                	(i)	
                  Transition Activities.

                

        

      

      

      

      
        
          For a period of up to
              [***] following the effective date of termination:

        

      

      

      

      
        
          	

                	(i)	
                  The Parties wish to provide a mechanism to ensure that, assuming the Discontinued Product is available to patients as of the reversion date, patients who were being
                      treated with the Discontinued Product prior to such termination or who desire access to the Discontinued Product can continue to have access to such Discontinued Product while the regulatory and commercial responsibilities for the
                      Discontinued Product are transitioned from Roche to Ionis. As such, Ionis may request Roche to perform transition activities that are necessary or useful to (1) transition Roche’s Commercialization activities (if any) to Ionis to
                      minimize disruption to sales, (2) provide patients with continued access to the applicable Discontinued Products (if applicable), (3) enable Ionis (or Ionis’ designee) to assume and execute the responsibilities under all Approvals and
                      ongoing Clinical Studies for the applicable Discontinued Product, and (4) ensure long-term continuity of supply for the Discontinued Product (collectively, the “Transition Activities”), including, if applicable, the categories of services and deliverables listed on Schedule 13.4.2(i), but no longer than [***] following the effective date of termination. If applicable, Roche will perform
                      such Transition Activities using commercially reasonable efforts for the periods set forth in Schedule 13.4.2(i); provided Roche and Ionis may mutually agree in writing to conduct the Transition Activities for a longer period of time.

                

        

      

      

      

      
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                	(ii)	
                  Ionis may elect to have Roche perform the applicable Transition Activities by providing written notice to Roche no later than forty-five (45) days following the effective
                      date of the termination. If Ionis requests Transition Activities, without limiting the provisions of Section 13.4.2, the Parties will mutually agree upon a
                      transition plan for Roche to perform the applicable Transition Activities including delivery and transition dates. In addition, the Parties will establish a transition committee consisting of at least each Party’s Alliance Managers, a
                      representative from each Party’s chemistry, manufacturing and controls (CMC) group who was responsible for the Discontinued Product prior to the termination, and up to two (2) additional representatives from each Party who are from
                      other relevant functional groups to facilitate a smooth transition. While Roche is providing applicable Transition Activities, Roche and Ionis will agree on talking points and a communication plan to customers, specialty pharmacies,
                      physicians, regulatory authorities, patient advocacy groups, and clinical study investigators, in each case only if applicable at the time of reversion, and Roche will make all such communications to such applicable entities in
                      accordance with the mutually agreed talking points.

                

        

      

      

      

      
        
          	

                	(iii)	
                  Ionis will [***] to perform the Transition Activities. In addition, Ionis will [***] to perform the Transition Activities. Ionis will own [***].

                

        

      

      

      

      ARTICLE 14.

      CONFIDENTIALITY

      

      

      
        
          	14.1.	
                  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”).

                

        

      

      

      

      
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          	14.2.	
                  Prior Confidentiality Agreement. The Non-Disclosure Agreement executed by
                      Ionis and Roche on February 7, 2018 (including any and all amendments thereto) (the “CDA”) will terminate as of the Effective
                      Date. All Confidential Information exchanged between the Parties under the CDA and on or after the Effective Date under this Agreement will be subject to the terms of this ARTICLE 14.

                

        

      

      

      

      
        
          	14.3.	
                  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: (i) 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, a Receiving
                      Party may disclose Confidential Information to a governmental entity or agency without requiring such entity or agency to enter into a confidentiality agreement; (ii) to the extent reasonably necessary to file or prosecute patent,
                      copyright and trademark applications (subject to Section 14.4 below), complying with applicable governmental regulations, obtaining Approvals, conducting
                      Non-Clinical Studies or Clinical Studies, marketing a 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; (iii) 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; (iv) 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 (v) as mutually agreed to in writing by the Parties.

                

        

      

      

      

      
        
          	14.4.	
                  Press Release; Publications; Disclosure of Agreement.

                

        

      

      

      

      
        
          	 	14.4.1.	
                  Public Announcements – Generally. Upon execution of this Agreement, Ionis
                      may issue a press release announcing the existence of this Agreement in a form and substance agreed to in writing 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 14.4, each Party agrees not to issue any other press release or other public statement disclosing other
                      information relating to this Agreement or the terms of this Agreement or the transactions contemplated hereby without the prior written consent of the other Party, which consent will not be unreasonably withheld or delayed.

                

        

      

      

      

      
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                	14.4.2.	
                  Use of Name. Except as set forth in Section 14.4.9, 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.

                

        

      

      

      

      
        
          	

                	14.4.3.	
                  Notice of Significant Events. Each Party will notify (no later than three
                      (3) Business Days after the information or results are obtained) the other Party of any significant event related to a Product (including any data, serious adverse event or regulatory advice or approval) so that the Parties may
                      analyze the need to or desirability of publicly disclosing or reporting such event. Notwithstanding Section 14.4.1 above, any press release or other similar
                      public communication by either Party related to a Product’s efficacy or safety data and/or results, will be submitted to the other Party for review and approval at least three (3) Business Days in advance of such proposed public
                      disclosure, which approval will not be unreasonably withheld or delayed.

                

        

      

      

      

      
        
          	

                	14.4.4.	
                  Before Option Exercise. Before Option exercise, Ionis will have the sole
                      right, consistent with its practice with its other compounds and products, to issue press releases, publish, present or otherwise disclose the progress and results regarding IONIS-FB-LRx to the public; 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 IONIS-FB-LRx, (i) Ionis will submit such proposed communication to Roche for review at least two (2) Business Days in advance of such proposed public disclosure, (ii) Roche will have the right to
                      review and recommend changes to such communication, and (iii) Ionis will in good faith consider any changes that are timely recommended by Roche.

                

        

      

      

      

      
        
          	

                	14.4.5.	
                  After Option Exercise. After Option exercise, Roche will have the sole
                      right, consistent with its practice with its other compounds and products, to issue press releases, publish, present or otherwise disclose the progress and results regarding IONIS-FB-LRx to the public; provided, that with respect to any proposed press release or other similar public
                      communication by Roche disclosing regulatory discussions, the efficacy or safety data or results related to the Products or Roche’s sales projections, (i) Roche
                      will submit such proposed communication to Ionis for review at least two (2) Business Days in advance of such proposed public disclosure, (ii) Ionis will have the right to review and recommend changes to such communication, and (iii)
                      Roche will in good faith consider any changes that are timely recommended by Ionis.

                

        

      

      

      

      
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                	14.4.6.	
                  Scientific or Clinical Presentations. Regarding any proposed scientific
                      publications related to results from any Clinical Studies regarding Products, the Parties agree to use Commercially Reasonable Efforts to control public scientific disclosures of such results to prevent any 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 JPC an early draft of all such publications or presentations,
                      at least forty-five (45) 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 to avoid the unauthorized disclosure of a Party’s Confidential Information and to preserve the patentability of inventions arising from the Development Plan or IDCP. If, during such
                      forty-five (45)-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 during such forty-five (45)-day period, the other Party informs such Party that its proposed publication discloses non-public inventions made by either Party in the course of the Development under this
                      Agreement, or the public disclosure of such proposed publication may 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 (i) delay such proposed
                      publication for up to sixty (60) days from the date of such Party’s objection, to permit the timely first filing of patent application(s), or (ii) remove the identified disclosures prior to publication.

                

        

      

      

      

      
        
          	

                	14.4.7.	
                  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.

                

        

      

      

      

      
        
          	

                	14.4.8.	
                  Subsequent Disclosure. Notwithstanding the foregoing, to the extent
                      information regarding this Agreement or a 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.

                

        

      

      

      

      
        
          	

                	14.4.9.	
                  Acknowledgment; Commercial Materials. Each Party will acknowledge in any
                      press release, public presentation, publication or commercial marketing materials regarding the Collaboration or a Product, the other Party’s role in discovering and developing a 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., Ionis: Nasdaq: IONIS; Roche: SIX: RO, ROG; OTCQX: RHHBY). Ionis may include the
                      Products (and identify Roche as its partner for the Product) in Ionis’ drug pipeline. In addition, subject to Applicable Law, the words “Discovered and developed by Ionis Pharmaceuticals” will be included and reasonably visible in
                      Product communications and branding, provided that Roche will have final decision-making authority regarding the applicability of any legal and regulatory requirements for such acknowledgement.

                

        

      

      

      

      
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      ARTICLE 15.

      MISCELLANEOUS

      

      

      
        
          	15.1.	
                  Dispute Resolution.

                

        

      

      

      

      
        
          	

                	15.1.1.	
                  Escalation. If any dispute occurs under this Agreement (other than a
                      dispute regarding the construction, validity or enforcement of either Party’s Patents, which disputes will be resolved pursuant to Section 15.2), either
                      Party may request in writing that the dispute be referred for resolution to the Head of Roche Partnering of Roche and the Chief Operating Officer of Ionis (the “Executives”). Within thirty (30) days after such a request, 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 the dispute. Each Party’s JSC representatives may participate in such meeting if desired. If the Executives fail to resolve the dispute within such thirty (30)-day period, then, except as set forth in Section 4.1.1(b)(ii), the dispute will be referred to binding arbitration under Section 15.1.2.

                

        

      

      

      

      
        
          	

                	15.1.2.	
                  Binding Arbitration. If a dispute subject to Section 15.1.1 is not resolved pursuant to Section 15.1.1, such dispute will be resolved through
                      binding arbitration in accordance with this Section 15.1.2 and under the Commercial Arbitration Rules of the American Arbitration Association (“AAA”) then in effect, including application of the “Expedited Procedures” (sections E-1, et al) of the Commercial Arbitration Rules of the AAA. The proceedings and decisions of the arbitrators will be confidential, final and binding on the Parties, and judgment upon
                      the award of such arbitrators may be entered in any court having jurisdiction thereof. The arbitration will take place in Boston, Massachusetts, U.S. and will be conducted by three arbitrators. Each of Roche and Ionis will appoint one
                      (1) arbitrator within thirty (30) days after the notice that initiated the arbitration. These two (2) arbitrators will in turn appoint a third arbitrator who will be reasonably acceptable to the Parties and who will be appointed in
                      accordance with AAA rules. Each arbitrator chosen hereunder will have educational training and industry experience sufficient to demonstrate a reasonable level of scientific, financial, medical and industry knowledge relevant to the
                      particular dispute.

                

        

      

      

      

      
        
          	15.2.	
                  Governing Law; Jurisdiction; Venue; Service of Process.

                

        

      

      

      

      
        
          	 	15.2.1.	
                  This Agreement and any dispute will be governed by and construed and enforced in accordance with the laws of the State of California, U.S., without reference to conflicts
                      of laws principles.

                

        

      

      

      

      
        
          	

                	15.2.2.	
                  Each Party hereby agrees that service of process: (a) made in any manner permitted by California law, or (b) made by overnight express courier service (signature
                      required), prepaid, at its address specified pursuant to Section 15.7, 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.

                

        

      

      

      

      
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          	15.3.	
                  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 may 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 12.1 or Section 12.2). Except
                      for the offsets and credits explicitly set forth in Section 9.10.3(b) and Section 9.12,
                      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.

                

        

      

      

      

      
        
          	15.4.	
                  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, 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, if a Party transfers or assigns this Agreement to [***] described in this
                      Agreement, then such transferring Party (or such Affiliate) (“Transferring Party”), will [***] that the Transferring Party is
                      obligated to pay to the non-transferring Party (“Non-Transferring Party”) under ARTICLE 9 for the taxes withheld such that the Non-Transferring Party receives [***] assignment. In addition, Ionis may assign or transfer its rights to receive payments under this Agreement (but no
                      liabilities), without Roche’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 15.4 will be null and void.

                

        

      

      

      

      To the extent the Non-Transferring Party utilizes a [***] in any year, the Non-Transferring Party will [***] to the Transferring Party
          [***]. To assist the Transferring Party  in determining when [***] pursuant to the foregoing sentence, beginning with the first Annual tax return for the year in which the [***] payment under this Section 15.4, and each year thereafter (including, for clarity, all years in which the Non-Transferring Party utilizes a [***], the Non-Transferring Party will provide the Transferring Party  with  the
          Non-Transferring Party’s Annual tax returns (federal and state) and, in years in which the Non-Transferring Party utilizes the [***], supporting documentation for such [***].

      

      

      
        
          	15.5.	
                  Change of Control. If Ionis undergoes a Change of Control, then Roche will
                      have the right at any time after it exercises the Option to disband the JSC and make unilateral decisions with respect to the Development Plan, IDCP, Development and Commercialization with no obligation to seek input from Ionis or its
                      successor, if applicable.

                

        

      

      

      

      
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          	15.6.	
                  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 ninety (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.

                

        

      

      

      

      
        
          	15.7.	
                  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), facsimile 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 Operating Officer

        Fax:  [***]

        

        

        
          
            	

                  	with a copy to:	
                    Ionis Pharmaceuticals, Inc.

                  

          

        

        2855 Gazelle Court

        Carlsbad, CA  92010

        Attention:  General Counsel

        Email: [***]

        

        

        
          
            	

                  	If to Roche, addressed to:	
                    F. Hoffmann-La Roche Ltd

                  

          

        

        Grenzacherstrasse 124

        4070 Basel, Switzerland

        Attention:  Corporate Legal Department

        Fax:  [***]

        

        

        
          
            	

                  	If to Roche, addressed to:	
                    Hoffmann-La Roche Inc.

                  

          

        

        150 Clove Road, Suite 8

        Little Falls, NJ 07424

        Attention:  Corporate Secretary

        Fax:  [***]

      

      

      

      
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                    	with a copy to:	
                      F. Hoffmann-La Roche Ltd

                    

            

          

          Grenzacherstrasse 124

          4070 Basel, Switzerland

          Attention:  Alliance Manager

          Fax:  [***]

          

        

      

      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 facsimile 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.

      

      

      
        
          	15.8.	
                  Invoices.  All invoices that are required or permitted hereunder will be
                      in writing and sent by Ionis to Roche at the following address or any other address that Roche may later provide:

                

        

      

      

      

      F. Hoffmann-La Roche AG

      Kreditorenbuchhaltung

      4070 Basel

      Switzerland

      

      

      with an electronic copy to Roche’s Alliance Manager.

      

      

      Upon Ionis’ request, Roche’s Alliance Manager will provide Ionis’ Alliance Manager with any additional information reasonably
          requested by Ionis to facilitate the prompt delivery of invoices to Roche, including a facsimile number for sending invoices.

      

      

      
        
          	15.9.	
                  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.

                

        

      

      

      

      
        
          	15.10.	
                  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.

                

        

      

      

      

      
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          	15.11.	
                  Severability. If any provision hereof should be held invalid, illegal or
                      unenforceable in any jurisdiction, 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.

                

        

      

      

      

      
        
          	15.12.	
                  Entire Agreement. This Agreement, together with the Schedules and
                      Appendices hereto, sets forth all the covenants, promises, agreements, warranties, representations, conditions and understandings between the Parties regarding the subject matter hereof and supersedes and terminates all prior
                      agreements and understandings between the Parties pertaining to the subject matter hereof. There are no covenants, promises, agreements, warranties, representations, conditions or understandings, either oral or written, between the
                      Parties regarding the subject matter hereof other than as set forth in this Agreement and the Schedules and Appendices hereto.  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.

                

        

      

      

      

      
        
          	15.13.	
                  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.

                

        

      

      

      

      
        
          	15.14.	
                  Interpretation. Except as otherwise explicitly specified to the contrary,
                      (a) references to a section, appendix or schedule means a section of, or appendix or schedule to this Agreement, unless another agreement is specified, (b) the word “including” (in its various forms) means “including without limitation”, (c) 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, (d) words in the singular or plural form include
                      the plural and singular form, respectively, (e) references to a particular Person include such Person’s successors and assigns to the extent not prohibited by this Agreement, (f) unless otherwise specified, “$” is in reference to
                      United States Dollars, and (g) the headings contained in this Agreement, in any appendix 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.

                

        

      

      

      

      
        
          	15.15.	
                  Further Actions. Each Party will execute, acknowledge and deliver such
                      further instruments, and do all such other acts, as may be necessary or appropriate to carry out the expressly stated purposes and the clear intent of this Agreement.

                

        

      

      

      

      
        
          	15.16.	
                  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.

                

        

      

      

      

      
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          	15.17.	
                  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.

                

        

      

      

      

      
        
          	15.18.	
                  Counterparts. This Agreement may be signed in counterparts, each of which
                      will be deemed an original, notwithstanding variations in format or file designation which 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.

                

        

      

      

      

      [SIGNATURE PAGES FOLLOW]

      

      

      * - * - * - *

      

      

      
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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 Effective Date.

      

      

      	
              F. Hoffmann-La Roche Ltd

            	 
	 	 	 
	
              By:

            	 	
              /s/ Stefan Arnold

            	 
	
              Name:

            	
              Stefan Arnold

            	 
	
              Title:

            	
              Head Legal Pharma

            	 
	 	 	 
	
              By:

            	 	
              /s/ Vikas Kabra

            	 
	
              Name:

            	
              Vikas Kabra

            	 
	
              Title:

            	
              Head of Transaction Excellence

            	 

      

      

      Signature Page to FB Development Collaboration, Option and License Agreement

      

      

      
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        Confidential

      

       

          

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

      

      

      	
              Hoffmann-La Roche Inc.

            	 
	 	 	 
	
              By:

            	 	
              /s/ John Parise

            	 
	
              Name:

            	
              John Parise

            	 
	
              Title:

            	
              Authorized Signatory

            	 

      

      

      Signature Page to FB Development Collaboration, Option and License Agreement

      

      

      
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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 Effective Date.

      

      

      	
              Ionis Pharmaceuticals, Inc.

            	 
	 	 	 
	
              By:

            	 	
              /s/ Stanley T. Crooke

            	 
	
              Name:

            	
              Stanley T. Crooke

            	 
	
              Title:

            	
              Chief Executive Officer

            	 

      

      

      Signature Page to FB Development Collaboration, Option and License Agreement

      

      

      
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      List of Appendices and
              Schedules

      

      

      Appendix 1 – Definitions

      

      

      Appendix 2 – Specific Performance Milestone Events

      

      

      Appendix 3 – Permitted Licenses as of the
          Effective Date

      

      

      Schedule 4.2 – Alliance Management Activities

      

      

      Schedule 4.4.2 – Ionis’ Fully Absorbed Cost of Goods Methodology

      

      

      Schedule 9.7.2(e) – Royalty Calculation Examples

      

      

      Schedule 9.7.2(f) – Allocation of Net Sales

      

      

      Schedule 11.2.4(a) – Ionis Core Technology Patents

      

      

      Schedule 11.2.4(b) – Ionis Manufacturing and Analytical Patents

      

      

      Schedule 11.2.4(c) – Ionis Product-Specific Patents

      

      

      Schedule 11.2.6 – Prior Agreement

      

      

      Schedule 13.4.2(i) – Transition Activities

      

      

      
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      Appendix 1

      

      

      DEFINITIONS

      

      

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

      

      

      “AAA” has the meaning
          set forth in Section 15.1.2.

      

      

      “Acceptance of Filing”
          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 of written notice of validation by the EMA of such MAA under the centralized European procedure in accordance with any feedback
          received from European Regulatory Authorities; provided that if the centralized filing procedure is not used, then Acceptance of Filing will be
          determined upon the validation of such MAA by the applicable Regulatory Authority in a Major Market in Europe, and (c) in Japan, receipt 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).

      

      

      “Additional Core IP” has
          the meaning set forth in Section 9.10.3(a).

      

      

      “Additional Ionis In-License
            Agreements” has the meaning set forth in Section 9.10.1(a).

      

      

      “Additional Product-Specific
            Patents” has the meaning set forth in Section 9.10.2(a).

      

      

      “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 (i) owns, directly or indirectly, more than fifty percent (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 (ii) has the power, whether pursuant to contract, ownership of securities or otherwise, to direct
          the management and policies of the entity. Anything to the contrary in this paragraph notwithstanding, Chugai Pharmaceutical Co., Ltd, a Japanese corporation (“Chugai”) and/or its subsidiaries (if any) and Foundation Medicine, Inc., a Delaware corporation (“FMI”)

          and/or its subsidiaries (if any), will not be deemed an Affiliate of Roche unless Roche provides written notice to Ionis of its desire to include Chugai and/or FMI as an Affiliate of Roche.

      

      

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

      

      

      “Agreement Term” has the meaning set forth in Section 13.1.

      

      

      “Alliance Manager” has the meaning set forth
          in Section 4.2.

      

      

       “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.

      

      

      
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      “API” means the bulk active pharmaceutical
          ingredient manufactured in accordance with cGMP (unless expressly stated otherwise) 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 (i) with respect to a
          Product in the EU, the earlier to occur of (A) approval from the applicable Regulatory Authority in at least one member state in the EU sufficient for the manufacture, distribution, use, marketing and sale of such Product, including pricing and
          reimbursement approval, in such jurisdiction in accordance with Applicable Laws, or (B) the First Commercial Sale of a Product in the EU or in a European country in a Major Market; and (ii) with respect to a Product in any regulatory jurisdiction
          other than the EU, approval sufficient for the manufacture, distribution, use, marketing and sale of such Product in such jurisdiction in accordance with Applicable Laws.

      

      

      “Approved Change” has the meaning set forth
          in Section 3.1.5.

      

      

      “Approved Change Costs” has the meaning set
          forth in Section 3.1.5.

      

      

      “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.

      

      

      “Audit Report” has the meaning set forth in
          Section 9.12.

      

      

      “Bankruptcy Code” has the meaning set forth
          in Section 13.2.5(b).

      

      

      “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 both New York, New York and Zurich, Switzerland are open for business.

      

      

      “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 2018, the Effective Date) and ending on December 31.

      

      

      “CDA” has the meaning set forth in Section 14.2.

      

      

      “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) the acquisition by any Third Party of beneficial ownership of more than fifty percent (50%) of the then outstanding common shares or voting power of such Party, other than acquisitions by employee benefit plans sponsored or maintained
          by such Party; (b) the consummation of a business combination involving such Party, unless, following such business combination, the stockholders of such Party immediately prior to such business combination beneficially own directly or indirectly
          more than fifty percent (50%) of the then outstanding common shares or voting power of the entity resulting from such business combination.

      

      

      
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      “Chugai” has the meaning set forth in the
          definition of Affiliate.

      

      

      “Claims” has the meaning set forth in Section 12.1.

      

      

      “Clinical Study” or “Clinical Studies” means a Phase 1 Trial, Phase 2 Trial, Registration-Directed 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, JNDA or other similar marketing application.

      

      

      “CMO” means a Third Party contract
          manufacturer Manufacturing API or finished drug Product for any purpose under this Agreement.

      

      

      “Collaboration” means the conduct of the
          Development Plan in accordance with this Agreement.

      

      

      “Collaboration Intellectual Property” means
          collectively Ionis Collaboration Intellectual Property and Roche Collaboration Intellectual Property.

      

      

      “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 a Product in the applicable country,
          including conducting pre-and post-Approval activities, including studies reasonably required to increase the market potential of a Product and studies to provide improved formulation and Product delivery, and launching and promoting a Product in
          each country.

      

      

      “Commercializing Party” means (a) Roche,
          with respect to a Product that is being Developed and Commercialized by or on behalf of Roche, 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, (A) Commercially Reasonable Efforts as it applies to Roche’s Development or Commercialization of a Product hereunder includes the use of
          Commercially Reasonable Efforts to (i) perform the activities assigned to Roche set forth in the Development Plan or IDCP in accordance with the timelines set forth therein, (ii) perform the “General Activities” set forth in Appendix
              2, and (iii) achieve the specific performance milestone events set forth in Appendix 2 (“Specific Performance Milestone Events”) for a Product on the timeline set forth in Appendix 2; and (B) Commercially Reasonable Efforts as it applies to
          Ionis’ Development of IONIS-FB-LRx hereunder includes use of Commercially Reasonable Efforts to perform the activities assigned to Ionis under the Development Plan in
          accordance with the timelines set forth therein and the Specific Performance Milestone Events set forth in Appendix 2; provided, however, in each case, if regulatory or Development issues arise that are outside of either Party’s reasonable control and make achievement of any Specific Performance Milestone
          Event on the stated timeline impossible, the Parties will meet and negotiate in good faith to revise, consistent with any applicable Additional Ionis In-License Agreements, the date by which the applicable Specific Performance Milestone Event
          must be achieved. However, Roche (and its Affiliates) does not always seek to market its own products in every country or seek to obtain regulatory approval in every country or for every potential Indication. As a result, the exercise of
          diligence by Roche is to be determined by judging Roche’s commercially reasonable efforts in the Major Markets, taken as a whole.

      

      

      
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      “Companion Diagnostic IP” has the meaning
          set forth in Section 13.4.2(b).

      

      

      “Companion Diagnostic Product” has the
          meaning set forth in Section 13.4.2(b).

      

      

      “Competitive Infringement” has the meaning
          set forth in Section 10.5.1.

      

      

      “Complete” 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 listing and tables of safety and efficacy data generated based on that primary database lock under the statistical analysis plan for such study are available.

      

      

      “Compound” means an ASO that is designed to
          bind to the RNA that encodes Factor B where such ASO is discovered by Ionis prior to or in the performance of the Development Plan.

      

      

      “Compulsory Sublicense” means a Sublicense
          granted to a Third Party, through the order, decree or grant of a governmental authority having competent jurisdiction, authorizing such Third Party to manufacture, use, sale, offer for sale, import or export a Product in any country.

      

      

      “Compulsory Sublicensee” means a Third Party
          that was granted a Compulsory Sublicense.

      

      

      “Confidential Information” has the meaning
          set forth in Section 14.1. “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;

                

        

      

      

      

      
        
          	

                	(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.

                

        

      

      

      

      
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      “Conjugate Technology” means a group of
          atoms covalently bound to an oligonucleotide designed to enhance one or more properties of the oligonucleotide, such as targeting of antisense drugs to specific tissues and cells.  Conjugate Technology includes N-acetylgalactosamine (GalNAc)
          ligand conjugates capable of binding to the asialoglycoprotein receptor (ASGP-R) and enhancing the targeting of antisense drugs.

      

      

      “Control”,  “Controlled” or “Controlling” 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 Roche Supported Pass-Through Costs in the case of Roche), 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.

      

      

      “Cover”, “Covered” or “Covering” means, with respect to a patent,
          that the act of making, using or selling by an unauthorized 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.

      

      

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

      

      

      “Development Plan” has the meaning set forth
          in Section 3.1.

      

      

      “Development Program has the meaning set
          forth in Section 3.1.

      

      

      “Disclosing Party” has the meaning set forth
          in Section 14.1.

      

      

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

      

      

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

      

      

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

      

      

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

      

      

      “Executives” has the meaning set forth in Section 15.1.1.

      

      

      “Existing Diagnostic Agreement” means that
          certain Non-Exclusive G-Clamp License Agreement between Isis (now Ionis) and F. Hoffmann-La Roche Ltd dated April 26, 2011.

      

      

      “Factor B” means the human gene complement
          factor B (GenBank accession # NM_001710; Gene ID: 629), or any alternative splice variants, mutants, polymorphisms and fragments thereof.

      

      

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

      

      

      “FDCA” will mean the United States Food,
          Drug and Cosmetics Act.

      

      

      “Field” means the prophylactic, therapeutic
          and diagnostic use or form of administration of a Product 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 of a Product by a Party under this Agreement.

      

      

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

      

      

      “FMI” has the meaning set forth in the
          definition of Affiliate.

      

      

      “FTE” means a total of forty-seven (47)
          weeks or one thousand eight hundred eighty (1,880) hours per year of work on the Development of a Product carried out by employees of a Party having the appropriate relevant expertise to conduct such activities.

      

      

      “Full Royalty Period” has the meaning set
          forth in Section 9.7.2(a).

      

      

      “Fully Absorbed Cost of Goods” means the
          costs incurred by Ionis as determined using the methodology set forth in Schedule 4.4.2 fairly applied and as employed on a consistent basis throughout Ionis’ operations.

      

      

      “GA” has the meaning set forth in ARTICLE 2.

      

      

      “Generic Product” means, on a Product-by-Product and country-by-country basis, any product sold by a Third Party that is not a licensee or Sublicensee of Roche where such product(s) has the same
          active pharmaceutical ingredient as a 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 such product(s) taken in the aggregate has a market share (measured in number of prescriptions during a Calendar Quarter with the numerator of such fractional share being the Generic Products taken in the aggregate, and the denominator being
          the total of the Generic Products taken in the aggregate plus the Product taken in the aggregate, as provided by IQVIA) in such country of at least [***].

      

      

      “Group Sublicensee” means any individual,
          corporation, association or other business entity:

      

      

      
        
          	

                	(i)	
                  to which Roche has granted a Sublicense;

                

        

      

      

      

      
        
          	

                	(ii)	
                  that is not an Affiliate of Roche; and

                

        

      

      

      

      
        
          	

                	(iii)	
                  that is consolidated within Roche’s externally published audited financial statements.

                

        

      

      

      

      “gRED” has the meaning set forth in Section 5.1.2.

      

      

      “HSR Act” means Section 7A of the Clayton
          Act, as added by Title II of the Hart-Scott-Rodino Antitrust Improvement Act of 1976, as amended, and the rules and regulations promulgated thereunder.

      

      

      
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      “IDCP” has the meaning set forth in Section 8.1.1.

      

      

      “[***]” has the meaning set forth in ARTICLE 2.

      

      

      “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.

      

      

      “Indemnitee” has the meaning set forth in Section 12.3.

      

      

      “Indication” means a primary sickness or
          medical condition or any interruption, cessation or disorder of a particular bodily function, system or organ (each a “disease”) including sub-types and pediatric populations of the same disease.  Indications that require separate pivotal trials
          to obtain Approval to market and sell a Product are separate Indications.

      

      

      “Initiation” means, with respect to any
          Clinical Study, dosing of the first human subject in such Clinical Study.

      

      

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

      

      

      “Ionis Collaboration Know-How” means
          Know-How discovered, developed, invented or created solely by or on behalf of Ionis or its Affiliate or a Third Party acting on their behalf in the performance of the Development Plan, that is necessary or useful to Develop, Manufacture or
          Commercialize a Product in the Field.

      

      

      “Ionis Collaboration Patents” means Patent
          Rights discovered, developed, invented or created solely by or on behalf of Ionis or its Affiliate or a Third Party acting on their behalf in the performance of the Development Plan, that are necessary or useful to Develop, Manufacture or
          Commercialize a Product in the Field.

      

      

      “Ionis Collaboration Intellectual Property”
          means Ionis Collaboration Know-How, Ionis Collaboration Patents and Ionis’ interest in any Jointly-Owned Collaboration Intellectual Property.

      

      

      “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 or Conjugate Technology and not limited to a single specified gene target, other than Ionis Manufacturing and Analytical Patents. A list of Ionis Core
          Technology Patents as of the Effective Date is set forth on Schedule 11.2.4(a) attached hereto.

      

      

      “IONIS-FB-LRx” means the compound known as ISIS 696844, which has the following structure:  [***].

      

      

      “Ionis’ Fully Absorbed Cost of Goods” means
          the costs incurred by Ionis as determined using the methodology set forth in Schedule 4.4.2 fairly applied and as employed on a consistent basis throughout Ionis’ operations.

      

      

      “Ionis Internal ASO Safety Database” has the
          meaning set forth in Section 8.2.2(a).

      

      

      “Ionis Know-How” means any Know-How,
          including Ionis’ interest in any Jointly-Owned Collaboration 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.

      

      

      
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      “Ionis Manufacturing and Analytical Know-How”
          means Know-How, including Ionis’ interest in any Jointly-Owned Collaboration 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 Ionis’ interest in any Jointly-Owned Collaboration 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 11.2.4(b) attached hereto. Ionis
          Manufacturing and Analytical Patents do not include the Ionis Product-Specific Patents or the Ionis Core Technology Patents.

      

      

      “Ionis Product Reverse Royalties” has the
          meaning set forth in Section 9.9.

      

      

      “Ionis Product-Specific Patents” means
          Product-Specific Patents 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 11.2.4(c) attached hereto.

      

      

      “Ionis Supported Pass-Through Costs” means
          the licensing costs and payments payable by Ionis to Third Parties to the extent arising from a Third Party agreement under [***] or [***].

      

      

      “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 Development Committee” or “JDC” has the meaning set forth in Section 4.1.2.

      

      

      “Joint Patent Committee” or “JPC” has
          the meaning set forth in Section 10.1.3(a).

      

      

      “Joint Steering Committee” or “JSC” has the meaning set forth in Section 4.1.1.

      

      

      “Jointly-Owned Collaboration Know-How” means
          Know-How discovered, developed, invented or created jointly in the performance of the Development Plan by or on behalf of both Parties or their respective Affiliates or Third Parties acting on their behalf that is necessary or useful to Develop,
          Manufacture or Commercialize a Product in the Field.

      

      

      “Jointly-Owned Collaboration Patents” means
          any Patent Rights discovered, developed, invented or created jointly in the performance of the Development Plan by or on behalf of both Parties or their respective Affiliates or Third Parties acting on their behalf that is necessary or useful to
          Develop, Manufacture or Commercialize a Product in the Field.

      

      

      “Jointly-Owned Collaboration Intellectual Property”
          means Jointly-Owned Collaboration Know-How and Jointly-Owned Collaboration Patents.

      

      

      “Key Meeting” has the meaning set forth in Section 8.1.6.

      

      

      “Know-How” means unpatented 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.

      

      

      
        73

        
          

      

      
        Confidential

      

       

        

      “Lead Party” has the meaning set forth in Section 10.4.1.

      

      

      “Licensed CMO” has the meaning set forth in
          Section 7.1.4(a)(ii).

      

      

      “Licensed Know-How” means Ionis
          Manufacturing and Analytical Know-How, Ionis Know-How, Ionis Collaboration Know-How, and Ionis’ interest in any Jointly-Owned Collaboration Know-How. For clarity, Licensed Know-How does not include any Know-How generated after the Effective Date
          covering formulation technology or delivery devices (other than any Conjugate Technology comprised in IONIS-FB-LRx) unless such Know-How is included in any Ionis Collaboration Know-How or Jointly-Owned Collaboration Know-How.

      

      

      “Licensed Patents” means the Ionis
          Product-Specific Patents, Ionis Core Technology Patents, Ionis Manufacturing and Analytical Patents, Ionis Collaboration Patents, and Ionis’ interest in any Jointly-Owned Collaboration Patents. For clarity, Licensed Patents do not include any
          Patent Rights filed after the Effective Date claiming formulation technology or delivery devices (other than any Conjugate Technology comprised in IONIS-FB-LRx) unless such Patent Rights are included in any Ionis Collaboration Patents or Jointly-Owned Collaboration Patents.

      

      

      “Licensed Intellectual Property” means any
          and all Licensed Patents and Licensed Know-How, in each case to the extent necessary or useful to Develop, Manufacture or Commercialize a Product.

      

      

      “Losses” has the meaning set forth in Section 12.1.

      

      

      “MAA” means a marketing authorization application filed with the EMA after
            completion of Clinical Studies to obtain Approval for a 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 the Approval of an MAA by (i) the EMA for a Product

          in any country in the EU, or (ii) a Regulatory Authority for a Product in a European country that is a Major Market.

      

      

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

      

      

      “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 non-clinical, clinical, or commercial purposes, of API, Finished Drug Product or a
          Product.

      

      

      “Milestone Event” means a Post-Licensing
          Milestone Event or a Sales Milestone Event, as applicable.

      

      

      “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.

      

      

      “Net Sales” of a Product in a particular
          period will mean the amount calculated by subtracting from the Sales of such Product for such period: (A) a lump sum deduction of four percent (4%) of Sales under item (i) of the “Sales” definition in lieu of those deductions that are not accounted for on a Product-by-Product basis (e.g., freight, postage charges,
          transportation insurance, packing materials for dispatch of goods, custom duties); (B) uncollectible amounts accrued during such period based on a proportional allocation of the total bad debts accrued during such period; (C) credit card charges
          (including processing fees) accrued during such period on such Sales; and (D) government mandated fees and taxes and other government charges accrued during such period for such Product including, for example, any fees, taxes or other charges
          that become due in connection with any healthcare reform, change in government pricing or discounting schemes, or other action of a government or regulatory body; provided that the foregoing deductions under (A) to (D) were not already taken as a
          gross-to-net deduction in accordance with the then currently used International Financial Reporting Standards (IFRS) in the calculation of Sales of such Product for such period.

      

      

      
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      Confidential

       

        

      “New Third Party Licenses” has the meaning
          set forth in Section 11.3.2.

      

      

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

      

      

      “Non-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 a Product and whether a Product has a desired effect.

      

      

      “Non-Rare Disease Indication” means an Indication that is not a Rare Disease Indication.

      

      

      “Non-Transferring Party” has the meaning set
          forth in Section 15.4.

      

      

      “Option” has the meaning set forth in Section 6.1.

      

      

      “Option Deadline” has the meaning set forth
          in Section 6.1.

      

      

      “Option Period” has the meaning set forth in
          ARTICLE 2.

      

      

      “Party” or “Parties” means Roche 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 (1) 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 (a) use oligonucleotides (or supply oligonucleotides to end users) solely to conduct non-clinical research, or (b) enable such Third Party to manufacture or formulate oligonucleotides, where Ionis does not assist such
          Third Party to identify, discover or make a Compound or Product; and (2) material transfer agreements with academic collaborators or non-profit institutions solely to conduct noncommercial research. A list of Permitted Licenses as of the
          Effective Date is set forth on Appendix 3 attached hereto.

      

      

      
        75

        
          

      

      Confidential

       

        

      “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.

      

      

      “Phase 1 Trial” means the initial clinical
          testing of a Product in humans (first in humans study) in any country that is designed to satisfy the requirements of 21 C.F.R. § 312.21(a) FDCA, as amended from time to time, or a foreign equivalent thereof.

      

      

      “Phase 2 GA Trial” means the Phase 2 Trial
          of IONIS-FB-LRx in GA commenced by Ionis and to be conducted in accordance with the Development Plan.

      

      

      “Phase 2 [***] Trial” means the anticipated
          phase 2a trial of IONIS-FB-LRx in [***] to be conducted by Ionis in accordance with the Development Plan.

      

      

      “Phase 2b [***] Trial” has the meaning set
          forth in Section 3.1.3.

      

      

      “Phase 2 Trial” means a human clinical study
          of a Product that is intended to explore a variety of dose and dose response to generate initial evidence of clinical safety and activity in a target patient population for which the primary endpoints include a determination of dose ranges and/or
          a preliminary determination of efficacy in patients being studied as described in 21 C.F.R. § 312.21(b) FDCA, as amended from time to time, or a foreign equivalent thereof.

      

      

      “Phase 2 Trial Data Package” means, with
          respect to the Phase 2 GA Trial and the Phase 2 [***] Trial, the listing and tables of safety and efficacy data available to Ionis after the last patient has received his/her last dose of a Product in each such trial.  If, as of the time the
          Phase 2 Trial Data Package is complete, there is available to Ionis additional Phase 2 Trial data or any additional earlier stage Clinical Study data for the Product pursuant to Section

              3.1.3, then Ionis will provide such additional data to Roche along with the Phase 2 Trial Data Package.

      

      

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

      

      

      “Post-Licensing Milestone Event” has the
          meaning set forth in Section 9.4.

      

      

      “Post-Licensing Milestone Payment” has the
          meaning set forth in Section 9.4.

      

      

      “Pre-Option Development Milestone Event” has
          the meaning set forth in Section 9.2.

      

      

      “Pre-Option Development Milestone Payment”
          has the meaning set forth in Section 9.2.

      

      

      “Prior Agreement” means the agreement listed
          on Schedule 11.2.6 attached hereto.

      

      

      “Proceeding” means an action, suit or
          proceeding.

      

      

      “Product” means any product, including any
          combination product, containing IONIS-FB-LRx as an active pharmaceutical ingredient regardless of its finished form, formulation or dosage.

      

      

      “Product-Specific Patents” means, with
          respect to a Product, Patent Rights Controlled by a Party or any of its Affiliates on or after the Effective Date claiming (i) the specific composition of matter of such Product, or (ii) methods of using such Product as a prophylactic or
          therapeutic, in each case to the extent necessary to Develop, Manufacture or Commercialize a Product; provided however, Patent Rights Controlled by Ionis
          or any of its Affiliates that (a) include claims that are directed to subject matter applicable to ASOs or products in general, or (b) include an ASO, the sequence of which targets the RNA that encodes Factor B and ASOs that do not target the RNA
          encoding Factor B, will not be considered Product-Specific Patents, and in the case of (a) and (b), such Patent Rights will be considered Ionis Core Technology Patents.

      

      

      
        76

        
          

      

      Confidential

       

        

      “Proposed Phase 2 Trials” means the Phase 2
          GA Trial and the Phase 2 [***] Trial.

      

      

      “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.

      

      

      “Rare Disease Indication” means an Indication for which the expected U.S. patient population with a disease eligible for treatment by the Product is two
            hundred thousand (200,000) or less as determined by the FDA Office of Orphan Products Development.

      

      

      “Receiving Party” has the meaning set forth in Section 14.1.

      

      

      “Reduced Royalty Period” has the meaning set
          forth in Section 9.7.2(d).

      

      

      “[***]” has the meaning set forth in Section 9.7.2(b).

      

      

      “Registration-Directed Trial” means a
          pivotal Clinical Study (whether or not called a “Phase 3” Clinical Study) [***] intended to establish that a Product is safe and effective for its intended
          use; and is intended to support NDA filing (or foreign equivalent filing) of such Product in patients having the disease or condition being studied, as described in 21 C.F.R. § 312.21(c) FDCA, as amended from time to time, or a foreign equivalent
          thereof.

      

      

      “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.

      

      

      “Regulatory Materials” means regulatory
          applications, submissions, notifications, communications, correspondence, registrations, Approvals and/or other filings made to, received from or otherwise conducted with a Regulatory Authority that are necessary in order to Develop, Manufacture,
          obtain marketing authorization, market, sell or otherwise Commercialize a Product in a particular country or regulatory jurisdiction. Regulatory Materials include INDs, NDAs, MAAs, JNDAs, drug master files, presentations, responses, and
          applications for other Approvals. For clarity, Regulatory Materials also include written minutes of any meeting with any Regulatory Authorities, including minutes prepared by said Regulatory Authorities and those prepared by a Party’s personnel.

      

      

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

      

      

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

      

      

      
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      Confidential

       

        

      “Roche Collaboration Know-How” means
          Know-How discovered, developed, invented or created solely by or on behalf of Roche or its Affiliate or a Third Party acting on their behalf in the performance of the Development Plan or the IDCP, that is necessary or useful to Develop,
          Manufacture or Commercialize a Product in the Field.

      

      

      “Roche Collaboration Patents” means Patent
          Rights discovered, developed, invented or created solely by or on behalf of Roche or its Affiliate or a Third Party acting on their behalf in the performance of the Development Plan or the IDCP, that are necessary or useful to Develop,
          Manufacture or Commercialize a Product in the Field.

      

      

      “Roche Collaboration Intellectual Property”
          means Roche Collaboration Know-How, Roche Collaboration Patents and Roche’s interest in any Jointly-Owned Collaboration Intellectual Property.

      

      

      “Roche Full Royalty” has the meaning set
          forth in Section 9.7.1.

      

      

      “Roche Know-How” means any Know-How that (i)
          did not arise in connection with the performance of the Development Plan, (ii) is owned, used, developed by, or licensed to Roche or its Affiliates, and (iii) is necessary or useful to Develop, Manufacture or Commercialize a Product in the Field,
          in each case to the extent Controlled by Roche or its Affiliates on the Effective Date or at any time during the Agreement Term.

      

      

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

      

      

      “Roche Patents” means any Patent Rights that
          (i) did not arise in connection with the performance of the Development Plan or IDCP, (ii) are owned, used, developed by, or licensed to Roche or its Affiliates, and (iii) are necessary or useful to Develop, Manufacture or Commercialize a Product
          in the Field, in each case to the extent Controlled by Roche or its Affiliates on the Effective Date or at any time during the Agreement Term.

      

      

      “Roche-Prosecuted Patents” has the meaning
          set forth in Section 10.2.4(b).

      

      

      “Roche Reduced Royalty” has the meaning set
          forth in Section 9.7.2(b).

      

      

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

      

      

      “Roche Intellectual Property” means Roche’s
          interest in Roche Collaboration Intellectual Property, Roche Know-How, Roche Patents and any trademarks described in Section 7.1.7, owned, used, developed by, or
          licensed to Roche or its Affiliates that is necessary or useful to Develop, Manufacture or Commercialize a Product.

      

      

      “[***]” has the meaning set forth in Section 9.7.2(b).

      

      

      “Sales” of a Product in a particular period
          will mean the sum of (i) and (ii):

      

      

      (i) the amount stated in Roche sales line of its externally published audited financial statements with respect to such Product for
          such period (excluding sales to any Sublicensee that are used for research or Development or re-sold by such Sublicensee as sales under item (ii) below). This amount reflects the gross invoice price at which such Product was sold or otherwise
          disposed of (other than for use as clinical supplies or free samples) by Roche, its Affiliates and Group Sublicensees to Third Parties (excluding sales to any Sublicensee that are used for research or Development or re-sold by such Sublicensee as
          sales under item (ii) below) in such period reduced by gross-to-net deductions, if not previously deducted from such invoiced amount, taken in accordance with the then currently used International Financial Reporting Standards (IFRS).

       

        

      
        78

        
          

      

      Confidential

       

        

      By way of example, the gross-to-net deductions taken in accordance with International Financial Reporting Standards (IFRS) as of the
          Effective Date include the following:

      

      

      
        
          	

                	(a)	
                  credits, reserves or allowances granted for (w) damaged, outdated, returned, rejected, withdrawn or recalled Product, (x) wastage replacement and short-shipments, (y)
                      billing errors and (z) indigent patient and similar programs (e.g., price capitation);

                

        

      

      

      

      
        	 	
                (b)

              	
                governmental price reductions and government mandated rebates;

              

      

      

      

      
        
          	

                	(c)	
                  chargebacks, including those granted to wholesalers, buying groups and retailers;

                

        

      

      

      

      
        
          	

                	(d)	
                  customer rebates, including cash sales incentives for prompt payment, cash and volume discounts; and

                

        

      

      

      

      
        
          	

                	(e)	
                  taxes, duties and any other governmental charges or levies imposed upon or measured by the import, export, use, manufacture or sale of a Product (excluding income or
                      franchise taxes).

                

        

      

      

      

      For the purpose of clarity, sales by Roche and its Affiliates to any Sublicensee and/or Group Sublicensee that are used for research
          or Development or re-sold by such Sublicensee or Group Sublicensee as sales under item (ii) below will be excluded from “Sales” calculated under this item
          (i).

      

      

      (ii) Sublicensee (excluding Compulsory Sublicensee) sales amounts reported to Roche and its Affiliates in accordance with Sublicensee
          contractual terms and their then currently used accounting standards. For the purpose of clarity, any Sublicensee sales as reported to Roche in accordance with Compulsory Sublicense agreements will be excluded from the Sales amount.

      

      

      “Sales Milestone Event” has the meaning set
          forth in Section 9.5.

      

      

      “Sales Milestone Payment” has the meaning
          set forth in Section 9.5.

      

      

      “Second Indication” means either (i) any
          second Indication if the applicable Post-Licensing Milestone Event has already been achieved by a Non-Rare Disease Indication, or (ii) the first Rare Disease Indication for which the applicable Post-Licensing Milestone Event is achieved.

      

      

      “Specific Performance Milestone Event” has
          the meaning set forth in the definition of “Commercially Reasonable Efforts”.

      

      

      “Step-In Party” has the meaning set forth in
          Section 10.4.1.

      

      

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

      

      

      “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 any Additional Ionis In-License Agreements) that relate to a Product, Factor B, including field
          or territory restrictions, covenants, milestone payments, diligence obligations, sublicense revenue, royalties, or other payments.

      

      

      
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      Confidential

       

        

      “Transferring Party” has the meaning set
          forth in Section 15.4.

      

      

      “Transition Activities” has the meaning set
          forth in Section 13.4.2(i)(i).

      

      

      “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 (i) 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 (ii) 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 (7) 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 (i) above with
          respect to such application issues.

      

      

      
        80

        
          

      

      Confidential

       

            

      Appendix 2

      

      

      Development and Commercialization Activities and

      Specific Performance Milestone Events

      

      

      [***]

      

      

      
        81

        
          

      

      Confidential

       

            

      Appendix 3

      

      

      Permitted Licenses as of the Effective Date

      

      

      [***]

      

      

      
        82

        
          

      

      Confidential

       

            

      Schedule 4.2

      

      

      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 one hundred (100) days after the
                      Effective Date to support the Development Plans;

                

        

      

      

      

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

                

        

      

      

      

      
        
          	(d)	
                  Supporting the co-chairs of the JSC and JDC 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 JSC and JDC;

                

        

      

      

      

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

                

        

      

      

      

      
        
          	(g)	
                  Ensuring proper approval of publications prior to submission as required in Section 14.4.

                

        

      

      

      

      
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      Confidential

       

            

      Schedule 4.4.2

      

      

      Ionis’ Fully Absorbed Cost of Goods Methodology

      Cost Estimate of API Cost per Kilogram

      

      

      [***]

      

      

      
        84

        
          

      

      Confidential

       

            

      Schedule 9.7.2(e)

      

      

      Royalty Calculation Examples

      

      

      [***]

      

      

      
        85

        
          

      

      Confidential

       

            

       Schedule 9.7.2(f)

      

      

      Allocation of Net Sales

      

      

      [***]

      

      

      
        86

        
          

      

      Confidential

       

            

      Schedule  11.2.4(a)

      

      

      Ionis Core Technology Patents

      

      

      [***]

      

      

      
        87

        
          

      

      Confidential

       

            

      Schedule 11.2.4(b)

      

      

      Ionis Manufacturing and Analytical Patents

      

      

      [***]

      

      

      
        88

        
          

      

      Confidential

       

            

      Schedule 11.2.4(c)

      

      

      Ionis Product-Specific Patents

      

      

      [***]

      

      

      
        
          

      

      Confidential

       

            

      Schedule 11.2.6

      

      

      Prior Agreement

      

      

      [***]

      

      

      
        
          

      

      Confidential

       

            

      Schedule 13.4.2(i)

      

      

      Transition Activities

      

      

      Roche will perform Transition Activities, to the extent applicable at the time of the applicable termination, that are necessary to (1) provide patients
          with continued access to the applicable Products, (2) enable Ionis (or Ionis’ designee) to assume and execute the responsibilities under all Approvals and then-ongoing Clinical Studies for the applicable Product, and (3) ensure long-term
          continuity of supply for the Product.  Roche will perform the Transition Activities for Ionis through an agreed-upon schedule as set forth in an agreed upon transition plan, including but not limited in the following areas:

      

      

      [***]Execution Copy

          

          
            Exhibit 10.68

             

              

             Second Amended and Restated

          

        

        Strategic Neurology Drug Discovery and Development Collaboration, Option and License Agreement

        

        

        Between

        

        

        Ionis Pharmaceuticals, Inc.

        

        

        And

        

        

        Biogen MA Inc.

        

        

        Dated October 17, 2018

         

          

        
          
            

        

        
        Table of Contents

        

        

        	 	
                Page

              
	 	 
	
                ARTICLE 1. RESEARCH AND DEVELOPMENT

              	
                2

              
	 	 
	 	
                1.1.

              	
                Collaboration Overview

              	
                2

              
	 	
                1.2.

              	
                Research Programs

              	
                3

              
	 	
                1.3.

              	
                Process for Designating High Interest Targets as
                      Collaboration Targets or Biogen Alternate Modality Targets

              	
                8

              
	 	
                1.4.

              	
                Process for Designating Ionis Neurology Targets as
                      Collaboration Targets

              	
                9

              
	 	
                1.5.

              	
                Process for Designating ALS Targets as Collaboration Targets

              	
                9

              
	 	
                1.6.

              	
                Consequences of Designating Collaboration Targets

              	
                10

              
	 	
                1.7.

              	
                Consequences of Designating Biogen Alternate Modality Targets

              	
                11

              
	 	
                1.8.

              	
                Deferring the Selection of a Collaboration Target or Biogen
                      Alternate Modality Target

              	
                11

              
	 	
                1.9.

              	
                End of Research Term

              	
                13

              
	 	
                1.10.

              	
                Ionis’ Research and Development Responsibilities

              	
                14

              
	 	
                1.11.

              	
                Resource Allocations

              	
                27

              
	 	
                1.12.

              	
                Research and Development Costs Paid by Ionis

              	28
	 	
                1.13.

              	
                Research and Development Costs Paid by Biogen

              	
                28

              
	 	
                1.14.

              	
                Payment Mechanisms

              	29
	 	
                1.15.

              	
                Participation in Regulatory Meetings

              	
                31

              
	 	
                1.16.

              	
                Participation in Meetings Sponsored by a Party’s Clinical
                      Development Group

              	32
	 	
                1.17.

              	
                Impact of Accelerated Development Path

              	
                32

              
	 	
                1.18.

              	
                Research and Development Management

              	33
	 	 
	
                ARTICLE 2. EXCLUSIVITY COVENANTS

              	40
	 	 
	 	
                2.1.

              	
                Exclusivity; Right of First Negotiation

              	40
	 	
                2.2.

              	
                Right of First Negotiation for Follow-On Compounds

              	44
	 	 
	
                ARTICLE 3. EXCLUSIVE OPTION

              	46
	 	 
	 	
                3.1.

              	
                Option

              	46
	 	
                3.2.

              	
                Changing or Adding Modalities

              	48
	 	
                3.3.

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

              	52

        

        

        
          i

          
            

        

        	
                ARTICLE 4. LICENSE GRANTS

              	52
	 	 
	 	
                4.1.

              	
                License Grants to Biogen

              	52
	 	
                4.2.

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

              	56
	 	
                4.3.

              	
                Enabling Licenses

              	56
	 	
                4.4.

              	
                Licenses to Ionis for Biogen Results

              	60
	 	
                4.5.

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

              	61
	 	
                4.6.

              	
                Ownership of and Assistance with Regulatory Filings

              	
                61

              
	 	
                4.7.

              	
                Subcontracting

              	62
	 	
                4.8.

              	
                Technology Transfer

              	63
	 	 
	
                ARTICLE 5. DEVELOPMENT, MANUFACTURING AND COMMERCIALIZATION

              	66
	 	 
	 	
                5.1.

              	
                Biogen Diligence

              	66
	 	
                5.2.

              	
                Regulatory Matters; Global Safety Database; Pharmacovigilance
                      Agreement

              	69
	 	
                5.3.

              	
                Research and Manufacturing Records

              	73
	 	
                5.4.

              	
                Product Development Plans for ALS Collaboration Programs and
                      Biogen Conducted Non-ALS Collaboration Programs

              	73
	 	 
	
                ARTICLE 6. FINANCIAL PROVISIONS

              	73
	 	 
	 	
                6.1.

              	
                Up-Front Fee

              	
                73

              
	 	
                6.2.

              	
                Drug Discovery Milestone Payments

              	
                73

              
	 	
                6.3.

              	
                Milestone Payments for Achievement of Milestone Events by
                      Biogen Alternate Modality Products

              	74
	 	
                6.4.

              	
                Non-ALS Collaboration Program Milestone Payments for
                      Achievement of Pre-Licensing Milestone Events

              	
                74

              
	 	
                6.5.

              	
                ALS Collaboration Program Milestone Payments for Achievement
                      of Pre-Licensing Milestone Events

              	75
	 	
                6.6.

              	
                License Fee

              	
                76

              
	 	
                6.7.

              	
                Milestone Payments for Achievement of Post-Licensing
                      Milestone Events

              	
                76

              
	 	
                6.8.

              	
                Limitations on Milestone Payments; Exceptions; Notice

              	
                77

              
	 	
                6.9.

              	
                Royalty Payments to Ionis for Biogen Alternate Modality
                      Products

              	
                78

              
	 	
                6.10.

              	
                Royalty Payments to Ionis for Collaboration Products

              	
                79

              
	 	
                6.11.

              	
                Limitation on Aggregate Reduction for Royalties for
                      Collaboration Products

              	
                82

              
	 	
                6.12.

              	
                Reverse Royalty Payments to Biogen for a Discontinued
                      Collaboration Product

              	
                82

              
	 	
                6.13.

              	
                Third Party Payment Obligations

              	
                83

              

        

        

        
          ii

          
            

        

        	 	
                6.14.

              	
                Payments

              	84
	 	
                6.15.

              	
                Audits

              	
                86

              
	 	
                6.16.

              	
                Taxes

              	
                86

              
	 	
                6.17.

              	
                Interest

              	
                88

              
	 	 
	
                ARTICLE 7. INTELLECTUAL PROPERTY

              	
                88

              
	 	 
	 	
                7.1.

              	
                Ownership

              	
                88

              
	 	
                7.2.

              	
                Prosecution and Maintenance of Patents

              	
                92

              
	 	
                7.3.

              	
                Patent Costs

              	
                97

              
	 	
                7.4.

              	
                Defense of Claims Brought by Third Parties

              	
                98

              
	 	
                7.5.

              	
                Enforcement of Patents Against Competitive Infringement

              	100
	 	
                7.6.

              	
                Other Infringement

              	103
	 	
                7.7.

              	
                Patent Listing

              	
                103

              
	 	
                7.8.

              	
                Joint Research Agreement under the Leahy-Smith America
                      Invents Act

              	104
	 	
                7.9.

              	
                Obligations to Third Parties

              	
                104

              
	 	
                7.10.

              	
                Additional Right and Exceptions

              	
                104

              
	 	
                7.11.

              	
                Patent Term Extension

              	105
	 	 
	
                ARTICLE 8. REPRESENTATIONS AND WARRANTIES

              	105
	 	 
	 	
                8.1.

              	
                Representations and Warranties of Both Parties

              	105
	 	
                8.2.

              	
                Representations and Warranties of Ionis

              	106
	 	
                8.3.

              	
                Ionis Covenants

              	108
	 	
                8.4.

              	
                DISCLAIMER

              	
                109

              
	 	 
	
                ARTICLE 9. INDEMNIFICATION; INSURANCE

              	109
	 	 
	 	
                9.1.

              	
                Indemnification by Biogen

              	109
	 	
                9.2.

              	
                Indemnification by Ionis

              	110
	 	
                9.3.

              	
                Procedure

              	110
	 	
                9.4.

              	
                Insurance

              	111
	 	
                9.5.

              	
                LIMITATION OF CONSEQUENTIAL DAMAGES

              	111
	 	 
	
                ARTICLE 10. TERM; TERMINATION

              	112
	 	 
	 	
                10.1.

              	
                Agreement Term; Expiration

              	112
	 	
                10.2.

              	
                Termination of the Agreement

              	113

        

        

        
          iii

          
            

        

        	 	
                10.3.

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

              	117
	 	
                10.4.

              	
                Consequences of Expiration or Termination of the Agreement

              	119
	 	 
	
                ARTICLE 11. CONFIDENTIALITY

              	132
	 	 
	 	
                11.1.

              	
                Confidentiality; Exceptions

              	132
	 	
                11.2.

              	
                Prior Confidentiality Agreement Superseded

              	132
	 	
                11.3.

              	
                Authorized Disclosure

              	132
	 	
                11.4.

              	
                Press Release; Publications; Disclosure of Agreement

              	133
	 	 
	
                ARTICLE 12. MISCELLANEOUS

              	138
	 	 
	 	
                12.1.

              	
                Dispute Resolution

              	138
	 	
                12.2.

              	
                Governing Law; Jurisdiction; Venue; Service of Process

              	139
	 	
                12.3.

              	
                Remedies

              	140
	 	
                12.4.

              	
                Assignment and Successors

              	141
	 	
                12.5.

              	
                Change of Control

              	141
	 	
                12.6.

              	
                Protective Provisions

              	146
	 	
                12.7.

              	
                Force Majeure

              	146
	 	
                12.8.

              	
                Notices

              	147
	 	
                12.9.

              	
                Export Clause

              	148
	 	
                12.10.

              	
                Waiver

              	148
	 	
                12.11.

              	
                Severability

              	148
	 	
                12.12.

              	
                Entire Agreement

              	148
	 	
                12.13.

              	
                Independent Contractors

              	149
	 	
                12.14.

              	
                Interpretation

              	149
	 	
                12.15.

              	
                Books and Records

              	149
	 	
                12.16.

              	
                Further Actions

              	
                149

              
	 	
                12.17.

              	
                Construction of Agreement

              	149
	 	
                12.18.

              	
                Supremacy

              	
                150

              
	 	
                12.19.

              	
                Counterparts

              	150
	 	
                12.20.

              	
                Compliance with Laws

              	150

         

        

        
          iv

          
            

        

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

        

        

        This SECOND AMENDED AND RESTATED STRATEGIC NEUROLOGY DRUG DISCOVERY AND DEVELOPMENT COLLABORATION, OPTION AND LICENSE AGREEMENT (the
            “Agreement”) is entered into as of the 17th day of October, 2018 (the “Second Amendment Date”) by and between Ionis Pharmaceuticals, Inc., a Delaware
            corporation, having its principal place of business at 2855 Gazelle Court, Carlsbad, CA 92010 (“Ionis”), and Biogen 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 is interested in entering into a strategic relationship with Ionis to explore potential targets for the treatment of neurological and neuromuscular diseases and to create antisense and other drugs to
            such targets;

        

        

        WHEREAS, Biogen and Ionis now desire to
            enter into a new strategic collaboration in neurological and neuromuscular diseases to include (i) a neurological disease research program focused on the identification, validation, and applications of novel targets, (ii) a broad core
            technology research program focused on enhancing the Parties’ knowledge of antisense oligonucleotide pharmacokinetics and pharmacodynamics in the central and peripheral nervous systems, (iii) a targeted drug discovery and development effort,
            and (iv) the exclusive opportunity for Biogen to select collaboration targets from among all available targets reaching target sanction status in Ionis’ neurology program;

        

        

        WHEREAS, with regard to certain neurology
            targets Biogen selects as collaboration targets for development using an antisense molecule, Biogen desires Ionis to (i) identify a development candidate for each of the collaboration targets, (ii) develop the development candidate through
            completion of the first clinical trial designed to demonstrate proof of mechanism or proof of therapeutic benefit, and (iii) provide Biogen an option to obtain an exclusive license under this Agreement to develop, manufacture and commercialize
            collaboration products in the Field;

        

        

        
          
            

        

        
        WHEREAS, for certain neurology targets
            relating to ALS and certain other indications, the Parties will collaborate to develop and identify antisense and other drugs to such targets as provided herein;

        

        

        WHEREAS, Biogen and Ionis entered into that
            certain Strategic Neurology Drug Discovery and Development Collaboration, Option and License Agreement, as amended (the “Original Agreement”)

            dated September 5, 2013 (the “Effective Date”) and subsequently entered into an Amended and Restated Strategic Neurology Drug Discovery
            and Development Collaboration, Option and License Agreement (the “First Amended and Restated Agreement”) dated October 20, 2017 (the “First Amendment Date”); and

        

        

        WHEREAS, Biogen and Ionis seek to amend and
            restate the First Amended and Restated 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:

        

        

        ARTICLE 1.

        RESEARCH AND DEVELOPMENT

        

        

        
          
            	1.1.	
                    Collaboration Overview.

                  

          

        

        

        

        
          
            	

                  	1.1.1.	
                    The intent of the Collaboration is for the Parties to conduct (i) a neurological disease research program focused on the identification, validation, and applications of
                        novel Neurology Targets, (ii) a broad core technology research program focused on enhancing the Parties’ knowledge of ASO pharmacokinetics and pharmacodynamics in the central and peripheral nervous systems, and (iii) an expanded
                        drug discovery and development effort in Neurological Disease, including a program specifically focused on certain ALS Targets. This Agreement also provides Biogen the exclusive opportunity to select Collaboration Targets and Biogen
                        Alternate Modality Targets from among all available Neurology Targets Ionis is independently researching up through Target Sanction.

                  

          

        

        

        

        
          
            	

                  	1.1.2.	
                    Once a Neurology Target reaches Target Sanction, the Neurology Target may be selected as a Collaboration Target, a Biogen Alternate Modality Target or both under this
                        Agreement. Ionis will generate at least one Development Candidate, if feasible for each Collaboration Program that is not focused on an ALS Target or a Biogen Conducted Non-ALS Target; and advance each such Development Candidate
                        through the completion of the first PoC Trial under the applicable Collaboration Program.

                  

          

        

        

        

        
          2

          
            

        

        
          
            	

                  	1.1.3.	
                    When an ALS Target is selected as a Collaboration Target, Ionis will generate at least one Development Candidate, if feasible, for each ALS Collaboration Program; and
                        Biogen will use Commercially Reasonable Efforts to advance each such Development Candidate through at least the completion of the first PoC Trial under the applicable Collaboration Program.

                  

          

        

        

        

        
          
            	

                  	1.1.4.	
                    Once a Biogen Conducted Non-ALS Target reaches Target Sanction, the Biogen Conducted Non-ALS Target may be selected as a Collaboration Target under this Agreement.
                        Ionis will generate at least one Development Candidate, if feasible for each Biogen Conducted Non-ALS Collaboration Program; and Biogen will use Commercially Reasonable Efforts to advance each such Development Candidate through at
                        least the completion of the first PoC Trial under the applicable Collaboration Program.

                  

          

        

        

        

        
          
            	

                  	1.1.5.	
                    Ionis will provide Biogen an option to further Develop and ultimately Commercialize (a) Compounds and Collaboration Products under such Collaboration Programs, (b)
                        Biogen Alternate Modality Products or (c) both Collaboration Products and Biogen Alternate Modality Products, in each case, under an exclusive license from Ionis.

                  

          

        

        

        

        
          
            	

                  	1.1.6.	
                    The Parties have agreed to form a collaboration steering committee to oversee the Collaboration under this Agreement, a joint research committee reporting to the CSC to
                        oversee the Core Research Program [***], the Neurological Disease Research Program, and each ASO Development Candidate Identification Plan, and one or more joint development committees reporting to the CSC to oversee the development
                        activities for Development Candidates.

                  

          

        

        

        

        
          
            	

                  	1.1.7.	
                    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.	
                    Research Programs. Subject to and in accordance with the terms of this
                        Agreement, during the Research Term, Ionis and Biogen will conduct two research programs, each under a separate mutually agreed plan. The first research program will cover research focused on enhancing the Parties’ knowledge of ASO
                        pharmacokinetics and pharmacodynamics in the central and peripheral nervous systems (such program, the “Core Research Program”
                        and the plan for such program, the “Core Research Plan”). The second research program will focus on the identification and
                        validation of High Interest Targets, and the identification of ALS Targets, that are eligible to become Collaboration Targets (such program, the “Neurological Disease Research Program” and the plan for such program, the “Neurological Disease
                          Research Plan”).  Drafts of the Core Research Plan and the initial Neurological Disease Research Plan have been mutually agreed upon by the Parties in writing on or prior to the Effective Date. The Parties will finalize these initially agreed draft plans within [***] days after the Effective Date. Thereafter, the Parties will update such plans at least
                        once before the beginning of each Calendar Year, and submit them to the Neurology JRC for its review and approval.  Each update to the Neurological Disease Research Plan will include, at a minimum (a) the activities to support
                        Target Sanction in the Calendar Year covered by such Neurological Disease Research Plan, (b) any Neurological Disease research to support Collaboration Programs, and (c) any ongoing work on High Interest Targets from prior Calendar
                        Years.  Notwithstanding the foregoing, neither Party will be required to complete any activities under the Core Research Plan or Neurological Disease Research Plan if such Party in good faith believes that such activities are not
                        technically feasible given the then-current state of the art.

                  

          

        

        

        

        
          3

          
            

        

        
          
            	

                  	1.2.1.	
                    Research Term. The term for the conduct of the Core Research Program and the Neurological Disease Research Program will begin on the Effective Date and will end on the sixth anniversary of the Effective Date,
                        unless either of such programs is terminated earlier by the Parties by written agreement (the “Research Term”); provided, however, that with respect to the Neurological Disease Research Program, (a) Ionis will not be required to begin target validation
                        activities under the Neurological Disease Research Program (i) after the [***] anniversary of the Effective Date for any target that is not an ALS Target or (ii) after the [***] anniversary of the Effective Date for any ALS Target,
                        in each case, unless otherwise agreed to by the Parties, and (b) if any target validation activities that are Ionis Activities are ongoing under the Neurological Disease Research Plan on such sixth anniversary, then Ionis will
                        complete such activities in accordance with the Neurological Disease Research Plan, and the Research Term will be extended until the completion thereof.

                  

          

        

        

        

        
          
            	

                  	1.2.2.	
                    Core Research Program. The Core Research Program activities will focus
                        primarily on investigating and optimizing delivery of ASOs to the CNS. Ionis will use Commercially Reasonable Efforts to conduct the Ionis Activities under the Core Research Program, and Biogen will use Commercially Reasonable
                        Efforts to conduct the Biogen Activities under the Core Research Program. The Neurology JRC will update the Core Research Plan as needed during the Research Term.  As of the Second Amendment Date the Parties have completed all
                        activities under the Core Research Program.

                  

          

        

        

        

        
          
            
              
                	 	
                        1.2.3.

                      	
                        Neurological Disease Research Program. The Neurological Disease
                            Research Program activities will focus primarily on identifying and validating novel Neurology Targets and prioritizing a list of High Interest Targets (defined below), including ALS Targets.

                      

              

            

          

        

        

        

        
          4

          
            

        

        
          
            	

                  	(a)	
                    High Interest Targets. Under the Neurological
                        Disease Research Plan, Biogen will establish a prioritized list of Neurology Targets, including ALS Targets to designate as high interest targets (each such target, a “High Interest Target” and such list the “High Interest Target List”).  The
                        number of High Interest Targets cannot exceed [***].  The initial High Interest Target List has been mutually agreed upon by the Parties in writing on or prior to the Effective Date.  Biogen will present updates, if any, to the High
                        Interest Target List at each meeting of the Neurology JRC. Each Neurology Target added to the High Interest Target List will be a High Interest Target; provided, however, that if Ionis notifies Biogen within [***] days after the date on which Ionis receives a High Interest
                        Target List containing a new High Interest Target that (i) [***], (ii) such gene target is not eligible to become a High Interest Target hereunder [***], or (iii) such gene target is [***], then the applicable gene target will not
                        be a High Interest Target hereunder. When Biogen adds a Neurology Target to the High Interest Target List, Biogen will identify on the High Interest Target List if Biogen intends such target to be an ALS Target.  Biogen may convert
                        an ALS Target into a High Interest Target that is not an ALS Target at any meeting of the Neurology JRC. For clarity, Biogen may add any Ionis Neurology Target to the High Interest Target List until such Ionis Neurology Target is
                        less than [***] months away from the date on which Ionis in good faith believes [***]. In addition, once target validating activities for a High Interest Target have been initiated under the Neurological Disease Research Plan or by
                        Ionis independently (as presented by Ionis to the Neurology JRC), Biogen may not remove a High Interest Target from the High Interest Target
                        List until [***]. The Parties acknowledge and agree that, as of August 4, 2014, [***] has been designated as a Collaboration Target that is an ALS Target under this Agreement. The Parties further acknowledge and agree that (1)
                        notwithstanding any scientific determination regarding [***], the ALS Collaboration Program for [***] shall be treated as an ALS Collaboration Program that is not a [***] Collaboration Program for purposes of this Agreement, (2) [***] is not a Multi-Indication Target (as defined below) and (3) [***] is deemed to be a Pre-Existing Target (as defined
                        below) for purposes of this Agreement.

                  

          

        

        

        

        
          5

          
            

        

        
          
            	

                  	(b)	
                    Multi-Indication Targets.  No later than [***] days
                        following the addition of a particular High Interest Target to the High Interest Target List, Ionis may notify Biogen in writing that Ionis believes, in good faith, based upon published scientific literature or the results of Ionis’
                        internal research efforts, that such High Interest Target may have therapeutic benefit beyond Neurological Disease (each such High Interest Target, a “Multi-Indication Target”, and each such notice a “Multi-Indication Target Notice”). The
                        Multi-Indication Target Notice will (i) include materials supporting Ionis’ belief that such High Interest Target may have therapeutic benefit beyond Neurological Disease and (ii) specify whether Ionis in good faith believes such
                        Multi-Indication Target is a Primarily Neuro Multi-Indication Target, Equal Multi-Indication Target or Primarily Other Multi-Indication Target. If within [***] days of its receipt of a Multi-Indication Target Notice Biogen notifies
                        Ionis in writing that Biogen wishes to remove the applicable Multi-Indication Target from the High Interest Target List, then such Multi-Indication Target will not be a High Interest Target but will continue to be a Neurology Target
                        unless and until its status changes by operation of this Agreement. If Biogen does not so notify Ionis that it wishes to remove the applicable Multi-Indication Target from the High Interest Target List within such [***] day period,
                        within [***] days after Biogen’s receipt of the applicable Multi-Indication Target Notice, Biogen will notify Ionis whether it agrees with Ionis’ determination as to whether the applicable Multi-Indication Target is a Primarily
                        Neuro Multi-Indication Target, Equal Multi-Indication Target or Primarily Other Multi-Indication Target. If Biogen and Ionis agree with respect to such determination, then the agreed upon designation will be binding upon the Parties
                        with respect to such Multi-Indication Target and the provisions of clauses (b)-(e) of Appendix 3 will apply with respect to such
                        Multi-Indication Target. If Biogen does not agree with such determination, the Multi-Indication Target will be designated as a Primarily Neuro Multi-Indication Target, Equal Multi-Indication Target or Primarily Other
                        Multi-Indication Target in accordance with Section 1.2.3(d) upon the Neurology JRC agreeing to conduct target validating activities for such
                        Multi-Indication Target under the Neurological Disease Research Plan pursuant to Section 1.2.3(d) and prior to the commencement of such activities. For
                        the avoidance of doubt, if Ionis fails to deliver a Multi-Indication Target Notice within [***] days after the addition of a particular High Interest Target to the High Interest Target List, such High Interest Target will not be a
                        Multi-Indication Target hereunder.

                  

          

        

        

        

        
          
            	

                  	(c)	
                    Target Validation Under the Neurological Disease Research
                            Program. The Neurology JRC will agree on an update to the Neurological Disease Research Plan annually. The first [***] years of
                        the Research Term are planned to focus on validating the role of novel Neurology Targets that are not ALS Targets in Neurological Disease, with the goal of achieving Target Sanction for High Interest Targets, and providing for all
                        pre-clinical development work under the Neurological Disease Research Plan required to validate such High Interest Targets. Biogen will have final decision-making authority with respect to [***]. The Neurology JRC will determine the
                        number of High Interest Targets for which activities to support Target Sanction will be conducted during each Calendar Year of the Research Term, which number will reflect the number of targets the Neurology JRC determines that
                        Ionis can, in the exercise of Commercially Reasonable Efforts, (i) [***], (ii) [***], (iii) [***], and taking into account resources that may be used for ALS Targets, in each case using the number of FTEs provided for under Section 1.11.  Prior to the initiation of any activities to support Target Sanction with respect to any High Interest Target, Biogen will notify Ionis if such
                        High Interest Target is a Neurology Target with respect to which Biogen has [***] intended for a neurology indication (a “Pre-Existing

                          Target”).  Ionis will use Commercially Reasonable Efforts to conduct such activities to support Target Sanction on such High Interest Targets each year during the Research Term.  The Neurological Disease Research Plan will
                        identify which Party will be responsible for the activities related to validation of such targets. It is anticipated that Biogen will perform the [***] required under the Neurological Disease Research Plan where Biogen, at such
                        time, already has in place at Biogen or through its collaborators the appropriate [***] and the ability to conduct such [***]; and that all other such [***] will be conducted by Ionis. Each Party will be responsible for the cost of
                        the work it conducts under the Neurological Disease Research Program as more specifically detailed in Section 1.12 and Section 1.13.  Neither Party will be required to conduct work using [***] that are not similar in cost or technical feasibility to the [***] such Party has obtained from Third
                        Parties and uses for its other programs.

                  

          

        

        

        

        
          6

          
            

        

        
          
            	

                  	(d)	
                    Target Validation for Multi-Indication Targets. If the Neurology JRC agrees to conduct target validating activities under the Neurological Disease Research Plan with respect to any
                        Multi-Indication Target that the Parties did not agree to designate as a Primarily Neuro Multi-Indication Target, Equal Multi-Indication Target or Primarily Other Multi-Indication Target pursuant to Section 1.2.3(b), within [***] days after such agreement, the CSC will meet to determine whether such target is a Primarily Neuro Multi-Indication Target, Equal Multi-Indication
                        Target or Primarily Other Multi-Indication Target. If the CSC agrees on the appropriate classification for such Multi-Indication Target, the provisions of clauses (b)-(e) of Appendix 3 will apply with respect to such Multi-Indication Target. If the CSC cannot unanimously agree on the appropriate classification for a Multi-Indication Target at the
                        applicable meeting, then such classification will be made pursuant to clause (a) of Appendix 3.

                  

          

        

        

        

        
          
            	

                  	(e)	
                    Neurology Targets that are not High Interest Targets.
                        Subject to the provisions of Section 1.4 and Section 2.1.1(b) below, during
                        the Research Term, either Party may work outside of the Collaboration on any Neurology Target that is not (i) a High Interest Target for which target
                        validating activities are planned under the then-current Neurological Disease Research Plan, (ii) a Collaboration Target, or (iii) a Biogen Alternate Modality Target.

                  

          

        

        

        

        
          7

          
            

        

        
          
            	

                  	1.2.4.	
                    Provision of ASOs for Research Outside of the Neurological
                            Disease Research Program. During the Research Term, in accordance with and subject to the terms and conditions set forth on Schedule 1.2.4 (which represent the
                        non-financial terms upon which Ionis generally provides its partners on a non-exclusive basis, research ASOs for independent research), Biogen may ask Ionis to use its ASO technology to provide research ASOs for up to [***] gene
                        targets each successive [***] month period that are the focus of Biogen programs that are not part of the Collaboration.

                  

          

        

        

        

        
          
            	1.3.	
                    Process for Designating High Interest Targets as Collaboration Targets or Biogen
                            Alternate Modality Targets.   After the Parties complete the activities to achieve Target Sanction for a particular High Interest Target that is not an ALS Target, Ionis will deliver a Target Sanction Data Package for
                        such High Interest Target to the Neurology JRC for review as soon as reasonably practicable.  Each time Ionis delivers the Neurology JRC a Target Sanction Data Package for a High Interest Target under this Section 1.3 the Parties will schedule a meeting of the Neurology JRC within [***] days following delivery of such Target Sanction Data Package. At such meetings the Neurology
                        JRC will determine and record in the Neurology JRC minutes whether an ASO or Alternate Modality is the best therapeutic approach to pursue for such High Interest Target.  If the Neurology JRC cannot unanimously agree on which
                        modality is the best therapeutic approach to pursue for a particular High Interest Target at such meeting, Biogen will have final decision-making authority on the matter. Within the later of (a) [***] days following such meeting of
                        the Neurology JRC or (b) [***] days after Biogen’s receipt of the Target Sanction Data Package for such High Interest Target, by written notice to Ionis, Biogen will either designate such High Interest Target as a Collaboration
                        Target (in which case Section 1.6 will apply), a Biogen Alternate Modality Target (in which case Section 1.7 will apply), or a Deferred Target (in which case Section 1.8 will apply). If Biogen does not designate such High
                        Interest Target as a Collaboration Target, a Biogen Alternate Modality Target, or Deferred Target within the timeframe set forth in the previous sentence, then (i) such High Interest Target (A) will not be designated a Collaboration
                        Target or Biogen Alternate Modality Target and (B) will no longer be a Neurology Target under this Agreement and (ii) the provisions of Section 2.1.1(f)
                        will apply with respect to such target.  Notwithstanding the foregoing, if Ionis delivers the Neurology JRC a Target Sanction Data Package for a High Interest Target under this Section 1.3 and such High Interest Target is a Pre-Existing Target, then the Neurology JRC will not meet to discuss which modality is the best therapeutic approach for such High Interest Target, but Biogen
                        will have [***] days after receipt of such Target Sanction Data Package to designate such High Interest Target as a Collaboration Target or a Deferred Target (treating, for purposes of Section 1.8, such target as a High Interest Target for which the best therapeutic modality was determined to be an ASO) by written notice to Ionis, but will not have the right to designate such
                        High Interest Target as a Biogen Alternate Modality Target.  If Biogen does not designate such High Interest Target as a Collaboration Target or Deferred Target within the timeframe set forth in the previous sentence, then (1) such
                        High Interest Target (I) will not be designated a Collaboration Target or a Deferred Target and (II) will no longer be a Neurology Target under this Agreement and (2) the provisions of clause (A) (but not clause (B)) of Section 2.1.1(f) will apply with respect to such target.

                  

          

        

        

        

        
          8

          
            

        

        
          
            	1.4.	
                    Process for Designating Ionis Neurology Targets as Collaboration Targets.  If, during the Research Term through June 7, 2018 (except, solely in the case of [***] and [***], through the end of the Research Term) in the
                        course of conducting work outside of the Collaboration with respect to any Ionis Neurology Target, Ionis achieves Target Sanction with respect to such Ionis Neurology Target, then Ionis will deliver a Target Sanction Data Package
                        for such Ionis Neurology Target to the Neurology JRC for review as soon as reasonably practicable. Within [***] days after the date Ionis delivered the applicable Target Sanction Data Package to the Neurology JRC, by written notice
                        to Ionis, Biogen will either designate such Ionis Neurology Target as a Collaboration Target (in which case Section 1.6 will apply), or, to the extent
                        permitted below, a Biogen Alternate Modality Target (in which case Section 1.7 will apply). If such Ionis Neurology Target was not a High Interest Target
                        on the date of Target Sanction, Biogen will only have the right to designate such target as a Collaboration Target (and not, for the avoidance of doubt, as a Biogen Alternate Modality Target). If Biogen does not designate such Ionis
                        Neurology Target as a Collaboration Target, or a Biogen Alternate Modality Target within [***] days after the date Ionis delivered the applicable Target Sanction Data Package to the Neurology JRC, such Ionis Neurology Target will no
                        longer be a Neurology Target under this Agreement and Ionis and its Affiliates may work independently or with any Third Party with respect to the discovery, research, development, and commercialization of ASOs (or any other
                        compounds) targeting such Ionis Neurology Target.

                  

          

        

        

        

        
          
            	1.5.	
                    Process for Designating ALS Targets as Collaboration Targets. If Biogen
                        desires Ionis to initiate ASO drug discovery activities on a particular ALS Target, then at the same time the Neurological Disease Research Plan for the Calendar Year in which Biogen desires Ionis to initiate such activities is
                        updated to include activities for such Calendar Year, Biogen will designate such ALS Target as a Collaboration Target by providing written notice to Ionis; provided, if such ALS Target is a Multi-Indication Target, Biogen cannot designate such ALS Target as a Collaboration Target until such target has been classified by the CSC or by operation of Appendix 3 as a Primarily Neuro Multi-Indication Target, Equal Multi-Indication Target or Primarily Other Multi-Indication Target. In
                        addition, Biogen cannot designate more than [***] ALS Targets as Collaboration Targets in any successive [***]-month period, and the total number of ALS Targets that are Collaboration Targets cannot exceed [***] without the Parties’
                        mutual agreement.

                  

          

        

        

        

        
          9

          
            

        

        
          
            	1.6.	
                    Consequences of Designating Collaboration Targets.

                  

          

        

        

        

        
          
            	

                  	1.6.1.	
                    Subject to and in accordance with the terms of this Agreement, for each Collaboration Target designated under Section 1.3, Section 1.4, Section 1.5, Section 1.8, Section 3.2.1 or Section 3.2.4.1, Ionis and Biogen will be responsible for conducting collaboration programs in accordance with this Agreement to discover, Develop and Manufacture Collaboration Products and, upon
                        Biogen’s exercise of the applicable Option, Biogen will be responsible for Commercializing Collaboration Products (each, a “Collaboration

                          Program”).  For each Collaboration Target, an ASO Development Candidate Identification Plan and Initial Development Plan will be established pursuant to Section

                            1.10.1 and Section 1.10.2(d), respectively. For each Collaboration Program, Ionis will use its Commercially Reasonable Efforts to (i)
                        conduct drug discovery activities, according to the applicable ASO Development Candidate Identification Plan to identify a Development Candidate for the applicable Collaboration Target, and (ii) for each Collaboration Program that
                        is not an ALS Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program, conduct drug development activities for each Development Candidate through completion of the first PoC Trial in accordance with the applicable
                        Initial Development Plan; provided that, in each case unless the Neurology JRC unanimously agrees under Section 1.11 to re-allocate resources to support additional Collaboration Programs and, except for any activities Ionis conducts for Collaboration Targets designated under that
                        certain side letter between the Parties, dated as of October 28, 2016 (the “ALS Letter Agreement”) attached hereto as Schedule 1.6.1, Ionis will not be required to commence
                        work on more than [***] Collaboration Programs in any rolling [***] month period; provided, further, that, if Biogen has designated more than [***] High Interest Targets as Collaboration Targets pursuant to Section

                            1.3 in any rolling [***] month period, such excess targets will be treated the same as “Deferred Targets” hereunder until the
                        earlier of (a) such time as Ionis has agreed to commence work on such excess targets, (b) such time as Ionis is otherwise obligated to commence such work hereunder because Ionis has commenced work on fewer than [***] targets in a
                        rolling [***] month period and (c) the expiration of the Research Term and, notwithstanding the provisions of Section 6.2.1, Biogen will not be obligated
                        to make the payment under Section 6.2.1 with respect to such target until such time. For each ALS Collaboration Program and each Biogen Conducted Non-ALS
                        Collaboration Program, Biogen will use its Commercially Reasonable Efforts to conduct drug development activities for each Development Candidate through completion of the [***] in accordance with the applicable Initial Development
                        Plan.

                  

          

        

        

        

        
          
            	

                  	1.6.2.	
                    Notwithstanding the foregoing, if the applicable Collaboration Target is an Equal Multi-Indication Target, the Parties will not conduct any activities under this Section 1.6 unless and until Ionis and Biogen have agreed on a development plan and enhanced economic provisions to be paid by Biogen for the Non-Neurological
                        Indications pursuant to clause (c) of Appendix 3.

                  

          

        

        

        

        
          10

          
            

        

        
          
            	1.7.	
                    Consequences of Designating Biogen Alternate Modality Targets. If Biogen
                        designates a particular Neurology Target as a Biogen Alternate Modality Target under this Agreement (including Section 1.3, Section 1.4, Section 1.8, Section
                            3.2.2 or Section 3.2.4.2), Biogen will pay Ionis the milestone payment under Section 6.2.2 within 45 days of the designation of such Biogen Alternate Modality Target, provided, however, if
                        Biogen determines that an HSR Filing is required to be made under the HSR Act for Biogen to receive the license under Section 4.1.1(b) with respect to
                        such Biogen Alternate Modality Target and notifies Ionis of such determination within five days after the designation of such Biogen Alternate Modality Target, the Parties will promptly file an HSR Filing in accordance with Section 3.1.4 and the due date for Biogen to pay Ionis the milestone payment under Section
                            6.2.2 will be extended until 5:00 pm (Eastern Time) on the [***] Business Day after the HSR Clearance Date.

                  

          

        

        

        

        
          
            	1.8.	
                    Deferring the Selection of a Collaboration Target or Biogen Alternate Modality
                            Target.

                  

          

        

        

        

        
          
            	

                  	1.8.1.	
                    Right to Defer. If under Section 1.3 Biogen provides Ionis a notice (each, a “Deferral Notice”)

                        electing to defer selecting a High Interest Target as a Collaboration Target or a Biogen Alternate Modality Target (each, a “Deferred

                          Target”), and there is at least [***] at the time of Deferral Notice, then Biogen may defer selecting such High Interest Target as a Collaboration Target or a Biogen Alternate Modality Target for a period of up to the
                        shorter of (i) (A) with respect to any High Interest Target for which the best therapeutic modality was determined to be an ASO, [***] or (B) with respect to any High Interest Target for which the best therapeutic modality was
                        determined to be an Alternate Modality, [***], or (ii) the end of the Research Term (the “Deferral Period”); provided, however, Biogen may only defer up to [***] High Interest Targets under this Section 1.8.1 at any given time. For the avoidance of doubt, the limitation in the preceding proviso will not apply with respect to any Collaboration Target that is treated the same as a Deferred Target
                        pursuant to Section 1.6.1.

                  

          

        

        

        

        
          
            	

                  	1.8.2.	
                    Deferral Fee. For each High Interest Target Biogen
                        elects to defer under this Section 1.8, Biogen will pay Ionis an annual deferral fee of (a) $[***] for each such Deferred Target for which the best
                        therapeutic approach is determined to be an ASO or (b) $[***] for each such Deferred Target for which the best therapeutic approach is determined to be an Alternate Modality, in each case, in accordance with Section 1.3. No deferral fee will be due under this Section 1.8.2 with respect to any Collaboration
                        Target that is treated the same as a Deferred Target pursuant to Section 1.6.1. Each annual deferral fee for a Deferred Target will be paid in advance for
                        the ensuing [***] month period, with the initial annual deferral fee for all Deferred Targets due within [***] days after the date Biogen delivers the applicable Deferral Notice to Ionis, and each annual deferral fee due thereafter
                        during the Deferral Period on the anniversary of the date Biogen delivered such Deferral Notice. If any such annual deferral fee is due after the date that is [***] prior to the expiration of the Research Term, such deferral fee
                        will be pro-rated to account for the number of days remaining in the Research Term (where such pro-ration will be based on the number of days between the due date for such deferral fee and the end of the Research Term, divided by
                        365).

                  

          

        

        

        

        
          11

          
            

        

        
          
            	

                  	1.8.3.	
                    Designating a Deferred Target as a Collaboration Target or
                            Biogen Alternate Modality Target; Credit for Deferral Fees. Biogen may designate a Deferred Target as a Collaboration Target or Biogen Alternate Modality Target, as applicable, by delivering written notice to Ionis of
                        such designation (and if a Biogen Alternate Modality Target, the milestone payment under Section 6.2.2), before the expiration of the applicable Deferral
                        Period under this Section 1.8; provided, however, that Biogen
                        will not be permitted to designate such Deferred Target as a Biogen Alternate Modality Target if such Deferred Target is a Pre-Existing Target.  Biogen may credit [***]% of the total amount paid to Ionis under Section 1.8.2 for such Deferred Target against the milestone payment under Section 6.2.1
                        or Section 6.2.2, as applicable, for such Deferred Target. If Biogen does not designate a Deferred Target as a Collaboration Target or Biogen Alternate
                        Modality Target in accordance with this Section 1.8.3 before the expiration of the applicable Deferral Period, then such gene target will no longer be a
                        Neurology Target under this Agreement and any payments made by Biogen under this Section 1.8 for such Deferred Target will be non-creditable and
                        non-refundable.

                  

          

        

        

        

        
          
            	

                  	1.8.4.	
                    Accelerating the Deferral Period with a Deferred Target Development Candidate.

                  

          

        

        

        

        
          
            	

                  	(a)	
                    Ionis and its Affiliates may, for its own benefit and not for the benefit of any Third Party, conduct drug discovery activities to identify a Development Candidate for
                        any Deferred Target for which the best therapeutic modality was determined to be an ASO (such Development Candidate, a “Deferred Target Development Candidate”); provided that
                        Ionis may not use the FTEs provided for under Section 1.11 to conduct such activities. Ionis will notify the Neurology JRC of any such activities and keep
                        the Neurology JRC reasonably apprised of the status thereof at each meeting of the Neurology JRC. If Ionis designates a Deferred Target Development Candidate targeting a particular Deferred Target (such target, an “Accelerated Target”), Ionis may notify Biogen in writing regarding Ionis’ designation of such Deferred Target Development
                        Candidate and will provide Biogen the applicable Development Candidate Data Package. Within [***] days following Biogen’s receipt of the applicable Development Candidate Data Package, Biogen may designate the Accelerated Target as a
                        Collaboration Target; provided however, that if Biogen designates such Accelerated Target as a Collaboration Target, in addition to any
                        credits for annual deferral fees under Section 1.8.3, Biogen may credit a pro-rated portion of the un-credited [***]% of the last annual deferral fee paid
                        to Ionis under Section 1.8.2 for such Deferred Target towards the applicable milestone payment under Section 6.2.1 (where such pro-ration will be based on the number of days between the payment of such deferral fee and the applicable designation of such Accelerated Target as a Collaboration Target,
                        divided by the lesser of 365 days and the number of days between the payment of such deferral fee and the end of the Research Term).

                  

          

        

        

        

        
          12

          
            

        

        
          
            	

                  	(b)	
                    If Biogen does not, within such [***] day period, designate the Accelerated Target as a Collaboration Target under this Section 1.8.4, then, such Accelerated Target will no longer be a Neurology Target and Ionis and its Affiliates may work independently or with any Third Party with respect to the discovery,
                        research, development, and commercialization of ASOs (or any other compounds) targeting such Accelerated Target; provided however that if
                        prior to the end of the Deferral Period originally applicable to such Accelerated Target, Ionis or any of its Affiliates enters into an agreement with a Third Party pursuant to which Ionis or its Affiliate grants such Third Party a
                        license to develop or commercialize such Deferred Target Development Candidate, Ionis will pay to Biogen [***]% of any amounts (other than Excluded Payments) received by Ionis or its Affiliate under such agreement with such Third
                        Party until such time as Ionis has reimbursed Biogen for [***]% of the last annual deferral fee paid to Ionis under Section 1.8.2 for such Deferred
                        Target.

                  

          

        

        

        

        
          
            	1.9.	
                    End of Research Term. At the end of the Research Term (or, with respect
                        to clauses (a), (d) and (e) in this Section 1.9, the earlier termination of
                        the Core Research Program), (a) neither Ionis nor Biogen will have an obligation to perform any activities under the Core Research Program or the Neurological Disease Research Program, (b) the High Interest Target List (including
                        the ALS Targets) will be dissolved, and any Neurology Targets that have not been designated Collaboration Targets or Biogen Alternate Modality Targets will no longer be Neurology Targets under this Agreement, (c) Ionis’ obligations
                        and Biogen’s rights under this Agreement with respect to such Neurology Targets and any ASOs targeting such Neurology Targets will then terminate, (d) to the extent not previously provided to Ionis during prior meetings of the
                        Neurology II JRC, at Ionis’ reasonable request, Biogen will provide to Ionis any data generated under the Core Research Program and the Neurological Disease Research Program and licensed to Ionis under Section 4.3.4 and (e) to the extent not previously provided to Biogen during prior meetings of the
                        Neurology JRC, at Biogen’s reasonable request, Ionis will provide to Biogen any data generated under the Core Research Program and the Neurological Disease Research Program and licensed to Biogen under Section 4.3.3. For clarity, the expiration of the Research Term will not affect Biogen’s rights or Ionis’
                        obligations with respect to Programs under this Agreement, including, in the case of Collaboration Programs, Ionis’ obligation under Section 1.10.1 to use
                        Commercially Reasonable Efforts to identify a Development Candidate for each applicable Collaboration Program.

                  

          

        

        

        

        
          13

          
            

        

        
          
            	1.10.	
                    Ionis’ Research and Development Responsibilities.

                  

          

        

        

        

        
          
            	

                  	1.10.1.	
                    Development Candidate Identification.

                  

          

        

        

        

        
          
            	

                  	(a)	
                    ASO Development Candidate Identification Plans. For each Collaboration
                        Program, within [***] days after the designation of each Collaboration Program, Ionis will submit to the Neurology JRC an initial draft plan to identify a Development Candidate under the applicable Collaboration Program, (such plan,
                        as may be modified from time to time to address the discovery, research and optimization activities Ionis will conduct under the applicable Collaboration Program an “ASO Development Candidate Identification Plan”). The Neurology JRC will review such plan and agree on a final ASO Development Candidate Identification Plan for such Collaboration
                        Program, which plan will be generally consistent with Ionis’ other plans for other gene targets. Ionis will carry out its drug discovery efforts for each Collaboration Program pursuant to the applicable ASO Development Candidate
                        Identification Plan in a manner consistent with its internal practices for other gene targets with the goal of identifying a Development Candidate for the applicable Collaboration Program as soon as practicable; provided that Ionis will not start work on any Equal Multi-Indication Target unless and until Ionis and Biogen have agreed on a development plan
                        and enhanced economic provisions to be paid by Biogen for Non-Neurological Indications in accordance with Appendix 3. Ionis will
                        update each ASO Development Candidate Identification Plan as needed and submit it to the Neurology JRC for its review and approval.  For each Collaboration Program, Biogen will pay Ionis the milestone payment set forth in Section 6.2.1 following receipt of the applicable Design Notice.

                  

          

        

        

        

        
          
            	

                  	(b)	
                    Biomarker Work. If the Neurology JRC agrees to include biomarker work,
                        natural history studies or endpoint development in the ASO Development Candidate Identification Plan, the [***] is responsible for performing such biomarker work taking into consideration [***].

                  

          

        

        

        

        
          14

          
            

        

        
          
            	

                  	(c)	
                    ASO Development Candidate Identification Term. On a Collaboration
                        Program-by-Collaboration Program basis, the term for the conduct of the applicable ASO Development Candidate Identification Plan (the “ASO Development Candidate Identification Term”) will begin on the date the applicable Neurology Target becomes a Collaboration Target and will end upon the earlier of (i) designation of a Development Candidate for
                        such Collaboration Program and (ii) the date on which Ionis notifies Biogen that, Ionis has in good faith determined that the identification of a Development Candidate under the applicable ASO Development Candidate Identification
                        Plan is no longer technically feasible under the then-current state of the art (a “Technical Failure”). If Biogen disagrees
                        with Ionis’ determination that a Technical Failure has occurred, it may refer the matter to an independent qualified Third Party expert accepted by both Parties for final resolution of the dispute. The expert will use the
                        information, materials and data provided to her or him by either Party to promptly resolve the dispute.  The decision of the expert will be binding upon both Parties. [***] the costs of the expert.  Should the Parties fail to agree
                        on the expert within [***] days following either Party’s request to nominate an expert under this Section 1.10.1(c), each Party will nominate an
                        independent expert (who will not be a current or former employee of a Party or any of their Affiliates or have any personal or financial interest in a Party or any of their Affiliates), and promptly thereafter, those two independent
                        experts will agree on the Third Party expert to resolve the dispute in accordance with this Section 1.10.1(c).  In the event of any expert proceeding
                        under this Section 1.10.1(c), Ionis will not be required to conduct the applicable ASO Development Candidate Identification Plan during the pendency of
                        such proceeding. The Parties anticipate that the last ASO Development Candidate Identification Term will end approximately [***] years after the Effective Date.

                  

          

        

        

        

        
          
            	

                  	(d)	
                    End of ASO Development Candidate Identification Term. At the end of the
                        ASO Development Candidate Identification Term for a particular Collaboration Program that did not reach the Development Candidate stage, subject to Section 1.10.1(e),
                        (i) neither Ionis nor Biogen will have an obligation to perform any activities under this Section 1.10 with respect to such Collaboration Program, (ii)
                        such program will no longer be a Collaboration Program and the applicable gene target associated therewith will no longer be a Collaboration Target, (iii) Ionis’ obligations and Biogen’s rights under this Agreement with respect to
                        the gene targets and any ASOs targeting such gene targets under such Collaboration Program will then terminate, (iv) to the extent not previously provided to Ionis during prior meetings of the Neurology JRC, upon Ionis’ request,
                        Biogen will provide to Ionis any data generated under the Collaboration Program and licensed to Ionis under Section 4.3.4 and (v) to the extent not previously provided to Biogen during prior meetings of the Neurology JRC, upon Biogen’s request, Ionis will provide to Biogen any data generated under
                        the Collaboration Program and licensed to Biogen under Section 4.3.3. For
                        clarity, with respect to each Development Candidate that has reached the Development Candidate stage by the end of the ASO Development Candidate Identification Term, the expiration of the ASO Development Candidate Identification
                        Term will not affect Ionis’ obligation under Section 1.10.3 and Section 1.10.4
                        to Develop each such Development Candidate through the completion of the first PoC Trial.

                  

          

        

        

        

        
          15

          
            

        

        
          
            	

                  	(e)	
                    Carryover Development Candidates. If, by the end of the ASO Development
                        Candidate Identification Term for a particular Collaboration Program, Ionis has not designated a Development Candidate for such Collaboration Program, and at any time during the [***] period after the end of the applicable ASO
                        Development Candidate Identification Term Ionis’ RMC designates an ASO discovered by Ionis that is designed to bind to the RNA that encodes the Collaboration Target for 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 amendment to this
                        Agreement 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 amendment to this Agreement
                        regarding such Carryover Development Candidate on such terms. Otherwise, Ionis will have no further obligations and Biogen will have no further rights with respect to such Carryover Development Candidate.

                  

          

        

        

        

        
          
            	

                  	1.10.2.	
                    Development Candidates; Initial Development Plans; Option Acceleration.

                  

          

        

        

        

        
          
            	

                  	(a)	
                    Appointment of JDC.  For each Development Candidate, the CSC will appoint a Neurology JDC approximately [***] days prior to the date Ionis expects to designate a Development Candidate.  Such Neurology JDC can be
                        either a new or existing Neurology JDC, but at least one of each Party’s Neurology JDC members must have the relevant disease area expertise for the particular Development Candidate.

                  

          

        

        

        

        
          
            	

                  	(b)	
                    Development Candidate Data Package. For each Collaboration Program, Ionis will notify the applicable Neurology JDC in writing within [***] days after designating a Development Candidate and will provide
                        such Neurology JDC the applicable Development Candidate Data Package. 

                  

          

        

        

        

        
          16

          
            

        

        
          
            	

                  	(c)	
                    IND-Enabling Toxicology Studies.

                  

          

        

        

        

        
          
            	

                  	(i)	
                    For each Development Candidate under a Collaboration Program that is not an ALS Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program, the
                        applicable Neurology JDC will agree upon a high level pre-clinical toxicology strategy no later than [***] days following its receipt of the applicable Development Candidate Data Package. Ionis will conduct the IND-Enabling
                        Toxicology Studies under such strategy to the extent consistent with the activities set forth on Schedule 1.10.2(c); provided, however, if the initial strategy or applicable Initial Development Plan requires IND-Enabling Toxicology Studies that are in addition to
                        or different from the activities set forth on Schedule 1.10.2(c), then Biogen will pay Ionis the costs of such additional or
                        different activities to the extent such costs exceed [***]% of the costs of the activities set forth on Schedule 1.10.2(c). Such
                        additional costs will be Biogen-Approved Costs and will be handled in accordance with the process described in Section 1.14.1.

                  

          

        

        

        

        
          
            	

                  	(ii)	
                    For each ALS Collaboration Program and each Biogen Conducted Non-ALS Collaboration Program, the applicable Neurology JDC will agree upon a high level pre-clinical
                        toxicology strategy no later than [***] days following its receipt of the applicable Development Candidate Data Package.  In addition, the applicable Neurology JDC will approve any study protocols for the IND-Enabling Toxicology
                        Studies at least [***] months prior to the anticipated commencement of such IND-Enabling Toxicology Studies. If the Neurology JDC is unable to agree on such high level pre-clinical toxicology strategy or study protocols for a
                        particular ALS Collaboration Program or Biogen Conducted Non-ALS Collaboration Program within the applicable time period as set forth above in this Section
                            1.10.2(c)(ii), the matter will be referred to the CSC for resolution. If the CSC cannot agree on such a high level pre-clinical toxicology strategy within [***] days after the matter is so referred, or on any such
                        study protocol within [***] days after the matter is so referred, as applicable, then Biogen will have final decision-making authority with respect thereto for IND-Enabling Toxicology Studies conducted by Biogen. Solely with respect
                        to the first ALS Collaboration Program to have a Development Candidate, Ionis will conduct the IND-Enabling Toxicology Studies utilizing the same mechanics as set forth in Section 1.10.2(c)(i), and upon Initiation of such IND-Enabling Toxicology Studies Biogen will pay Ionis the applicable milestone payment under Section

                            6.5, which IND-Enabling Toxicology Studies are complete as of the First Amendment Date for the Collaboration Program for SOD-1.  Biogen will conduct, [***], all other IND-Enabling Toxicology Studies for the ALS
                        Collaboration Programs and the Biogen Conducted Non-ALS Collaboration Programs, provided that Ionis may perform study analyses with respect to
                        the Biogen Conducted Non-ALS Collaboration Programs if mutually agreed by the Parties.  If, with respect to a particular ALS Collaboration Program or a particular Biogen Conducted Non-ALS Collaboration Program, Biogen desires Ionis
                        to provide consulting or advisory services, and Ionis agrees to perform such services, Biogen will pay the costs of performing such services using the payment mechanisms set forth in Section 1.14.1.

                  

          

        

        

        

        
          17

          
            

        

        For each ALS Collaboration Program and each Biogen Conducted Non-ALS Collaboration Program (other than the Collaboration Program
            for [***]), provided Ionis has delivered the API to support the IND-Enabling Toxicology Studies for such Collaboration Program to Biogen under Section 1.10.6 at least
            [***] days prior to the anticipated commencement of IND-Enabling Toxicology Studies for such Collaboration Program (subject to Biogen’s timely delivery of an order for such API), Biogen will Initiate the first IND-Enabling Toxicology Study for
            such Collaboration Program within [***] days following Biogen’s receipt of the applicable Development Candidate Data Package. If Biogen does not Initiate the first IND-Enabling Toxicology Study for such Collaboration Program within [***] days
            following Biogen’s receipt of the applicable Development Candidate Data Package, if Ionis delivered the API to support the IND-Enabling Toxicology Studies for such Collaboration Program to Biogen under Section 1.10.6 at least [***] days prior to the anticipated commencement of IND-Enabling Toxicology Studies for such Collaboration Program, then Biogen will be deemed to have terminated this
            Agreement under Section 10.2.1 solely with respect to such Collaboration Program; provided,

              however, that if there is a delay in Initiating such IND-Enabling Toxicology Study caused by a condition outside of Biogen’s control (including a delay by a Third Party vendor or a delay in supply of API from Ionis from the timeline
            described in this Section 1.10.2(c)(ii)), Biogen shall be excused from Initiating such IND-Enabling Toxicology Study for so long as such condition continues, and this
            Agreement shall not be deemed to be terminated with respect to such Collaboration Program, for so long as such condition continues.

        

        

        
          18

          
            

        

        With regard to the Collaboration Program for [***], notwithstanding any provision to the contrary in this Agreement, within [***]
            days following Biogen’s receipt of the data generated from the 13 week monkey [***] biomarker study, Biogen will notify Ionis whether it has received all necessary internal approvals to commence Development of [***]. If Biogen does not notify
            Ionis within such [***]-day period that it has received all necessary internal approvals to commence Development of [***], Biogen will be deemed to have terminated this Agreement under Section 10.2.1 solely with respect to such Collaboration Program. If Biogen notifies Ionis within such [***]-day period that it has received all necessary internal approvals to commence Development of [***], Biogen
            shall, within [***] days of the later of the date of delivery of such notice and Biogen’s receipt from Ionis of an invoice for such amount, pay Ionis an amount equal to $[***] for the API Ionis will supply to Biogen to support such
            Collaboration Program. If Biogen does not pay Ionis an amount equal to $[***] for such API within the time period described in the preceding sentence, then, if Ionis notifies Biogen in writing of such failure to pay and Biogen has not cured
            such payment failure within [***] days of such written notice, Biogen will be deemed to have terminated this Agreement under Section 10.2.1 solely with respect to
            such Collaboration Program.

        

        

        
          
            	

                  	(d)	
                    Initial Development Plans. For each Development Candidate under a
                        Collaboration Program, within [***] days after designation of such Development Candidate, the applicable Neurology JDC will agree on an appropriate clinical development plan for such Development Candidate through completion of the
                        first PoC Trial (each, an “Initial Development Plan”). With respect to each ALS Collaboration Program and each Biogen Conducted Non-ALS Collaboration Program, Biogen shall propose the initial draft of such Initial Development Plan to the
                        Neurology JDC for review, comment and approval. With respect to each Collaboration Program that is not an ALS Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program, Ionis shall propose the initial draft of such
                        Initial Development Plan to the Neurology JDC for review, comment and approval. In each case, any such initial draft of an Initial Development Plan shall include the information set forth on Schedule 1.10.2(d). If the Neurology JDC cannot agree upon the Initial
                        Development Plan for a particular Collaboration Program, the matter will be referred to the CSC for resolution. If the CSC cannot agree on the Initial Development Plan within [***] days after the matter is so referred, [***] will
                        have final decision-making authority with respect to the contents of the Initial Development Plan. In addition, prior to the Initiation of the first Clinical Study under the Initial 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.

                  

          

        

        

        

        
          19

          
            

        

        
          
            	

                  	(i)	
                    The Party responsible for conducting the Clinical Studies under a Collaboration Program will file and maintain the IND and other communications with Regulatory
                        Authorities for each Collaboration Program consistent with Section 5.2.1.  Notwithstanding the foregoing, with respect to each Collaboration Program for
                        which Biogen is responsible for conducting the Clinical Studies, including each ALS Collaboration Program and each Biogen Conducted Non-ALS Collaboration Program, Ionis shall provide such reports and/or data as reasonably requested
                        by Biogen generated from Ionis’ activities performed under the applicable Initial Development Plan (“Ionis Activities Data”)

                        that may be useful in support of the IND for the Development Candidate under such Collaboration Program; provided, that, if, after receiving
                        the Ionis Activities Data, Biogen requests that Ionis provide Biogen with additional information outside of the scope of the Ionis Activities Data that Biogen reasonably believes is necessary or useful to support the IND, then, to
                        the extent such additional information is in Ionis’ possession and delivering such data to Biogen will not breach any obligation Ionis owes to a Third Party, Ionis will promptly deliver such additional information to Biogen solely
                        for Biogen to use to support the IND.  [***] will bear the cost of the transfer of such additional information to Biogen pursuant to the preceding sentence; provided, that if [***] would incur out-of-pocket costs in excess of $[***] or FTE Costs in excess of the equivalent of [***] for one FTE at the then-applicable Ionis FTE Rate in connection with the delivery of
                        such additional information, then [***] shall reimburse [***] for such excess.

                  

          

        

        

        

        
          
            	

                  	(ii)	
                    If the requirements of the Phase 1 Trial Design for a Collaboration Program that is not an ALS Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program
                        require (i) more than [***] human subjects, including single ascending dose and multiple ascending dose arms, or (ii) dosing longer than [***], then Ionis may elect to either (1) conduct such larger or longer Phase 1 Trial (in which
                        case Section 1.10.2(e) will apply), or (2) have Biogen conduct such Phase 1 Trial.  If Ionis elects to have Biogen conduct such Phase 1 Trial, then Biogen
                        will conduct the Phase 1 Trial with Ionis’ reasonable cooperation and in lieu of the applicable milestone payment payable to Ionis pursuant to Section 6.4
                        (as calculated in accordance with Section 1.10.2(e)) with respect to such Phase 1 Trial, Biogen will pay Ionis a milestone payment equal to $[***].

                  

          

        

        

        

        
          20

          
            

        

        
          
            	

                  	(iii)	
                    If the Initial Development Plan relates to an ALS Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program, then Biogen will conduct the Phase 1 Trial
                        and will pay Ionis a milestone payment in the amount as set forth in Table 2 of Section 6.5 or Table 1 of Section

                            6.4, as applicable.

                  

          

        

        

        

        
          
            	

                  	(iv)	
                    Based on such Initial Development Plan, the CSC will update Schedule 5.1.4
                        to add Specific Performance Milestone Events related to Biogen’s Development and Commercialization of the Development Candidate after the License Effective Date with respect to a 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.  If the CSC cannot unanimously agree upon the Specific Performance
                        Milestone Events for a particular Collaboration Program within [***] days after the date the CSC started discussing such Specific Performance Milestone Events, the matter will be referred to expert resolution pursuant to Section 12.1.4. Ionis will update each Initial Development Plan as needed, but at least once Annually, and submit it to the applicable Neurology JDC for its
                        review and approval. If the applicable Neurology JDC cannot agree on the contents of any updated Initial Development Plan, the matter will be resolved in accordance with the procedures for establishing the Initial Development Plan
                        set forth in this Section 1.10.2(d).

                  

          

        

        

        

        
          
            	

                  	(v)	
                    The study synopsis for each Clinical Study for a Collaboration Program other than an ALS Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program shall
                        be agreed on by the applicable Neurology JDC no later than [***] months prior to the anticipated Initiation of such Clinical Study, and shall contain the information set forth on Schedule 1.10.2(d)(v) with respect to the applicable Clinical Study.

                  

          

        

        

        

        
          21

          
            

        

        
          
            	

                  	(e)	
                    Cost Estimates. After designation of a Development Candidate under a
                        Collaboration Program that is not an ALS Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program, the applicable Neurology JDC will agree on an initial estimate of the expected cost for Ionis to conduct the work
                        [***] specified in the applicable Initial Development Plan, including Ionis’ expected [***] and [***] costs (each, a “Cost
                          Estimate”). The initial Cost Estimate [***] shall be agreed on by the applicable Neurology JDC no later than [***] months prior to the anticipated [***]. Based on the Cost Estimates, the Neurology JDC will establish the
                        [***] and [***] 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 Additional 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 1.10.2(e); provided, however, that if [***], then the Neurology JDC 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 the event
                        that triggered such milestone payment. 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 JDC with a good faith estimate of the cost to conduct the work necessary to develop such Development Candidates under the
                        applicable Initial Development Plan using a similar methodology as used under the Ionis/Biogen Additional Agreements. [***] months prior to the [***], using the process set forth above, the Neurology JDC will re-assess the total
                        cost of such [***] and, if the cost has changed from the initial Cost Estimate, the Neurology JDC 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 1.10.2(e), or (B) if such cost is increased by [***], such increase will not affect the milestone payments for such [***] established under this Section 1.10.2(e), but instead will be handled in accordance with Section 1.14.1.  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. If the Neurology JDC cannot agree on the Cost Estimates within [***] days of receiving the proposed Cost Estimate, the matter will
                        be referred to the CSC for resolution. Once the Neurology JDC has agreed on a Cost Estimate and/or the [***] milestone payments for such Collaboration Program are established under this Section 1.10.2(e) or Section 1.14.1, such agreement will be documented in a written side letter, in the form and
                        format attached hereto as Appendix 4, which shall be executed by both Parties.

                  

          

        

        

        

        
          22

          
            

        

        
          
            	

                  	(f)	
                    Obligation to Start Development Activities. Ionis will not be required
                        to conduct any Development activities for a Development Candidate if the Initial Development Plan, Specific Performance Milestone Events and the corresponding Cost Estimates have not been agreed to pursuant to this Section 1.10.2.  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 1.10.2(e), 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.

                  

          

        

        

        

        
          
            	

                  	(g)	
                    Option Acceleration. If the PoC Trial for a Collaboration Program that
                        is not an ALS Collaboration Program or a Biogen Conducted Non-ALS 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 pursuant to Section 1.10.2(d) (or each time there is a material change thereto) for a Collaboration Program that is not an ALS Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program 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 1.10.2(g), 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.

                  

          

        

        

        

        
          23

          
            

        

        After Biogen’s receipt of an Option Acceleration Notice with respect to a particular Collaboration Program, the Parties will
            mutually agree on the contents of all correspondence with and submissions to Regulatory Authorities to the extent related to the PoC Trial for the applicable Collaboration Program; provided, however, that if the Parties cannot so mutually agree, then [***] will have final decision-making authority but will not deliver any correspondence to Regulatory Authorities related to the PoC Trial for
            the applicable Collaboration Program that is not mutually agreed by the Parties unless [***] determines such correspondence is required to be delivered and cannot be delayed.

        

        

        
          
            	

                  	(h)	
                    Attaching Plans to Neurology JDC Minutes. The Neurology JDC will attach
                        each Initial Development Plan and, if applicable, associated Cost Estimates to the minutes of the Neurology JDC for the meeting at which such Initial Development Plan and, if applicable, Cost Estimates were agreed. For clarity, such
                        Initial Development Plan and Cost Estimates need not be agreed to at the same meeting of the Neurology JDC.

                  

          

        

        

        

        
          
            	

                  	1.10.3.	
                    Development Term. 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) completion of the Initial Development Plans under all Collaboration Programs, which the Parties estimate will be
                        approximately [***] years after the Effective Date, (b) exercise by Biogen of its Option for all Collaboration Programs, (c) the termination of the last Collaboration Program and (d) mutual agreement of the Parties to terminate the
                        Drug Development Program.

                  

          

        

        

        

        
          
            	

                  	1.10.4.	
                    Drug Development.

                  

          

        

        

        

        
          
            	

                  	(a)	
                    Collaboration Programs Other than ALS Collaboration Programs
                            and Biogen Conducted Non-ALS Collaboration Programs.  For each Collaboration Program that is not an ALS Collaboration Program or
                        a Biogen Conducted Non-ALS Collaboration Program, Ionis will use Commercially Reasonable Efforts to conduct all activities under each Initial Development Plan on the timeline set forth in the applicable Initial Development Plan. For
                        each Biogen Conducted Non-ALS Collaboration Program, Ionis will use Commercially Reasonable Efforts to conduct all activities allocated to Ionis under each Initial Development Plan on the timeline set forth in the applicable Initial
                        Development Plan. Without limiting the foregoing, Ionis may discontinue Development under an Initial Development Plan if after having consulted, and having given good faith consideration to the recommendations of the Neurology JDC
                        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 under an Initial Development Plan, Ionis will provide Biogen with reasonable advance notice of such discontinuation, including the grounds for Ionis’
                        determination. If Ionis elects to discontinue Development under an Initial Development Plan pursuant to this Section 1.10.4(a), Biogen may, in its
                        discretion, elect to continue Development of the applicable 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
                        and [***]. If Biogen does not timely exercise its Option under this Section 1.10.4(a), then the Option will expire.

                  

          

        

        

        

        
          24

          
            

        

        
          
            	

                  	(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 Initial Development Plan.

                  

          

        

        

        

        
          
            	

                  	(i)	
                    At meetings of the applicable Neurology JDC and at other times as appropriate, Ionis will keep Biogen informed of the progress and status of each Phase 1 Trial
                        conducted by Ionis. When [***] under a Phase 1 Trial, Ionis will notify Biogen in writing of such [***] within [***] days of the conclusion of such Phase 1 Trial. Ionis will provide Biogen with the data generated under the [***] for
                        such Phase 1 Trial as soon as practicable after such notice.

                  

          

        

        

        

        
          
            	

                  	(ii)	
                    If Biogen conducts a Phase 1 Trial for a Collaboration Program, including an ALS Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program, at meetings
                        of the applicable Neurology JDC and at other times as appropriate, Biogen will keep Ionis informed of the progress and status of such Phase 1 Trial. When Biogen [***] a Phase 1 Trial, Biogen will notify Ionis in writing of such
                        [***] within [***] days of the conclusion of such Phase 1 Trial. Biogen will provide Ionis with the data generated under the [***] for such Phase 1 Trial as soon as practicable after such notice.

                  

          

        

        

        

        
          25

          
            

        

        
          
            	

                  	(c)	
                    PoC Trial. Each PoC Trial will be conducted in accordance with the PoC Trial Design set forth in the applicable Initial Development Plan.

                  

          

        

        

        

        
          
            	

                  	(i)	
                    At meetings of the applicable Neurology JDC and at other times as appropriate, Ionis will keep Biogen informed of the progress and status of each PoC Trial conducted by
                        Ionis. When Ionis [***] a PoC Trial under the applicable Initial 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.

                  

          

        

        

        

        
          
            	

                  	(ii)	
                    If Biogen conducts a PoC Trial for a Collaboration Program, including an ALS Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program, then at meetings
                        of the applicable Neurology JDC and at other times as appropriate, 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.

                  

          

        

        

        

        
          
            	

                  	1.10.5.	
                    Briefing the Neurology JRC, Neurology JDC and CSC; Conduct of Research and
                            Development. At each regularly scheduled meeting of the Neurology JRC, the Parties will provide progress updates on (a) the Neurological Disease Research Program and progress toward achieving Target Sanction for each
                        High Interest Target and progress related to ALS Targets, (b) activities conducted under the Core Research Program, (c) progress under each ASO Development Candidate Identification Plan toward designating a Development Candidate,
                        (d) activities on the Deferred Targets conducted pursuant to Section 1.8.4 and (e) the progress of any Ionis Neurology Targets (including the estimated
                        time for each Ionis Neurology Target to achieve Target Sanction), in each case, together with a summary of data associated with each Party’s research and/or Development activities for each Collaboration Program. At each Neurology
                        JDC meeting, the Parties will provide progress updates on activities conducted under the Initial Development Plans for the applicable Development Candidates, together with a summary of data associated with each Party’s Development
                        activities for the applicable Collaboration Program. At each CSC meeting, the Parties will provide any information reasonably requested by the members of the CSC in advance of such meeting.

                  

          

        

        

        

        
          26

          
            

        

        
          
            	

                  	1.10.6.	
                    Clinical Supplies by Ionis. For Collaboration Programs that are not ALS
                        Collaboration Programs or Biogen Conducted Non-ALS Collaboration Programs, 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 Neurology Plan through the License Effective Date with respect to a Collaboration Program. If Biogen exercises an Option for a Collaboration Program that is not an ALS Collaboration Program or a Biogen
                        Conducted Non-ALS Collaboration Program 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 for a Collaboration Program that is not an ALS Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program 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 [***]. For ALS Collaboration
                        Programs and Biogen Conducted Non-ALS Collaboration Programs, Ionis will supply API (on its own or through a CMO approved by Biogen) for clinical purposes in accordance with Schedule 1.10.6, and such supply will be at Biogen’s expense using the mechanism set forth in Section 1.14.1,
                        and Biogen will be responsible for all other aspects of Clinical Supply for such clinical activities.

                  

          

        

        

        

        
          
            	

                  	1.10.7.	
                    Collaborations with Academics and Non-Profit Institutions. Each Party
                        (the “Contracting Party”) may engage one or more academic or non-profit institutions to conduct work under any Neurology
                        Plan or on any High Interest Target, Collaboration Target or Deferred Target, provided, however that with respect to any such academic or non-profit institution engaged to conduct such activities with respect to a High Interest Target, Collaboration Target or Deferred Target
                        where such engagement begins after the date such High Interest Target, Collaboration Target or Deferred Target is placed on the High Interest Target List or designated, as applicable, (a) the Contracting Party shall provide the
                        other Party with an opportunity to comment on the proposed terms of any agreement or amendment to an existing agreement to be entered into with such institution, and (b) so long as the other Party provides the Contracting Party such
                        comments within [***] days after receiving a draft of such agreement from the Contracting Party, the Contracting Party will [***].  The Contracting Party will not be responsible for [***] as a result of the other Party’s [***] to
                        the terms of any agreement with any such academic or non-profit institution.

                  

          

        

        

        

        
          
            	1.11.	
                    Resource Allocations. During the first [***] following the Effective
                        Date, Ionis will use Commercially Reasonable Efforts to build a team of [***] FTEs to perform the activities under the Core Research Plan, the Neurological Disease Research Plan, and the target validation activities contemplated
                        under Schedule 1.2.4; and thereafter until the sixth anniversary of the Effective Date, Ionis will dedicate [***] FTEs to
                        perform such activities; provided, Ionis may utilize such number of such [***] FTEs to perform drug discovery activities on ALS Targets as
                        agreed by the Neurology JRC. At all times during such period, such FTEs will have experience and qualifications similar to that of the FTEs initially assigned to perform such activities hereunder. Biogen will be responsible for
                        devoting its resources toward specific research efforts under the Core Research Program and Neurological Disease Research Program as reasonably determined by Biogen. During the [***] after the Effective Date, [***] of Ionis’ [***]
                        FTEs will be allocated to activities focused on core technology research and the Neurology JRC will determine the appropriate allocation of resources thereafter. Ionis will update the Neurology JRC at each meeting thereof on the
                        utilization of such FTEs and provide the Neurology JRC with summaries of resource and FTE utilization in a format mutually agreed to by each Party’s Alliance Managers. Biogen may also choose to supplement Ionis’ efforts under the
                        Core Research Plan and the Neurological Disease Research Plan with its own scientists at various points throughout the Research Term. After the sixth anniversary of the Effective Date, Ionis will provide sufficient resources to
                        perform its obligations under each Collaboration Program as reasonably determined by Ionis.

                  

          

        

        

        

        
          27

          
            

        

        
          
            	1.12.	
                    Research and Development Costs Paid by Ionis.

                  

          

        

        

        

        
          
            	

                  	1.12.1.	
                    Research Programs. During the Research Term, Ionis will be responsible
                        for all Ionis Activities under the Core Research Program and the Neurological Disease Research Program, and all costs and expenses associated therewith.

                  

          

        

        

        

        
          
            	

                  	1.12.2.	
                    Collaboration Programs. During the Option Period, on a Collaboration
                        Program-by-Collaboration Program basis, Ionis will be responsible for all Ionis Activities under the ASO Development Candidate Identification Plan and the Initial Development Plan and, except as otherwise provided under Section 1.13.1, all costs and expenses associated therewith.

                  

          

        

        

        

        
          
            	1.13.	
                    Research and Development Costs Paid by Biogen.

                  

          

        

        

        

        
          
            	

                  	1.13.1.	
                    Before the

                            License Effective Date.

                  

          

        

        

        

        
          
            	

                  	(a)	
                    Research Programs. During the Research Term, Biogen will be responsible
                        for all Biogen Activities under the Core Research Program and Neurological Disease Research Program, and all costs and expenses associated therewith.

                  

          

        

        

        

        
          
            	

                  	(b)	
                    Collaboration Programs. During the Option Period, on a Collaboration
                        Program-by-Collaboration Program basis, Biogen will be responsible for any Biogen Activities under the ASO Development Candidate Identification Plan and the Initial Development Plan and all costs and expenses associated therewith.
                        In addition, Biogen will be responsible for paying any Biogen-Approved Costs resulting from Biogen-Approved Changes using the payment mechanisms set forth in Section
                            1.14.

                  

          

        

        

        

        
          28

          
            

        

        
          
            	

                  	(c)	
                    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 Collaboration Product, including [***], prior to the License Effective Date, and Ionis agrees
                        to perform such work, Biogen will pay the costs of conducting such work using the payment mechanisms set forth in Section 1.14.1.

                  

          

        

        

        

        
          
            	

                  	1.13.2.	
                    After the License Effective Date. After the License Effective Date with respect to the applicable Collaboration Program, Biogen will be solely responsible for the costs and expenses related to the
                        Development, Manufacture and Commercialization of Collaboration Products, including any work performed by Ionis at Biogen’s request, and all supply chain planning and decision-making.

                  

          

        

        

        

        
          
            	1.14.	
                    Payment Mechanisms.

                  

          

        

        

        

        
          
            	

                  	1.14.1.	
                    Payment Mechanics for Additional Activities Approved 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 1.10.2(e), if such cost is increased by [***] as described in Section 1.10.2(e)).  For the
                        avoidance of doubt, if such cost is increased by more than [***] as described in Section 1.10.2(e)), such increased costs will constitute an additional
                        milestone payment to be paid in accordance with the provisions of Section 1.10.2(e), and will not be handled under this Section 1.14.1.  Ionis will permit Biogen to review, negotiate (with Ionis) and approve (including through the Neurology JDC) 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 1.14.1 will not be used to establish the initial milestone payments under Section 1.10.2(e), and
                        (2) expenses paid under Section 1.14.1(a) and Section 1.14.1(b) are not
                        subject to reconciliation. Once Biogen-Approved Costs are mutually agreed under this Section 1.14.1, such agreement will be documented in a written side
                        letter, in the form and format attached hereto as Appendix 4, 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.

                  

          

        

        

        

        
          29

          
            

        

        
          
            	

                  	(a)	
                    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 1.10.2(e), 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 1.10.2(e) (or, if such Biogen-Approved Costs result from changes to a [***], then the Neurology JDC
                        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.

                  

          

        

        

        

        
          
            	

                  	(b)	
                    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 [***].

                  

          

        

        

        

        
          
            	

                  	(c)	
                    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 1.10.2(e) 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 1.14.1(c) for such Biogen-Approved Costs within [***] days after receipt of the applicable invoice by Biogen.  For purposes of this Section 1.14.1(c), “Measurement Period” means each [***].

                  

          

        

        

        

        
          30

          
            

        

        
          
            	

                  	(d)	
                    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 1.10.2(e) 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 1.14.1(d) for such Biogen-Approved Costs within [***] days after receipt of the applicable invoice by Biogen.  For purposes of this Section 1.14.1(d), “Measurement Period” means each [***].

                  

          

        

        

        

        
          
            	

                  	(e)	
                    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 1.14.1 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.

                  

          

        

        

        

        
          
            	1.15.	
                    Participation in Regulatory Meetings. For each Collaboration Program,
                        each Party will conduct its interactions and communications with Regulatory Authorities in accordance with Section 5.2.

                  

          

        

        

        

        
          31

          
            

        

        
          
            	1.16.	
                    Participation in Meetings Sponsored by a Party’s Clinical Development Group.
                        With respect to each Collaboration Program (including each ALS Collaboration Program and each Biogen Conducted Non-ALS Collaboration Program), each Party will provide the other Party with an invitation to attend, and allow such
                        other Party to participate in, any meetings sponsored by a Party’s clinical development group relating to the Development Candidate or the conduct or design of any Clinical Study; provided, however, that such first Party may exclude the other Party from any portions of such meetings that do not pertain to such Development Candidate or all of any such meeting if such
                        Party determines that it is not feasible for the other Party to attend any such meeting because other products or matters will be discussed in combination with the Development Candidate at such meeting; and provided, further, that, the organizing Party will endeavor to structure such meetings that discuss topics unrelated to the Development Candidate in a manner that
                        permits the non-organizing Party to attend (e.g., structuring the agenda of such meeting so that the Development Candidate is discussed first so that the
                        non-organizing Party may attend that portion of such meeting only). With respect to any such meetings organized by a Party, the non-organizing Party shall comply with the organizing Party’s internal policies disclosed to the
                        non-organizing Party regarding attendance and participation in such meetings, and the non-organizing Party will participate in such meeting in a manner that is consistent with the organizing Party’s strategy for the applicable
                        Development Candidate. If a Party is excluded from any such meeting, the organizing Party will provide such Party with a written summary of the portions of such meeting relevant to such Development Candidate within [***] days after
                        such meeting. For the avoidance of doubt, this Section 1.16 shall not apply to unplanned meetings or unplanned discussions with investigators or key
                        opinion leaders. Biogen’s obligation under this Section 1.16 to invite Ionis to attend and participate in any meetings organized by Biogen will cease, on
                        a Collaboration Product-by-Collaboration Product basis, on the date Biogen submits an NDA or MAA to a Regulatory Authority for such Collaboration Product.

                  

          

        

        

        

        
          
            	1.17.	
                    Impact of [***] Development Path. If the Parties mutually agree to amend
                        an Initial Development Plan for a Collaboration Program that is not an ALS Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program, 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 [***]; provided, that if the Initial Development Plan for a Biogen Conducted Non-ALS
                        Collaboration Program contemplates such [***] development path, then the Parties will determine by mutual agreement prior to commencing any [***] under such Initial Development Plan whether to designate such [***] for such Biogen
                        Conducted Non-ALS Collaboration Program. Nothing in this Section 1.17 will affect either Party’s rights or obligations under Section 1.10.2(g).

                  

          

        

        

        

        
          32

          
            

        

        
          
            	1.18.	
                    Research and Development Management.

                  

          

        

        

        

        
          
            	

                  	1.18.1.	
                    Collaboration Steering Committee. The Parties will establish a
                        Collaboration steering committee (“CSC”) with the powers, roles and responsibilities set forth on Schedule 1.18.1 and in this Section 1.18.1 to oversee the Collaboration. The CSC will consist of up to three representatives appointed by Ionis and up to three representatives appointed by Biogen. The Neurology JRC and
                        Neurology JDC under this Agreement will report to the CSC. The CSC will determine the CSC operating procedures at its first meeting, including the CSC’s policies for replacement of CSC members, policies for participation by
                        additional representatives or consultants invited to attend CSC meetings, and the location of meetings, which will be codified in the written minutes of the first CSC meeting. Each Party will be responsible for the costs and
                        expenses of its own employees or consultants attending CSC meetings. Any decision that may be made by the Neurology JRC or Neurology JDC may be made by the CSC and such decision by the CSC will have the same effect as if made by the
                        Neurology JRC or the Neurology JDC under this Agreement. The CSC may delegate any of its functions specified in Section 1.18.1(a) below to a Neurology JDC
                        by agreeing to and codifying such delegation in the minutes of the CSC.

                  

          

        

        

        

        
          
            	

                  	(a)	
                    Role of the CSC. Without limiting any of the foregoing, subject to Section 1.18.4, the CSC will perform the following functions, some or all of which may be addressed directly at any given CSC meeting:

                  

          

        

        

        

        
          
            	

                  	(i)	
                    approving the terms on which Biogen would develop and commercialize a Multi-Indication Product as described in Appendix 3;

                  

          

        

        

        

        
          
            	

                  	(ii)	
                    determining the primary disease association of a Multi-Indication Target;

                  

          

        

        

        

        
          
            	

                  	(iii)	
                    appointing a Neurology JDC for each Development Candidate under this Agreement, whether by creating a new Neurology JDC or assigning an existing Neurology JDC to
                        oversee such Development Candidate;

                  

          

        

        

        

        
          
            	

                  	(iv)	
                    establishing the Initial Development Plan in the event of a Neurology JDC dispute as described in Section

                            1.10.2(d);

                  

          

        

        

        

        
          
            	

                  	(v)	
                    establishing the Specific Performance Milestone Events as described in Section 1.10.2(d)(iv);

                  

          

        

        

        

        
          33

          
            

        

        
          
            	

                  	(vi)	
                    establishing the [***] and [***] milestone payments if the Neurology JDC is unable to agree on such payments as described in Section 1.10.2(e);

                  

          

        

        

        

        
          
            	

                  	(vii)	
                    reviewing and assessing reports provided by the Neurology JRC and the Neurology JDCs;

                  

          

        

        

        

        
          
            	

                  	(viii)	
                    providing input to the JPC as appropriate;

                  

          

        

        

        

        
          
            	

                  	(ix)	
                    reviewing and providing input on the CTDs and IDPs as appropriate;

                  

          

        

        

        

        
          
            	

                  	(x)	
                    assisting with and participating in the resolution of disputes as contemplated in Section 12.1.1;
                        and

                  

          

        

        

        

        
          
            	

                  	(xi)	
                    such other review and advisory responsibilities as may be assigned to the CSC by the Parties pursuant to this Agreement.

                  

          

        

        

        

        
          
            	

                  	1.18.2.	
                    Neurology JRC. The Parties will establish a joint research committee
                        (the “Neurology JRC”) reporting to the CSC, to provide advice and make recommendations on the conduct of activities under
                        the Core Research Program, Neurological Disease Research Program and each Collaboration Program up to Development Candidate designation. The Neurology JRC will consist of up to three representatives appointed by Ionis and up to
                        three representatives appointed by Biogen. Each Neurology JRC member will have experience and expertise appropriate for the Core Research Program, Neurological Disease Research Program and/or the stage of development of the
                        Collaboration Programs. Each Party will designate one of its 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 JRC. The co-chairs will be responsible for overseeing the activities of the Neurology JRC consistent with the responsibilities set forth below in this Section

                            1.18.2. Schedule 1.18.2 sets forth
                        certain Neurology JRC governance matters agreed to as of the Effective Date. The Neurology JRC will determine the Neurology JRC operating procedures at its first meeting, including the Neurology JRC’s policies for replacement of
                        Neurology JRC members, policies for participation by additional representatives or consultants invited to attend Neurology JRC meetings, and the location of meetings, which will be codified in the written minutes of the first
                        Neurology JRC meeting. Each Party will be responsible for the costs and expenses of its own employees or consultants attending Neurology JRC meetings. Ionis and Biogen will use reasonable efforts to schedule meetings of the
                        Neurology JRC to take place at the same location and on the same dates as meetings of the CSC and 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.

                  

          

        

        

        

        
          34

          
            

        

        
          
            	

                  	(a)	
                    Role of the Neurology JRC. Without limiting any of the foregoing,
                        subject to Section 1.18.4, the Neurology JRC will perform the following functions, some or all of which may be addressed directly at any given Neurology
                        JRC meeting:

                  

          

        

        

        

        
          
            	

                  	(i)	
                    maintain the list of High Interest Targets, ALS Targets, Collaboration Targets, and Biogen Alternate Modality Targets, as such lists may be updated from time to time in
                        accordance with this Agreement, and attach such lists to the minutes of the meeting of the Neurology JRC where any update to the High Interest Target List, ALS Target List or Collaboration Targets, Biogen Alternate Modality Targets
                        occurred;

                  

          

        

        

        

        
          
            	

                  	(ii)	
                    as described in Section 1.2.3(c), determine the number of High Interest Targets for which
                        activities to support Target Sanction will be conducted during each year of the Research Term;

                  

          

        

        

        

        
          
            	

                  	(iii)	
                    review and approve amendments to the Core Research Plan and the Neurological Disease Research Plan (including any amendments thereto that terminate all activities under
                        such plans) as described in Sections 1.2.2 and 1.2.3;

                  

          

        

        

        

        
          
            	

                  	(iv)	
                    allocate resources under Section 1.11;

                  

          

        

        

        

        
          
            	

                  	(v)	
                    determine the number of FTEs Ionis will use to perform drug discovery activities on ALS Targets;

                  

          

        

        

        

        
          
            	

                  	(vi)	
                    as contemplated under Section 1.6.1, determine whether to re-allocate resources on
                        additional Collaboration Programs;

                  

          

        

        

        

        
          
            	

                  	(vii)	
                    during years [***] through [***] after the Effective Date, determine the appropriate allocation of Ionis’ resources to the Core Research Plan, the Neurological Disease
                        Research Plan and each ASO Development Candidate Identification Plan, as described in Section 1.11;

                  

          

        

        

        

        
          35

          
            

        

        
          
            	

                  	(viii)	
                    review the overall progress of Ionis’ efforts to achieve Target Sanction with respect to each High Interest Target that has not achieved Target Sanction status;

                  

          

        

        

        

        
          
            	

                  	(ix)	
                    as described in Section 1.3, review each Target Sanction Data Package and determine the
                        best therapeutic modality to pursue for a High Interest Target;

                  

          

        

        

        

        
          
            	

                  	(x)	
                    as described in Section 1.4, review each Target Sanction Data Package for an Ionis
                        Neurology Target;

                  

          

        

        

        

        
          
            	

                  	(xi)	
                    establish an ASO Development Candidate Identification Plan for each Collaboration Program as described in Section 1.10.1(a);

                  

          

        

        

        

        
          
            	

                  	(xii)	
                    agree on any biomarker work to be performed in the ASO Development Candidate Identification Plan, and [***] is responsible for performing such biomarker work [***];

                  

          

        

        

        

        
          
            	

                  	(xiii)	
                    as described in Section 1.10.2(c) and Section 1.10.2(d), agree upon a high level pre-clinical toxicology strategy and Initial Development Plan for each Development Candidate;

                  

          

        

        

        

        
          
            	

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

                  

          

        

        

        

        
          
            	

                  	(xv)	
                    monitoring progress of each Collaboration Program and maintaining a calendar of anticipated milestone achievement dates for each Collaboration Program;

                  

          

        

        

        

        
          
            	

                  	(xvi)	
                    establishing teams and committees to oversee and manage activities under the Core Research Program, Neurological Disease Research Program and each Collaboration Program
                        up to Development Candidate designation as it deems necessary;

                  

          

        

        

        

        
          
            	

                  	(xvii)	
                    discuss upcoming academic and non-profit collaborations that a Party is negotiating or considering entering into; and

                  

          

        

        

        

        
          36

          
            

        

        
          
            	

                  	(xviii)	
                    such other review and advisory responsibilities as may be assigned to the Neurology JRC by the CSC pursuant to this Agreement.

                  

          

        

        

        

        
          
            	

                  	1.18.3.	
                    Joint Development Committees. For each Development Candidate, the CSC
                        will appoint a joint development committee (each, a “Neurology JDC”) approximately [***] days prior to the date Ionis expects to designate a Development Candidate, to govern the activities under this Agreement with respect to such
                        Collaboration Program. Each Neurology JDC will report to the CSC and will consist of an equal number of representatives appointed by Ionis and Biogen. Each Neurology JDC member will be a senior clinical development leader or have
                        other experience and expertise appropriate for the stage of development of the Collaboration Program in the applicable disease area, and at least one of each Party’s members will have operational responsibility for the applicable
                        Collaboration Program. Each Party will designate one of its 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 JDC. The co-chairs will be responsible for overseeing the activities of the Neurology JDC consistent with the responsibilities set forth below in this Section

                            1.18.3. Schedule 1.18.3 sets forth
                        certain Neurology JDC governance matters agreed to as of the Effective Date. Each Neurology JDC will determine its operating procedures at its first meeting, including the Neurology JDC’s policies for replacement of Neurology JDC
                        members, policies for participation by additional representatives or consultants invited to attend Neurology JDC meetings, and the location of meetings, which will be codified in the written minutes of the first Neurology JDC
                        meeting. Each Party will be responsible for the costs and expenses of its own employees or consultants attending Neurology JDC meetings. If practical, Ionis and Biogen will use reasonable efforts to schedule meetings of each
                        Neurology JDC to take place at the same location and on the same dates as meetings of the CSC and 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.

                  

          

        

        

        

        
          
            	

                  	(a)	
                    Role of the Neurology JDCs. Without limiting any of the foregoing,
                        subject to Section 1.18.4, each Neurology JDC will perform the following functions, some or all of which may be addressed directly at any given Neurology
                        JDC meeting:

                  

          

        

        

        

        
          
            	

                  	(i)	
                    establish the Initial Development Plan for each Development Candidate and update such plan as needed as provided in Section 1.10.2(d);

                  

          

        

        
          37

          
            

        

        
          
            	

                  	(ii)	
                    agree on Cost Estimates and the [***] milestone payments under Section 1.10.2(e);

                  

          

        

        

        

        
          
            	

                  	(iii)	
                    approve Biogen-Approved Costs pursuant to Section 1.14.1;

                  

          

        

        

        

        
          
            	

                  	(iv)	
                    if the milestone payment agreed upon in writing by the Parties pursuant to Section 1.10.2(e)
                        with respect to a [***] exceeds $[***], establishing whether and how such payment shall be apportioned into smaller milestone payments as described in Section
                            1.10.2(e);

                  

          

        

        

        

        
          
            	

                  	(v)	
                    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 1.14.1(a);

                  

          

        

        

        

        
          
            	

                  	(vi)	
                    establish a high-level preclinical toxicology strategy for each Collaboration Program under Section
                            1.10.2(c);

                  

          

        

        

        

        
          
            	

                  	(vii)	
                    establishing teams and committees to oversee and manage activities under each Collaboration Program after Development Candidate designation as it deems necessary; and

                  

          

        

        

        

        
          
            	

                  	(viii)	
                    such other review and advisory responsibilities as may be assigned to the Neurology JDC by the CSC pursuant to this Agreement.

                  

          

        

        

        

        
          
            	

                  	1.18.4.	
                    Decision Making.

                  

          

        

        

        

        
          
            	

                  	(a)	
                    Committee Decision Making. Decisions by each of the CSC, Neurology JRC and Neurology JDC will be made by unanimous consent with each Party’s representatives having, collectively, one vote.  At any given
                        meeting of any such committee, 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 any such committee 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 CSC, Neurology JRC or Neurology JDC, as applicable, has not reached unanimous
                        consensus.

                  

          

        

        

        

        
          38

          
            

        

        
          
            	

                  	(b)	
                    Implementation. Each Party will give due consideration to, and consider in good faith, the recommendations and advice of the CSC, the Neurology JRC and Neurology JDC (as applicable) regarding the conduct of
                        the Core Research Program, Neurological Disease Research Program and each Collaboration Program. Subject to Section 1.10.1 and Section 1.10.2, prior to the License Effective Date with respect to the applicable Collaboration Program, (i) Ionis will have the final decision-making authority regarding [***]
                        and (ii) Biogen will have the final decision-making authority regarding [***]. After the License Effective Date with respect to a particular Collaboration Program, Biogen will have sole decision-making authority regarding [***] of
                        Collaboration Products for such Collaboration Program, provided, however, that [***]. Except as otherwise expressly stated in this
                        Agreement, the CSC, the Neurology JRC and Neurology JDC 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.

                  

          

        

        

        

        
          
            	

                  	1.18.5.	
                    Ionis Obligation to Participate in the Neurology JRC, Neurology JDC and CSC.
                        Ionis’ obligation to participate in (i) the Neurology JRC, will terminate at the end of the ASO Development Candidate Identification Term, (ii) the Neurology JDC, will terminate upon Biogen’s exercise (or expiration) of the Option
                        for the last Collaboration Program, and (iii) the CSC, will terminate upon Biogen’s exercise (or expiration) of the Option for the last Collaboration Program. Thereafter, for each such governing body, Ionis will have the right, but
                        not the obligation, to participate in such meetings upon Ionis’ request.

                  

          

        

        

        

        
          
            	

                  	1.18.6.	
                    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 CSC, the Neurology JRC and Neurology JDC, and performing the activities listed in Schedule 1.18.6.

                  

          

        

        

        

        
          39

          
            

        

        ARTICLE 2.

        EXCLUSIVITY COVENANTS

        

        

        
          
            	2.1.	
                    Exclusivity; Right of First Negotiation.

                  

          

        

        

        

        
          
            	

                  	2.1.1.	
                    Exclusivity Covenants.

                  

          

        

        

        

        
          
            	

                  	(a)	
                    The Parties’ Exclusivity Covenants During the Research Term for High Interest
                            Targets. 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 1.8.4, Section 2.1.2, Section 2.2, Section 10.4.3 or Section 10.4.4, or as contemplated by any Neurology Plan, neither it nor any of its Affiliates will work independently or for or with any Third Party (including the grant of any license to any Third
                        Party) with respect to the discovery, research, development, manufacture or commercialization in the Field of an Oligonucleotide that is designed to bind to the RNA that encodes a High Interest Target from the Effective Date until
                        the earlier to occur of (i) the date such target is removed from the High Interest Target List, by Biogen or ceases to be a High Interest Target by operation of this Agreement, or (ii) the date on which the High Interest Target List
                        is dissolved in accordance with Section 1.9.

                  

          

        

        

        

        
          
            	

                  	(b)	
                    Ionis’ Exclusivity Covenants during the Research Term for Ionis Neurology Targets. Ionis agrees that neither it nor any of its Affiliates will work for the benefit of any Third Party (including the grant of
                        any license to any Third Party that would diminish Biogen’s rights under Section 1.4 or prevent Ionis from granting Biogen a license under Section 4.1.1) with respect to the discovery, research, development, manufacture or commercialization in the Field of an Oligonucleotide that is designed to
                        bind to the RNA that encodes an Ionis Neurology Target from the Effective Date until the earlier to occur of (i) the date such target ceases to be a Neurology Target by operation of this Agreement, or (ii) the expiration of the
                        Research Term.

                  

          

        

        

        

        
          40

          
            

        

        
          
            	

                  	(c)	
                    Ionis’ Exclusivity Covenants for Biogen Alternate Modality Targets. With
                        respect to each Biogen Alternate Modality Target, 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 10.4.3 or Section 10.4.4, neither Ionis nor any of its Affiliates will work independently or for or with 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 Oligonucleotide designed to bind to the RNA encoding such Biogen Alternate Modality Target without Biogen’s prior written consent; provided, however, that if (A) Biogen, its Affiliates or Sublicensees have not [***] within [***] (or, if Biogen has used Commercially Reasonable
                        Efforts to [***], within [***]) after the date the applicable Neurology Target becomes a Biogen Alternate Modality Target in accordance with this Agreement, or (B) after [***], Biogen, its Affiliates and Sublicensees thereafter
                        cease to use Commercially Reasonable Efforts to develop or commercialize such Product (or otherwise stops developing or commercializing such Product), then (i) the exclusive license granted to Biogen under Section 4.1.1(b) for such Biogen Alternate Modality Target will convert to a non-exclusive license, and (ii) Ionis and its Affiliates may independently or for or with any Third
                        Party (including the grant of any license to any Third Party) research, develop, and commercialize Oligonucleotides designed to bind to the RNA encoding such Biogen Alternate Modality Target (each such Oligonucleotide, an “Ionis Non-Exclusive Product”), but not, for the avoidance of doubt, any molecule or product designed to [***] that is not
                        [***], and the license to Biogen under Section 4.1.1(b) will become a non-exclusive license to the extent necessary to allow Ionis to conduct such
                        activities.

                  

          

        

        

        

        
          
            	

                  	(d)	
                    The Parties’ Exclusivity Covenants during the Option Period for Collaboration Targets. 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 2.2, Section 10.4.3 or Section

                            10.4.4, neither it nor any of its Affiliates will work independently or for or with any Third Party (including the grant of any license to any Third Party) with respect to discovery, research, development, manufacture
                        or commercialization in the Field of an Oligonucleotide that is designed to bind to the RNA that encodes a Collaboration Target from the date such gene target was designated a Collaboration Target under this Agreement through the
                        expiration or earlier termination of the applicable Option Period.

                  

          

        

        

        

        
          
            	

                  	(e)	
                    The Parties’ Exclusivity Covenants after the License Effective Date. 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 2.2, Section 10.4.3 or Section 10.4.4,
                        if Biogen timely exercises an Option in accordance with this Agreement, then neither Ionis nor Biogen nor their respective Affiliates will work independently or for or with any Third Party (including the grant of any license to any
                        Third Party) with respect to:

                  

          

        

        

        

        
          41

          
            

        

        
          
            	

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

                  

          

        

        

        

        
          
            	

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

                  

          

        

        

        

        
          
            	

                  	(f)	
                    Failure to Defer or Designate a High Interest Target a Collaboration Target or
                            Biogen Alternate Modality Target. If, after a High Interest Target achieves Target Sanction, Biogen (i) fails to timely designate such High Interest Target as a Collaboration Target or a Biogen Alternate Modality
                        Target (or, if applicable elect to defer under Section 1.3) on the applicable timelines set forth in Section 1.3 or Section 1.8, (ii) fails to timely pay the applicable milestone payment under Section 6.2.1 or Section 6.2.2, (iii) under Section 10.2.1 or Section 10.2.2 voluntarily terminates its license under Section 4.1.1(b) with respect to a High Interest Target Biogen designated as a Biogen Alternate Modality Target, or (iv) notifies Ionis that it has terminated an ALS Collaboration Program after the
                        Initiation of a Phase 1 Trial for such program or fails to timely pay a milestone payment under Section 6.5 with respect to a particular ALS Collaboration
                        Program, then in each case for a period of [***] after the date of such failure or such termination, as applicable, (A) neither Biogen nor its Affiliates will independently or for or with any Third Party (including the grant of any
                        license to any Third Party) discover, research, develop, manufacture or commercialize an Oligonucleotide designed to bind to the RNA encoding such High Interest Target and (B) if Biogen or any of its Affiliates or licensees
                        discovers, researches, develops, manufactures or commercializes a Biogen Alternate Modality Product for such High Interest Target and such High Interest Target is not a Pre-Existing Target, then (1) the provisions of ARTICLE 6 will apply with respect to such Biogen Alternate Modality Product, (2) Biogen will pay Ionis all amounts owed (or which would have been owed absent
                        such original failure or such termination) under such ARTICLE 6 with respect to such Biogen Alternate Modality Product (to the extent such amounts have
                        not previously been paid with respect to the applicable Biogen Alternate Modality Target) in accordance with the terms hereof, (3) to the extent Ionis has the ability to do so, Ionis will grant Biogen the license under Section 4.1.1(b) with respect to such Biogen Alternate Modality Target, and (4) Section
                            2.1.1(c) will not apply with respect to such Biogen Alternate Modality Product.  For the avoidance of doubt, nothing in this Agreement shall restrict Biogen’s or its Affiliate’s or licensee’s discovery, research,
                        development, manufacture, or commercialization of a product for a Pre-Existing Target that is not an Oligonucleotide designed to bind to the RNA that encodes such Pre-Existing Target.

                  

          

        

        

        

        
          42

          
            

        

        
          
            	

                  	2.1.2.	
                    Limitations and Exceptions to Ionis’ Exclusivity Covenants. Notwithstanding anything to the contrary in this Agreement, Ionis’ practice of the following will not violate Section 2.1.1, Section 2.2 or clause (d) of Appendix 3:

                  

          

        

        

        

        
          
            	

                  	(a)	
                    The discovery, research, development, manufacture or commercialization of Gene-Editing Products or messenger RNA solely to the extent agreed by the Parties in writing;

                  

          

        

        

        

        
          
            	

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

                  

          

        

        

        

        
          
            	

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

                  

          

        

        

        

        
          
            	

                  	(d)	
                    The research, development or commercialization of an Ionis Multi-Indication Compound to the extent permitted under Appendix 3;

                  

          

        

        

        

        
          
            	

                  	(e)	
                    The exercise of its rights under Section 3.2.2;

                  

          

        

        

        

        
          
            	

                  	(f)	
                    The discovery, research, development, manufacture or commercialization of a Pre-Existing Competitive Collaboration Product in accordance with Section 12.5.2(b) and Section 12.6; and

                  

          

        

        

        

        
          
            	

                  	(g)	
                    The limited continuation of discovery, research, development, manufacture or commercialization of Acquired Competitive Product(s) as permitted under Section 12.5.3(a) and in accordance with Section 12.5.3(a) and Section 12.6.

                  

          

        

        

        

        
          
            	

                  	2.1.3.	
                    Limitations and Exceptions to Biogen’s Exclusivity Covenants.
                        Notwithstanding anything to the contrary in this Agreement, Biogen’s or its Affiliates’ practice of the following will not violate Section 2.1.1 or clause (b) of Appendix 3:

                  

          

        

        

        

        
          
            	

                  	(a)	
                    The discovery, research, development, manufacture or commercialization of Gene-Editing Products or messenger RNA solely to the extent agreed by the Parties in writing;

                  

          

        

        

        

        
          43

          
            

        

        
          
            	

                  	(b)	
                    the discovery, research, development, manufacture or commercialization of a Pre-Existing Competitive Collaboration Product in accordance with Section 12.5.2(b) and Section
                            12.6; or

                  

          

        

        

        

        
          
            	

                  	(c)	
                    the limited continuation of discovery, research, development, manufacture or commercialization of Acquired Competitive Product(s) as permitted under Section 12.5.3(a) and in accordance with Section 12.5.3(a) and Section 12.6.

                  

          

        

        

        

        
          
            	

                  	2.1.4.	
                    Effect of Exclusivity on Indications. The Compounds are designed to bind
                        to the RNA that encodes a Collaboration Target with the intent of treating a Neurological Disease in the Field. Ionis and Biogen are subject to exclusivity obligations under Section 2.1; however, the Parties acknowledge and agree that, except as otherwise provided herein, each Party and
                        its Affiliates (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 (i) a High Interest Target to the extent Section 2.1.1(a) still applies, (ii) a
                        Biogen Alternate Modality Target to the extent Section 2.1.1(c) still applies, or (iii) a Collaboration Target, in each case for any indication, even if
                        such products are designed to treat a Neurological Disease.

                  

          

        

        

        

        
          
            	2.2.	
                    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:

                  

          

        

        

        

        
          
            	

                  	2.2.1.	
                    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 (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 date of the License Effective
                        Date with respect to 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; 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”) 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 [***].

                  

          

        

        

        

        
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                  	2.2.2.	
                    If Biogen or one of its Affiliates responds within [***] after its receipt of the 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 a 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 2.2.1 and this Section 2.2.2 will reset and Ionis will provide Biogen with a new Follow-On Negotiation Notice.

                  

          

        

        

        

        
          
            	

                  	2.2.3.	
                    Any Follow-On Agreement entered into by Ionis with a Third Party in accordance with Section 2.2.2
                        will be a Permitted License to the extent related to the Follow-On Compound.

                  

          

        

        

        

        
          
            	

                  	2.2.4.	
                    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 2.2, unless Ionis enters into a Follow-On Agreement with a
                        Third Party pursuant to this Section 2.2 and the terms of such agreement do not permit Ionis to grant Biogen rights with respect to the applicable
                        Follow-On Compound.

                  

          

        

        

        

        Except as expressly set forth in Section 2.1.2, Section 2.2, or Section 10.4.4, in no event will Ionis have the right to [***].

        

        

        
          45

          
            

        

        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 (i) a copy of the most recent Investigator’s Brochure for the applicable Collaboration Product, (ii) written notice
                        from Ionis regarding completion of the first PoC Trial, and (iii) 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.

                  

          

        

        

        

        
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                  	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(a) with respect to
                        such Collaboration Program (each an “Option”). Each Option for a Collaboration Program that is not an ALS Collaboration
                        Program or a Biogen Conducted Non-ALS Collaboration Program 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 “Standard Option Deadline”). Each Option for an ALS Collaboration Program will be available to Biogen and its Affiliates until 5:00 pm (Eastern Time) on the earlier of (A) the [***] following Biogen’s
                        receipt of the data generated under the statistical analysis plan after initial database lock for the first PoC Trial for the applicable ALS Collaboration Program, and (B) the [***] of the date a Development Candidate under such ALS
                        Collaboration Program was designated (the “ALS Option Deadline”). Each Option for a Biogen Conducted Non-ALS Collaboration Program will be available to Biogen and its Affiliates until 5:00 pm (Eastern Time) on the earlier of (X) the [***]
                        following Biogen’s receipt of the data generated under the statistical analysis plan after initial database lock for the first PoC Trial for the applicable Biogen Conducted Non-ALS Collaboration Program, and (Y) the [***] of the
                        date a Development Candidate under such Biogen Conducted Non-ALS Collaboration Program was designated (the “Biogen Conducted
                          Non-ALS Option Deadline”). Notwithstanding the foregoing, if Biogen determines that an HSR Filing is required to
                        be made under the HSR Act to exercise an 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 (i) notifies Ionis in writing that it wishes to exercise the applicable Option, and (ii) pays to Ionis the license fee set forth in Section 6.6, Ionis will, and hereby does, grant to Biogen or its designated Affiliate the license set forth in Section 4.1.1(a).
                        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 6.6, then Biogen’s Option for the applicable Collaboration Program will expire and Biogen will promptly 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 such Collaboration Program 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 [***] 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).

                  

          

        

        

        

        
          47

          
            

        

        
          
            	

                  	3.1.4.	
                    HSR Compliance.

                  

          

        

        

        

        
          
            	

                  	(a)	
                    HSR Filing. If Biogen
                        notifies Ionis pursuant to Section 1.7 or Section 3.1.3
                        that an HSR Filing is required for Biogen to receive the license under Section 4.1.1(b) or exercise an Option under this Agreement, 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.	
                    Changing or Adding Modalities.

                  

          

        

        

        

        
          
            	

                  	3.2.1.	
                    Changing to a Collaboration Target. Provided that Biogen has complied
                        with its diligence obligations under Section 2.1.1(c) and Section 5.1.2, at
                        any time during the Research Term after Biogen has made the applicable payment under Section 6.2.2 with respect to a Biogen Alternate Modality Product,
                        subject to Section 3.2.3(a), Biogen may elect to change such Biogen Alternate Modality Target to a Collaboration Target upon written notice to Ionis.
                        Thereafter, (i) Biogen will pay Ionis the milestone payment under Section 6.2.1 (as such payment may be modified pursuant to Section 3.2.3(a)), such payment to be made within [***] days after Biogen’s notice under this Section 3.2.1,
                        (ii) Ionis will prepare and submit to the Neurology JRC an ASO Development Candidate Identification Plan for such Collaboration Target within [***] days after receipt of Biogen’s notice pursuant to this Section 3.2.1, which plan will be agreed upon as provided in Section 1.10.1(a), (iii) the Parties
                        will seek to discover and develop a Development Candidate for such target pursuant to such plan and the provisions of this Agreement and (iv) such target will no longer be a Biogen Alternate Modality Target hereunder.

                  

          

        

        

        

        
          48

          
            

        

        
          
            	

                  	3.2.2.	
                    Changing to a Biogen Alternate Modality Target.  At any time during the Term after Biogen has made the applicable payment under Section 6.2.1
                        for a Collaboration Program, Biogen may elect to change the applicable Collaboration Target under such Collaboration Program to a Biogen Alternate Modality Target upon written notice to Ionis, in which case the provisions of Section 3.2.3(b) will apply, and as of the date of such notice, Ionis will be deemed to have granted Biogen the license under Section 4.1.1(b) with respect to such target and such target will no longer be a Collaboration Target hereunder; provided, however, that Biogen will not have the right to change a Collaboration Target to a Biogen Alternate Modality Target if such Collaboration Target is a Pre-Existing Target.  Within [***] days of
                        the later of (a) Ionis’ receipt of Biogen’s notice electing to change a particular Collaboration Target to a Biogen Alternate Modality Target, and (b) Ionis’ receipt of the data generated under the statistical analysis plan after
                        initial database lock for any ongoing Clinical Study under the applicable Collaboration Program, by written notice to Biogen, Ionis may elect to either (i) cease all development activities under this Agreement relating to any ASO
                        designed to bind to the applicable Biogen Alternate Modality Target (i.e., the former Collaboration Target), until otherwise permitted to conduct such
                        development activities under Section 2.1.1(c), or (ii) subject to Section 3.2.3(b),
                        continue to develop and commercialize on its own or with a Third Party such ASOs (or any other Oligonucleotides) designed to bind to the applicable Biogen Alternate Modality Target (i.e., the former Collaboration Target).  If Ionis makes an election under clause (ii) of this Section 3.2.2, then Section 10.4.3(d) will apply to such former Collaboration Target.

                  

          

        

        

        

        
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                  	3.2.3.	
                    Economics for Changing Modalities.

                  

          

        

        

        

        
          
            	

                  	(a)	
                    If, pursuant to Section 3.2.1, Biogen elects to change a Biogen Alternate Modality Target
                        to a Collaboration Target, the provisions related to Collaboration Programs under this Agreement, including to Sections 6.2, 6.4, 6.6, 6.7, and 6.10 will apply with respect to such Collaboration Target, provided,
                          however, that (i) if Biogen paid Ionis the milestone payment under Section 6.2.2 with respect to such target prior to the date such target
                        changed to a Collaboration Target, then the milestone payment under Section 6.2.1 with respect to such Collaboration Target will be reduced to $[***],
                        (ii) if Biogen paid Ionis a milestone payment under Section 6.3 with respect to such target prior to the date such target changed to a Collaboration
                        Target, then Biogen may credit the amount of such payments against the amounts due Ionis under Sections 6.6 and, to the extent applicable, Section 6.7.

                  

          

        

        

        

        
          
            	

                  	(b)	
                    If, pursuant to Section 3.2.2, Biogen elects to designate a Collaboration Target as a
                        Biogen Alternate Modality Target, the provisions related to Biogen Alternate Modality Programs under this Agreement, including Sections 6.3 and 6.9 will apply with respect to such Biogen Alternate Modality Target; provided,

                          however, that (i) if the Collaboration Target Biogen changed to a Biogen Alternate Modality Target was not an ALS Target, then no payment will be due under Section

                            6.2.2 with respect to such Biogen Alternate Modality Target and (ii) if Ionis elects to continue to develop and commercialize such Oligonucleotides under clause (ii) of Section 3.2.2 Biogen will not be required to pay Ionis any un-accrued milestone payments or royalties under Section 6.3
                        and Section 6.9 solely with respect to the applicable Biogen
                        Alternate Modality Product Developed and Commercialized by Biogen as a result of its conversion to a Biogen Alternate Modality Target under Section 3.2.2.

                  

          

        

        

        

        
          
            	

                  	3.2.4.	
                    Adding an Additional Modality.

                  

          

        

        

        

        
          
            	

                  	(a)	
                    Adding a Collaboration Target. Provided that Biogen has complied with
                        its diligence obligations under Section 2.1.1(c) and Section 5.1.2, at any
                        time during the Research Term after Biogen has made the applicable payment under Section 6.2.2 with respect to a Biogen Alternate Modality Target, Biogen
                        may elect to add such Biogen Alternate Modality Target as a Collaboration Target upon written notice to Ionis. Thereafter, (i) Biogen will pay Ionis the milestone payment under Section 6.2.1, such payment to be made within [***] days after Biogen’s notice under this Section 3.2.4(a), (ii) Ionis will
                        prepare and submit to the Neurology JRC an ASO Development Candidate Identification Plan for such Collaboration Target within [***] days after receipt of Biogen’s notice pursuant to this Section 3.2.4(a), which plan will be agreed upon as provided in Section 1.10.1(a) and the Parties will seek to
                        discover and develop a Development Candidate for such target pursuant to such plan and the provisions of this Agreement (including, for the avoidance of doubt, the provisions of ARTICLE 6), (iii) Section 2.1.1(c) will not apply with respect to any activities conducted by Ionis pursuant to a Neurology Plan
                        with respect to such target and (iv) Biogen may continue Developing, Manufacturing and Commercializing a Biogen Alternate Modality Product for the applicable Biogen Alternate Modality Target in accordance with the terms of this
                        Agreement (including, for the avoidance of doubt, the provisions of ARTICLE 6).

                  

             

            

          

        

        
          50

          
            

        

        
          
            
              
                	

                      	 (b)	
                        Adding a Biogen Alternate Modality Target. At any time during the
                            Term after Biogen has made the applicable payment under Section 6.2.1 for a Collaboration Program, Biogen may elect to add such Collaboration Target
                            as a Biogen Alternate Modality Target upon written notice to Ionis; provided, however, that Biogen shall not have the right to add such
                            Collaboration Target as a Biogen Alternate Modality Target if such Collaboration Target is a Pre-Existing Target. Thereafter, (a) upon Biogen’s payment of the applicable milestone under Section 6.2.2, subject to Section 3.2.5, such payment to be made within [***] days after Biogen’s
                            notice under this Section 3.2.4(b), (i) Ionis will be deemed to have granted Biogen the license under Section 4.1.1(b) with respect to such target and (ii) Biogen may Develop, Manufacture and Commercialize a Biogen Alternate Modality Product for the applicable Biogen Alternate Modality Target
                            in accordance with the terms of this Agreement (including, for the avoidance of doubt, the provisions of ARTICLE 6) and (b) the Parties will continue
                            all activities under this Agreement with respect to the applicable Collaboration Program.

                      

              

            

            

            

            
              
                	

                      	3.2.5.	
                        HSR Compliance with Respect to Biogen Alternate Modality Targets.  If Biogen determines that an HSR Filing is required to be made under the HSR Act for Biogen to receive the license under Section 4.1.1(b) with respect to any Biogen Alternate Modality Target that is designated under Section 3.2.2 or Section 3.2.4.2 and notifies Ionis of such determination within 10 days after Biogen’s notice to Ionis under
                            such section, the Parties will promptly file an HSR Filing in accordance with Section 3.1.4 and the deadline for Biogen to pay Ionis the milestone
                            payment (or, if applicable, a portion thereof as provided in Section 3.2.3) under Section

                                6.2.2 will be extended until 5:00 pm (Eastern Time) on the fifth Business Day after the HSR Clearance Date.

                      

              

            

            

            

            
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                            	3.2.6.	
                              Changes One-Time Only. Once Biogen has elected to change a Collaboration Target to a Biogen Alternate Modality Target, or to change a Biogen Alternate Modality Target to a
                                  Collaboration Target under Section 3.2.1 or Section 3.2.2, as
                                  applicable, Biogen cannot exercise its rights under Section 3.2 to change such target back to a Collaboration Target or Biogen Alternate
                                  Modality Target, as applicable, or add such a Collaboration Target or Biogen Alternate Modality Target, as applicable, without Ionis’ written consent.

                            

                       

                      

                    

                  

                

                	3.3.	
                        Restrictions on Ionis’ Right to Grant Diagnostic Rights; Right to Negotiate
                                Diagnostic Rights.

                      

              

            

            

            

            
              
                	

                      	3.3.1.	
                        On a Collaboration Product-by-Collaboration Product and Biogen Alternate Modality Product-by-Biogen Alternate Modality Product basis, Ionis hereby grants to Biogen
                            and its Affiliates an option (the “Diagnostic Option”) to negotiate during the Full Royalty Period or Biogen Alternate
                            Modality Royalty Period, as applicable, the terms of an agreement under which [***]. The Diagnostic Option will be available to Biogen and its Affiliates until the expiration of the [***] or [***], as applicable, for the
                            applicable Collaboration Product or Biogen Alternate Modality Product.

                      

              

            

            

            

            
              
                	

                      	3.3.2.	
                        During the [***] or [***], as applicable, Ionis (i) has the right to [***], and (ii) will not [***].

                      

              

            

            

            

            
              
                	

                      	3.3.3.	
                        If, during the [***] or [***], as applicable, Ionis grants any Third Party a [***], then Ionis will promptly notify Biogen of such [***] and will offer Biogen a
                            [***].

                      

              

            

            

            

            ARTICLE 4.

            LICENSE GRANTS

            

            

            
              
                	4.1.	
                        License Grants to Biogen.

                      

              

            

            

            

            
              
                	

                      	4.1.1.	
                        Development and Commercialization Licenses.

                      

              

            

            

            

            
              
                	

                      	(a)	
                        Collaboration Products. 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 Collaboration Products under such
                            Collaboration Program in the Field.

                      

              

            

            

            

            
              52

              
                

            

            
              
                	

                      	(b)	
                        Biogen Alternate Modality Products. Subject to the terms and
                            conditions of this Agreement, on a Biogen Alternate Modality Target-by-Biogen Alternate Modality Target basis, effective upon the date Biogen pays Ionis the milestone payment under Section 6.2.2 for a particular Biogen Alternate Modality Target, 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 Biogen Alternate Modality Products in the Field.

                      

              

            

            

            

            
              
                	

                      	4.1.2.	
                        Sublicense Rights; CMO Licenses.

                      

              

            

            

            

            
              
                	

                      	(a)	
                        Subject to the terms and conditions of this Agreement, Biogen will have the right to grant sublicenses under the licenses granted under Section 4.1.1(a) and Section 4.1.1(b) 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 (y) [***] or (z) [***];

                      

              

            

            

            

            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, 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.

            

            

            
              53

              
                

            

            
              
                	

                      	(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 a license is granted under Section

                                4.1.1, or supply API and Finished Drug Product for Commercialization, Ionis will, at Biogen’s option, either (1) grant a license from Ionis to [***] under the [***] to the extent necessary for [***], which Ionis
                            agrees it will grant to [***], or (2) permit Biogen to grant a sublicense from Biogen to [***]. For Collaboration Products, 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, Biogen will
                            have the right to [***].

                      

              

            

            

            

            
              
                	

                      	4.1.3.	
                        Effect of Termination on Sublicenses.

                      

              

            

            

            

            
              
                	

                      	(a)	
                        If this Agreement terminates for any reason, 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.

                      

              

            

            

            

            
              
                	

                      	(b)	
                        If this Agreement terminates for any reason, any Sublicensee of Biogen under Section 4.3.2 and any Sublicensee of Ionis under Section 4.5.2 will, from the effective date of such termination, automatically become a direct licensee with respect to the rights sublicensed to the Sublicensee by the applicable
                            Party hereunder; 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 such Sublicensee, and (iii) 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 (i) of the foregoing in writing at the request and for the benefit of the other Party and if requested, the Sublicensee.

                      

              

            

            

            

            
              54

              
                

            

            
              
                	

                      	4.1.4.	
                        No Implied Licenses. All rights in and to 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 or to perform Biogen Activities or Ionis Activities, as applicable, 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.

                      

              

            

            

            

            
              
                	

                      	4.1.5.	
                        License Conditions; Limitations. Subject to Section 6.13, any license granted under Section 4.1.1, and the sublicense rights under Section 4.1.2 are subject to and limited by (i) any applicable Third Party Obligations, (ii) the Prior Agreements, and (iii) 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 the date the applicable license under Section 4.1.1 is granted hereunder. With respect to Collaboration Products, Ionis will disclose to Biogen any Third Party Obligations Ionis believes apply
                            to applicable Collaboration Products each time Ionis provides (x) the [***]; (y) 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 with respect to a particular Program. If, prior to the date the applicable license under Section 4.1.1 is granted hereunder, Biogen provides Ionis with such a written notice to exclude certain Third Party Patent Rights and Know-How from such license, 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 date the applicable license under Section 4.1.1 is granted hereunder, 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.

                      

              

            

            

            

            
              
                	

                      	4.1.6.	
                        Trademarks for Products. If Biogen is granted a license under Section 4.1.1 for a particular Product, to the extent that (i) Ionis owns any trademark(s) specific to such Product which Ionis used prior to the date such
                            license was granted, and (ii) 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 the date the applicable
                            license under Section 4.1.1 is granted hereunder, 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.

                      

              

            

            

            

            
              55

              
                

            

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

                      

              

            

            

            

            
              
                	

                      	4.2.1.	
                        Assignment to Biogen. After Biogen has obtained the license for a
                            particular 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 (i) all Ionis Product-Specific Patents related to such Program in the Field that are owned by Ionis (whether solely owned or jointly owned with one or more Third
                            Parties), and (ii) any Jointly-Owned Program Patents Covering Products related to such Program, and thereafter 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.

                      

              

            

            

            

            
              
                	

                      	4.2.2.	
                        Grant Back to Ionis. 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 its activities with respect to such Program  under the applicable ASO Development Candidate Identification
                            Plans and applicable Initial Development Plans to the extent permitted by this Agreement, (c) to [***] with respect to such Program to the extent
                            permitted by this Agreement, (d) to [***] to the extent permitted under Appendix 3 and (e) to exercise Ionis’ rights under Section 2.1.1(f) (if applicable) or Section 3.2.2.

                      

              

            

            

            
              56

              
                

            

            
              
                
                  
                    
                      	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 4.3.2 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 (including the activities set forth on Schedule

                                    4.3.1(a)); 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 Collaboration Product or to Manufacture any such Collaboration Product for Commercialization.

                      

              

            

            

            

            
              
                	

                      	4.3.2.	
                        Biogen’s Right to Sublicense.  Biogen will have the right to grant sublicenses under the license granted under Section 4.3.1(a) above (a) 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 (i) [***] or (ii) [***] and (b) 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 4.3.2,
                            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 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
                              4.3.2 within [***] days after the execution thereof.  For the avoidance of doubt, Section 4.1.3(b) shall apply to sublicenses granted under this Section 4.3.2.

                      

              

            

            

            

            
              57

              
                

            

            
              
                	

                      	4.3.3.	
                        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 4.3.3(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 4.3.3(a) and

                            in Section 4.3.3(b) are royalty-free; except that if a product that is not a Product is 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 4.3.3(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.

                      

              

            

            

            

            
              
                	

                      	(c)	
                        Biogen may share any raw data included in the Ionis Program Know-How licensed to Biogen under Sections 4.3.3(a) and 4.3.3(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.

                      

              

            

            

            

            
              58

              
                

            

            
              
                	

                      	4.3.4.	
                        Enabling License 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 4.3.4(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 under this Agreement or any Ionis/Biogen Additional Agreement) and (b) Gene-Editing Products. The licenses
                            set forth in this Section 4.3.4(a) and in Section 4.3.4(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 6.14.1,
                            6.14.2, 6.14.3, 6.15, 6.16.1, 6.16.2(a), 6.16.3 and 6.17 shall apply, mutatis mutandis, to any royalty payments by Ionis to Biogen under this Section 4.3.4. 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 4.3.4(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 4.3.4(a) and 4.3.4(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 6.14 (other than Section 6.14.4), Section 6.15, Section 6.16 (other than Section 6.16.2(b)) and Section

                                6.17 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 completed no later than [***] prior to such anticipated filing date, for drafting and reviewing the sections of the NDA and
                            MAA for the applicable Collaboration Product (including establishing responsibilities for drafting and reviewing common technical document (“CTD”) modules, authorship, plan activity timelines and associated costs and expenses) and assigning  all necessary filings with any Regulatory Authority related to the applicable Collaboration
                            Product to Biogen to ensure a smooth transition to Biogen, accelerate CTD completion and facilitate rapid NDA and MAA filing. Each CTD will be consistent with the Specific Performance Milestone Events for the applicable
                            Collaboration Program.  The Parties regulatory teams will submit such plan to the CSC, if still active.  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 exercising an Option for a particular
                            Collaboration Program, if Biogen requests, Ionis will assist Biogen in preparing regulatory filings for the Collaboration 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, utilizing the payment mechanism set forth in Section 1.14.1.

                      

              

            

            

            

            
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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, 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.  For clarity, solely with respect to the Biogen Results, this
                            Section 4.7.2 shall supersede and replace Section 7.1.3 of this Agreement to the extent of any conflict.  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 First 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 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 Option expiration, including the transfer to Ionis of data and
                            information in such (sub)contractor’s possession related to the Product.

                      

              

            

            

            

            
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                	4.8.	
                        Technology Transfer. 

                      

              

            

            

            

            
              
                	

                      	4.8.1.	
                        Technology Transfer to Biogen during the Option Period. Within [***]
                            days after the First Amendment Date, Ionis will deliver to Biogen or one or more designated Affiliates, solely for use by Biogen, [***] to conduct any Biogen Activities that are Development activities with respect to any High
                            Interest Target or Collaboration Target in accordance with this Agreement, all Ionis Manufacturing and Analytical Know-How in Ionis’ Control [***] to conduct such Biogen Activities. 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, using the payment mechanism set forth in Section 1.14.1.

                      

              

            

            

            

            
              
                	

                      	4.8.2.	
                        Technology Transfer to Biogen after the License Effective Date. On a Collaboration Program-by-Collaboration Program basis, Ionis will promptly, but no later than [***] after the License Effective
                            Date with respect to a Collaboration Program, deliver to Biogen or one or more designated Affiliates:

                      

              

            

            

            

            
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                      	(a)	
                        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 10.4.2, 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; provided that, (i) 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 (A) any non-public
                            data or information, in each case, related solely to the applicable Development Candidate, or (B) any Confidential Information of Biogen, and (ii) 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 (i)
                            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 and assignment 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 4.8.2(a). 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, using the payment mechanism set forth in Section 1.14.1.

                      

              

            

            

            

            
              
                	

                      	(b)	
                        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, which is necessary for the exercise by Biogen, its Affiliates or a Third Party of the Manufacturing rights granted under Section 4.1.1(a).
                            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(b)
                            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, 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, using the payment mechanism set forth in Section

                                1.14.1.

                      

              

            

            

            

            
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                      	(c)	
                        API and Product. Upon Biogen’s written request, Ionis will sell to Biogen any bulk API, Clinical Supplies and Finished Drug Product in Ionis’ possession at the time of the License Effective Date with
                            respect to such Collaboration Program, at a price equal to [***].

                      

              

            

            

            

            
              
                	

                      	(d)	
                        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 Collaboration Product, this Section 4.8.2(d) will apply to such Discontinued Collaboration Product mutatis mutandis such that Biogen will transfer
                            to Ionis Biogen’s trial master file for such Discontinued Collaboration Product.

                      

              

            

            

            

            
              
                	

                      	4.8.3.	
                        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, (a) 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 (b) 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 processes.

                      

              

            

            

            

            
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                      	(b)	
                        For clarity, the Manufacturing Process Development Terms, and not the enabling licenses set forth in Section

                              4.3.3 and Section 4.3.4, shall govern with respect to all Results.

                      

              

            

            

            

            ARTICLE 5.

            DEVELOPMENT, MANUFACTURING AND COMMERCIALIZATION

            

            

            
              
                	5.1.	
                        Biogen Diligence.

                      

              

            

            

            

            
              
                	

                      	5.1.1.	
                        Collaboration Products.

                      

              

            

            

            

            
              
                	

                      	(a)	
                        Prior to the License Effective Date with respect to a Collaboration Program, Biogen will use Commercially Reasonable Efforts to conduct (i) any Biogen Activities on
                            the timeline set forth in the applicable Neurology Plan, (ii) except as provided under Section 1.10.2(c)(ii), for each ALS Collaboration Program all
                            activities under each Initial Development Plan on the timeline set forth in the applicable Initial Development Plan, and (iii) except as provided under Section
                                1.10.2(c)(ii) and Section 1.10.4(a), for each Biogen Conducted Non-ALS Collaboration Program all activities under each Initial
                            Development Plan on the timeline set forth in the applicable Initial Development Plan. Without limiting the foregoing, Biogen may discontinue Development under such an Initial Development Plan if after having consulted, and
                            having given good faith consideration to the recommendations of the Neurology JDC and a mutually-agreed Third Party expert, Biogen in good faith believes that continuing such Development would (1) pose an unacceptable risk or
                            threat of harm in humans, or (2) violate any Applicable Law, ethical principles, or principles of scientific integrity, in which case Biogen will provide Ionis with reasonable advance notice of such discontinuation, including
                            the grounds for Biogen’s determination, and Section 10.4.3 will apply.

                      

              

            

            

            

            
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                      	(b)	
                        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 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.

                      

              

            

            

            

            
              
                	

                      	5.1.2.	
                        Biogen Alternate Modality Products. Following the date a license is
                            granted to Biogen under Section 4.1.1(b) for a particular Biogen Alternate Modality Product, 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 applicable Biogen Alternate Modality Products; and Biogen
                            will use Commercially Reasonable Efforts to develop, manufacture and commercialize at least one Biogen Alternate Modality Product for each Biogen Alternate Modality Target.

                      

              

            

            

            

            
              
                	

                      	5.1.3.	
                        Multi-Indication Targets for Non-Neurological Indications. Without
                            limiting any of the foregoing, with respect to any plan for the development and commercialization of a Multi-Indication Target Biogen has agreed to conduct pursuant to a plan mutually-agreed under Appendix 3, Biogen will use Commercially Reasonable Efforts to develop, manufacture and commercialize at least one Product for such Multi-Indication
                            Target in accordance with such agreed plan.

                      

              

            

            

            

            
              
                	

                      	5.1.4.	
                        Specific Performance Milestone Events for Collaboration Products.
                            Without limiting any of the foregoing, (i) after the License Effective Date for a Collaboration Program that is not an ALS Collaboration Program, and (ii) following the designation of the Development Candidate for an ALS
                            Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program, Biogen will use Commercially Reasonable Efforts to achieve the specific performance milestone events set forth in Schedule 5.1.4, as such schedule may be updated from time to time in
                            accordance with Section 1.10.2(d) (“Specific
                              Performance Milestone Events”) for a Collaboration Product on the timeline set forth in Schedule 5.1.4; provided, however, [***].

                      

              

            

            

            

            
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                      	5.1.5.	
                        Development Results under ALS Collaboration Programs and Biogen Conducted
                                Non-ALS Collaboration Programs.  Without limiting the other provisions of this Agreement, promptly following its generation or receipt of the results of a [***] or a Clinical Study under an ALS Collaboration
                            Program or a Biogen Conducted Non-ALS Collaboration Program, as applicable, Biogen will provide Ionis (i) all study reports from [***] studies for the applicable Collaboration Product that are intended to support an
                            investigational new drug application, (ii) all study reports for any pre-clinical and clinical trials conducted by Biogen for such Collaboration Product, (iii) the data generated under the [***] for the applicable PoC Trial(s),
                            and (iv) copies of all filings submitted to Regulatory Authorities regarding such Collaboration Product.

                      

              

            

            

            

            
              
                	

                      	5.1.6.	
                        Integrated Development Plan for Products. 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 forecasts (each, an “Integrated Development Plan” or “IDP”). Biogen will prepare the IDP no later than (i) [***] after the License Effective Date with respect to a Collaboration
                            Program or (ii) after the First Commercial Sale of a Biogen Alternate Modality Product, and the IDP will include information consistent in scope and content with the information Biogen’s senior management uses for internal
                            decision-making for such Product. Schedule 5.1.6
                            sets forth examples of the types of information Biogen expects will be available to include in the IDP at different stages of development and commercialization. Once Biogen has prepared such plans, Biogen will update the IDP
                            consistent with Biogen’s standard practice and provide such updates to the CSC [***] (or Ionis after the CSC terminates under Section 1.18.5). 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 the CSC (or Ionis after the CSC terminates under Section 1.18.5) 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 5.1.6 will terminate if [***].

                      

              

            

            

            

            
              
                	

                      	5.1.7.	
                        Investigator’s Brochure for Collaboration Products. 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 Collaboration Product. Biogen will keep Ionis reasonably
                            informed with respect to the status, activities and progress of Development of Collaboration Products by providing updated versions of the Investigator’s Brochure for each Collaboration Product to Ionis [***] and when
                            Development of such Collaboration Product results in any substantive change to the safety or risk to the Collaboration Product. Biogen’s obligations under this Section

                                5.1.7 will terminate with respect to a Collaboration Product if [***].

                      

              

            

            

            

            
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                      	5.1.8.	
                        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.	
                        Regulatory Matters; Global Safety Database; Pharmacovigilance Agreement.

                      

              

            

            

            

            
              
                	

                      	5.2.1.	
                        IND-Holder. Subject to this Section 5.2, for Collaboration Programs that are not ALS Collaboration Programs or Biogen Conducted Non-ALS Collaboration Programs, Ionis will be the IND-holder and will be
                            responsible for all communications with Regulatory Authorities regarding such Collaboration Programs prior to the applicable License Effective Date.  Subject to this Section 5.2, for ALS Collaboration Programs and Biogen Conducted Non-ALS Collaboration Programs, Biogen will be the IND-holder and will be responsible for all communications with Regulatory Authorities
                            regarding such ALS Collaboration Programs and Biogen Conducted Non-ALS Collaboration Programs.  Biogen will be the IND-holder 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 5.2, shall
                            thereafter have sole decision-making authority with respect to the matters set forth in this Section 5.2.

                      

              

            

            

            

            
              
                	

                      	5.2.2.	
                        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 or Biogen anticipates filing an IND for the associated Collaboration Product with a Regulatory
                            Authority, the Parties will enter into a Safety Drug Exchange Agreement relating to the collection, review, assessment, tracking, exchange and filing of information related to adverse events associated with such Collaboration
                            Product occurring prior to the First Commercial Sale in any country on terms substantially the same as the terms of the Safety Drug Exchange Agreement to be entered into by the Parties with respect to adverse events associated
                            with products developed under the Ionis/Biogen Additional Agreements. In addition, following the First Amendment Date the Parties will discuss in good faith the possibility of entering into a single Safety Drug Exchange
                            Agreement with respect to all activities under this Agreement and the Ionis/Biogen Additional Agreements. No later than [***] days prior 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 Collaboration 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 Collaboration Product will be
                            the global commercial safety database owner for such Collaboration 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 the License Effective Date for a particular Collaboration Program, the Parties will communicate updates on safety data
                            regarding a Collaboration 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 Initial Development Plan for such Collaboration Program. Biogen may suggest actions to address Collaboration 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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                      	5.2.3.	
                        Regulatory Communications Regarding Clinical Study Trial Designs.

                      

              

            

            

            

            
              
                	

                      	(a)	
                        The Party who is the IND-holder will not initiate discussions with a Regulatory Authority regarding the [***] for a Collaboration Program until such [***] have been
                            established pursuant to Section 1.10.2(d), as applicable.

                      

              

            

            

            

            
              
                	

                      	(b)	
                        With respect to a Collaboration Program, to the extent practical, prior to any scheduled meeting with a Regulatory Authority regarding the [***] for such
                            Collaboration Program, (i) the applicable Neurology JDC (or the Parties, if Ionis ceases its participation in such Neurology JDC under Section 1.18.5)
                            will discuss and mutually agree upon the approximate timing and objectives for such meeting and (ii) the Party who is the IND-holder will provide the other Party with (A) an invitation to attend at least [***] and (B) an [***]
                            with the IND-holder. In addition, the IND-holder will allow the other Party to participate in any such meeting under the direction of The IND-holder provided, however, that the IND-holder may exclude such other Party from any portion of such meeting that does not pertain to such Collaboration Program.

                      

              

            

            

            

            
              
                	

                      	(c)	
                        With respect to a Collaboration Program, in each case, to the extent regarding the [***] for such Collaboration Program, the Party who is the IND-holder will
                            promptly provide the other Party with (i) final copies of all material correspondence with and submission to any Regulatory Authority promptly following submission thereof, (ii) a [***] from a Regulatory Authority, and (iii) a
                            [***] with a Regulatory Authority.

                      

              

            

            

            

            
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                      	(d)	
                        With respect to a Collaboration Program, the Party who is the IND-holder will provide the other Party with [***] any Regulatory Authority that materially impact the
                            [***] for such Collaboration Program sufficiently [***] to the applicable Regulatory Authority to enable the other Party to have a meaningful [***] thereof.  The [***] any Regulatory Authority must reflect the Initial
                            Development Plan. The applicable Neurology JDC (or the Parties if Ionis ceases its participation in such Neurology JDC under Section 1.18.5) will
                            [***] on the [***]; provided that if [***] prior to a Regulatory Authority’s requirement for a response as determined by [***] will
                            consider in good faith [***].

                      

              

            

            

            

            
              
                	

                      	5.2.4.	
                        Participation in Regulatory Meetings for Collaboration Products.
                            With respect to a Collaboration Program, each Party will 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 Collaboration 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 Collaboration 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
                            Collaboration Product or to Ionis’ antisense oligonucleotide chemistry platform.

                      

              

            

            

            

            
              
                	

                      	5.2.5.	
                        Regulatory Communications for Collaboration Products. With respect
                            to a Collaboration Program, each Party will promptly 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 Collaboration 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 [***].

                      

              

            

            

            

            
              
                	

                      	5.2.6.	
                        Class Generic Claims for Collaboration Products. To the extent
                            Biogen intends to make any claims in a Collaboration 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.

                      

              

            

            

            

            
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                      	5.2.7.	
                        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, 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 Collaboration Product 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 Collaboration Product, 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 5.2.7(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 Collaboration 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 5.2.7(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 Collaboration Product (including any potential class-related
                            toxicity), Ionis will promptly (and in no event later than five 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 Collaboration Products in sufficient detail and in a good scientific manner appropriate for (i) inclusion in filings
                            with Regulatory Authorities for such Collaboration Products, and (ii) obtaining and maintaining intellectual property rights and protections, including Patent Rights for such Collaboration 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.

                      

              

            

            

            

            
              
                	5.4.	
                        Product Development Plans for ALS Collaboration Programs and Biogen Conducted
                                Non-ALS Collaboration Programs. With respect to each ALS Collaboration Program and each Biogen Conducted Non-ALS Collaboration Program, Biogen shall propose and develop a product development plan, which shall
                            govern CMC-related matters for the applicable Collaboration Product.  Ionis shall have the opportunity to review and comment on each such product development plan and Biogen shall consider any such comments in good faith.

                      

              

            

            

            

            ARTICLE 6.

            FINANCIAL PROVISIONS

            

            

            
              
                	6.1.	
                        Up-Front Fee. Within five Business Days following the Effective
                            Date, Biogen will pay Ionis an up-front fee of $100,000,000.

                      

              

            

            

            

            
              
                	6.2.	
                        Drug Discovery Milestone Payments.

                      

              

            

            

            

            
              
                	

                      	6.2.1.	
                        Collaboration Targets. For each Collaboration Program, after (a) a
                            Collaboration Target is designated under this Agreement, and (b) Ionis begins designing human development candidates under such Collaboration Program for human candidate screening under the applicable ASO Development Candidate
                            Identification Plan ([***]), Ionis will so notify Biogen (such notice, the “Design Notice”) and Biogen will pay Ionis a
                            milestone payment equal to (i) $[***] for Collaboration Programs that are not ALS Collaboration Programs [***], subject to any applicable credits permitted by Section

                                1.8.3 or Section 1.8.4, (ii) $[***] for ALS Collaboration Programs [***], or (iii) $[***].

                      

              

            

            

            

            
              73

              
                

            

            
              
                	

                      	6.2.2.	
                        Biogen Alternate Modality Targets. On a Biogen Alternate Modality
                            Target-by-Biogen Alternate Modality Target basis, each time a Neurology Target is designated a Biogen Alternate Modality Target under this Agreement, Biogen will pay Ionis a milestone payment equal to $[***], subject to any
                            applicable credits permitted by Section 1.8.3 or Section 1.8.4.

                      

              

            

            

            

            
              
                	6.3.	
                        Milestone Payments for Achievement of Milestone Events by Biogen Alternate
                                Modality Products. Subject to Section 3.2.3(b), for each Biogen Alternate Modality Target, Biogen will pay to Ionis the milestone
                            payments as set forth in Table X below when a milestone event (each, a “Biogen Alternate Modality Milestone Event”) listed in Table X
                            is first achieved by a Biogen Alternate Modality Product related to such Biogen Alternate Modality Target:

                      

                 

                

              

            

            
              	
                      Table X

                    
	
                      Biogen Alternate Modality Milestone 

                      Event

                    	
                      Milestone Event Payment per Biogen 

                      Alternate Modality Target

                    
	
                      [***] 	 $[***] 
	
                      [***]

                    	 $[***] 
	
                      [***] 	 $[***] 
	
                      [***]

                    	
                      $[***]

                    
	
                      [***] 	 $[***] 
	 [***] 	
                      $[***]

                    

            

            
              
                 

                

                	6.4.	
                        Non-ALS Collaboration Program Milestone Payments for Achievement of
                                Pre-Licensing Milestone Events. As further consideration for Biogen’s Options, on a Collaboration Program-by-Collaboration Program basis where such a Collaboration Program is not an ALS Collaboration Program,
                            Biogen will pay to Ionis the milestone payments as set forth in Table 1 below when a milestone event (each, a “Standard Pre-Licensing Milestone Event”) listed in Table 1 is first achieved by a Collaboration Product under such Collaboration Program:

                      

                 

                

                
                  74

                  
                    

                

              

            

            	
                    Table 1

                  
	
                    Standard Pre-Licensing 

                    Milestone Event

                  	
                    Milestone Event Payment per 

                    Collaboration Program that is not 

                    an ALS Collaboration Program 

                    or Biogen Conducted Non-ALS

                     Collaboration Program

                  	
                    Milestone Event Payment per 

                    Biogen Conducted Non-ALS

                     Collaboration Program

                  
	 [***]
                  	 $[***]
                  	 $[***]
                  
	
                    [***]

                  	
                    [***]

                  	
                    $[***]

                  
	 [***]
                  	 [***]
                  	 $[***]
                  

            

            

            On a Collaboration
                  Program-by-Collaboration Program basis, where such a Collaboration Program is not an ALS Collaboration Program, 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 Collaboration
                  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 reduced to $[***].

            

            

            
              
                	6.5.	
                        ALS Collaboration Program Milestone Payments for Achievement of Pre-Licensing
                                Milestone Events. As further consideration for Biogen’s Options, on an ALS Collaboration Program-by-ALS Collaboration Program basis, Biogen will pay to Ionis the milestone payments as set forth in Table 2 below when a milestone event (each, an “ALS Pre-Licensing Milestone Event”) listed in Table 2 is first achieved by a Collaboration
                            Product under such a Collaboration Program. Subject to the penultimate paragraph of Section 6.7, the amount of the payment for such Milestone Events
                            will be determined based on whether or not such ALS Collaboration Program is a [***] Collaboration Program:

                      

                 

                

              

            

            	
                    Table 2

                  
	
                     

                     

                    ALS Pre-Licensing 

                    Milestone Event

                  	
                    Column 1

                    Milestone Event 

                    Payment per ALS 

                    Collaboration Program

                     that is not a [***] 

                    Collaboration Program 

                    [***]

                  	
                    Column 2

                    Milestone Event

                     Payment per [***] 

                    Collaboration Program

                  	
                    Column 3

                    Milestone Event 

                    Payment for the [***]

                  
	
                    [***] 	
                    $[***] 	
                    $[***] 	
                    [***] 
	
                    [***] 	
                    $[***] 	
                    $[***] 	
                    [***] 
	
                    [***] 	
                    $[***] 	
                    $[***] 	
                    [***] 
	
                    [***] 	
                    [***] 	
                    [***] 	
                    $[***] 
	
                    [***] 	
                    $[***] 	
                    $[***] 	
                    $[***] 

            

            

            
              75

              
                

            

            On an ALS Collaboration Program-by-ALS Collaboration Program basis, Biogen will pay to Ionis the Milestone Event payments as set
                forth in Table 2 after the applicable Milestone Event is first achieved by a Collaboration Product under such an ALS Collaboration
                Program, even if Biogen has exercised the applicable Option prior to achievement of the Milestone Event.

            

            

            
              
                	6.6.	
                        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 (A) $[***] for any Collaboration Program [***]; provided, however, that if (i) Biogen exercises the Option prior to the [***], the license fee for such Option will be [***] or (ii) Biogen exercises the Option to a
                            [***] Collaboration Program, subject to the last paragraph of Section 6.7, the license fee for such Option will be [***], or (B) $[***]; provided, however, that if Biogen exercises the Option prior to the [***], the license fee for such Option will be [***]. If Biogen notifies
                            Ionis that it desires to exercise an Option prior to the [***], then the Parties will discuss and negotiate in good faith.

                      

              

            

            

            

            
              
                	6.7.	
                        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 3
                            below when a milestone event (each, a “Post-Licensing Milestone Event”) listed in Table 3 is first achieved by a Collaboration Product under such Collaboration Program, where (subject to the last paragraph of Section 6.7) the amount of the payment for such Milestone Event will be determined based on whether or not such Collaboration Program is a [***] Collaboration Program:

                      

                 

                

              

            

            	
                    Table 3

                  
	
                     

                    Post-Licensing Milestone 

                    Event

                  	
                    Column 1

                    Milestone Event Payment per

                     Collaboration Program that is 

                    not a [***] Collaboration

                     Program

                  	
                    Column 2

                     

                          

                    Milestone Event Payment

                     per [***] Collaboration 

                    Program

                  
	 [***]
                  	 $[***]
                  	 $[***]
                  
	 [***]
                  	 $[***]
                  	 $[***]
                  
	 [***]
                  	 $[***]
                  	 $[***]
                  
	 [***]
                  	 $[***]
                  	 $[***]
                  

             

            

            On a Collaboration Program-by-Collaboration Program basis, if Biogen exercises an Option for a Collaboration Program that is not a [***] Collaboration Program, prior to the [***], Biogen will pay to Ionis [***] upon the earlier of (a) [***] or (b) [***]. 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 3 above.

            

            

            
              76

              
                

            

            If, with respect to a particular [***] Collaboration Program, Biogen Initiates a Phase 2 Trial in an indication other than [***]
                (e.g., [***] or a [***] indication) Biogen will pay Ionis [***] within [***] days of the Initiation of such Phase 2 Trial.

            

            

            If, with respect to a particular [***] Collaboration Program, Biogen Initiates a Phase 3 Trial or files for Approval in an
                indication other than [***] (e.g., [***] or a [***] indication) such Collaboration Program will thereafter be a Collaboration Program (and not a [***]
                Collaboration Program) under this Agreement, and Biogen will pay Ionis (i) $[***] and (ii) [***] within [***] days of the Initiation of such Phase 3 Trial or filing for Approval.

            

            

            
              
                	6.8.	
                        Limitations on Milestone Payments; Exceptions; Notice.

                      

              

            

            

            

            
              
                	

                      	6.8.1.	
                        On a Collaboration Product-by-Collaboration Product basis, the [***] milestone payment in Table 3 is creditable against the first Milestone Event payment for [***]. For example, if the [***] Milestone Event is achieved by a Collaboration Product in the United States, then
                            the milestone payment for such Milestone Event is creditable against the first to occur of the (i) [***] (ii) [***] or (iii) [***] milestone payments for such Collaboration Product.

                      

              

            

            

            

            
              
                	

                      	6.8.2.	
                        On a Biogen Alternate Modality Target-by-Biogen Alternate Modality Target basis, each milestone payment set forth in Table X above will be paid only once upon the first achievement of the Milestone Event regardless of how many Biogen Alternate Modality Products related to such
                            Biogen Alternate Modality Target achieve such Milestone Event.

                      

              

            

            

            

            
              
                	

                      	6.8.3.	
                        On a Collaboration Program-by-Collaboration Program basis, each milestone payment set forth in Table 1, Table 2 and Table 3 above will be paid only once upon the first achievement of the Milestone
                            Event regardless of how many Collaboration Products under such Collaboration Program achieve such Milestone Event.

                      

              

            

            

            

            
              
                	

                      	6.8.4.	
                        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. Similarly, if a Party proceeds directly to [***] without achieving the [***] then upon achieving the
                            [***] Milestone Event, both the [***] and [***] Milestone Event payments are due. If Biogen [***] for a Biogen Alternate Modality Product, then both the [***] milestone payment and the [***] milestone payment will be due upon
                            [***].

                      

              

            

            

            

            
              77

              
                

            

            
              
                	

                      	6.8.5.	
                        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 five Business Days) following the date of achievement of such Milestone Event and such payment will be due within [***] days of
                            the date such notice was delivered.

                      

              

            

            

            

            
              
                	

                      	6.8.6.	
                        With respect to the [***] Collaboration Program for [***], except as expressly set forth in Section

                                6.5, the milestone payments and license fees set forth in Section 6.5, Section

                                6.6 and Section 6.7 for [***] Collaboration Programs that are not [***] Collaboration Programs shall apply with respect to such [***]
                            Collaboration Program.  For clarity, the provisions of the Neurology Drug Discovery and Development Collaboration, Option and License Agreement between Ionis and Biogen, dated as of December 10, 2012, as such agreement may be
                            amended from time to time, shall not apply with respect to the [***] Collaboration Program for [***].

                      

              

            

            

            

            
              
                	6.9.	
                        Royalty Payments to Ionis for Biogen Alternate Modality Products.

                      

              

            

            

            

            
              
                	

                      	6.9.1.	
                        Royalties for Biogen Alternate Modality Products. As partial
                            consideration for the rights granted to Biogen hereunder, subject to the provisions of Section 3.2.3(b) and Section 6.9.2, Biogen will pay to Ionis a [***]% royalty on Annual worldwide Net Sales of Biogen Alternate Modality Products sold by Biogen, its Affiliates or Sublicensees, on a
                            country-by-country basis (the “Biogen Alternate Modality Royalty”).

                      

              

            

            

            

            
              
                	

                      	6.9.2.	
                        Royalty Period for Biogen Alternate Modality Products. Biogen’s
                            obligation to pay Ionis the Biogen Alternate Modality Royalty above with respect to a Biogen Alternate Modality Product will continue on a country-by-country and Biogen Alternate Modality Product-by-Biogen Alternate Modality
                            Product basis from the date of First Commercial Sale of such Biogen Alternate Modality Product until the [***] anniversary of the First Commercial Sale of such Biogen Alternate Modality Product in such country (such royalty
                            period, the “Biogen Alternate Modality Royalty Period”); provided, that Biogen will pay [***] (if applicable) for as long as Biogen, its Affiliates or Sublicensees
                            are selling Biogen Alternate Modality Products.

                      

              

            

            

            

            
              78

              
                

            

            
              
                	

                      	(a)	
                        Biogen will pay Ionis royalties on Net Sales of Biogen Alternate Modality Products arising from named patient and other similar programs under Applicable Laws, and
                            Biogen will provide reports and payments to Ionis consistent with Section 6.14.

                      

              

            

            

            

            
              
                	

                      	(b)	
                        No royalties are due on Net Sales of Biogen Alternate Modality Products arising from compassionate use and other programs providing for the delivery of Biogen
                            Alternate Modality Product at no cost.

                      

              

            

            

            

            
              
                	

                      	(c)	
                        The sales of Biogen Alternate Modality Products arising from named patient, compassionate use, or other similar programs will not be considered a First Commercial
                            Sale for purposes of calculating the Biogen Alternate Modality Royalty Period.

                      

              

            

            

            

            
              
                	6.10.	
                        Royalty Payments to Ionis for Collaboration Products.

                      

              

            

            

            

            
              
                	

                      	6.10.1.	
                        Biogen Full Royalty for Collaboration Products. As partial
                            consideration for the rights granted to Biogen hereunder, subject to the provisions of this Section 6.10.1 and Section 6.10.2, Biogen will pay to Ionis royalties on a Collaboration Program-by-Collaboration Program basis, on Annual worldwide Net Sales of Collaboration 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 4 below (the “Biogen Full Royalty”):

                      

                
                  

                  

                  
                    
                      	
                              Table 4

                            
	
                              Royalty

                              Tier

                            	
                              Annual Worldwide Net Sales of Collaboration 

                              Products for the applicable Collaboration 

                              Program

                            	
                              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  > $[***] 	
                              [***]% 

                       

                      

                    

                  

                  
                    79

                    
                      

                  

                

              

            

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

            

            

            
              
                	

                      	(a)	
                        Biogen will pay Ionis royalties on Net Sales of Collaboration Products arising from named patient and other similar programs under Applicable Laws, and Biogen will
                            provide reports and payments to Ionis consistent with Section 6.14. No royalties are due on Net Sales of Collaboration Products arising from
                            compassionate use and other programs providing for the delivery of Collaboration Product at no cost. The sales of Collaboration 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 Section 6.10 shall apply to Net Sales of
                            Collaboration Products under the [***] Collaboration Program for [***], and the provisions of the Neurology Drug Discovery and Development Collaboration, Option and License Agreement between Ionis and Biogen, dated as of
                            December 10, 2012, as such agreement may be amended from time to time, shall not apply.

                      

              

            

            

            

            
              
                	

                      	6.10.2.	
                        Application of Royalty Rates for Collaboration Products. All
                            royalties set forth under Section 6.10.1 are subject to the provisions of this Section

                                6.10.2, and are payable as follows:

                      

              

            

            

            

            
              
                	

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

                      

              

            

            

            

            
              80

              
                

            

            
              
                	

                      	(b)	
                        Competition from Generic Products for Collaboration Products.
                            Subject to Section 6.11, on a country-by-country and Collaboration Product-by-Collaboration 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 Collaboration 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 Collaboration Product under this Section 6.10.2(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 Collaboration Products are being sold.

                      

              

            

            

            

            
              
                	

                      	(c)	
                        Reduced Royalty Period for Collaboration Products. Subject to Section 6.11, on a country-by-country and Collaboration Product-by-Collaboration 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 4 of Section 6.10.1, Biogen will pay Ionis royalty rates (the “Biogen Reduced
                              Royalty”) on Net Sales of Collaboration 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)	
                        End of Royalty Obligation for Collaboration Products. On a
                            country-by-country and Collaboration Product-by-Collaboration Product basis, other than [***], Biogen’s obligation to make royalty payments hereunder for such Collaboration 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 Collaboration Product in such country and ending when the [***].

                      

              

            

            

            

            
              
                	

                      	(e)	
                        Royalty Examples. Schedule 6.10.2(e) attached hereto contains examples of how royalties will be calculated under
                            this Section 6.10.

                      

              

            

            

            

            
              
                	

                      	(f)	
                        Allocation of Net Sales. If, by reason of one or more royalty rate
                            adjustments under this Section 6.10.2, different royalty rates apply to Net Sales of Collaboration Products from different countries, Biogen will
                            [***] such Net Sales [***]. Schedule 6.10.2(f)
                            attached hereto contains examples of how Net Sales of Collaboration Products from different countries at different royalty rates will be [***].

                      

              

            

            

            

            
              81

              
                

            

            
              
                	6.11.	
                        Limitation on Aggregate Reduction for Royalties for Collaboration Products.

                      

              

            

            

            

            
              
                	

                      	6.11.1.	
                        In no event will the aggregate royalty reductions under Section 6.10.2(b) and Section 6.10.2(c) reduce the royalties payable to Ionis on Net Sales of a Collaboration Product in any given period to an amount that is less than the
                            [***] for such Collaboration Product.

                      

              

            

            

            

            
              
                	

                      	6.11.2.	
                        In no event will the aggregate royalty offsets under Section 6.13.3(b), Section 6.13.3(d) and Section 7.1.3(c) reduce the royalties payable to Ionis on Net Sales of a Collaboration 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 6.13.3(b), Section 6.13.3(d) and Section 7.1.3(c) will not apply during such Calendar Year but the full Royalty Quotient reduction pursuant
                to Section 6.10.2(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 4 of Section 6.10.1, then Biogen may apply the offsets under Section 6.13.3(b), Section 6.13.3(d) and Section 7.1.3(c) until the actual
                royalty payment made to Ionis in such Calendar Year is equal to [***]% of the applicable royalty rates in Table 4 of Section 6.10.1.

            

            

            
              
                	6.12.	
                        Reverse Royalty Payments to Biogen for a Discontinued Collaboration Product.

                      

              

            

            

            

            
              
                	

                      	6.12.1.	
                        Reverse Royalty for a Discontinued Collaboration Product. If Ionis
                            or any of its Affiliates or Sublicensees Commercializes a Discontinued Collaboration Product for which Biogen has paid Ionis the license fee under Section 6.5,
                            then following the First Commercial Sale of such Discontinued Collaboration 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 Collaboration Product (“Reverse Royalties”). Ionis’ obligation to pay Biogen Reverse Royalties will [***].

                      

              

            

            

            

            
              
                	

                      	6.12.2.	
                        Applicable Royalty Provisions. In addition to this Section 6.12, 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 6.12, mutatis mutandis,
                            including the provisions of Sections 6.10.2, 6.13, 6.14, 6.15, 6.16,
                            and 6.17.

                      

              

            

            

            

            
              82

              
                

            

            
              
                	6.13.	
                        Third Party Payment Obligations.

                      

              

            

            

            

            
              
                	

                      	6.13.1.	
                        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(a) or Section 4.1.1(b) were in-licensed or were acquired by Ionis under the agreements with Third Party
                            licensors or sellers listed on Schedule 6.13.1
                            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 Collaboration Products for High Interest
                            Targets designated as of the Effective Date, will be paid by [***] as [***].  

                      

              

            

            

            

            
              
                	

                      	6.13.2.	
                        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(a) or Section

                                4.1.1(b) (as applicable) if Biogen agrees in writing to pay Ionis as [***].

                      

              

            

            

            

            
              
                	

                      	6.13.3.	
                        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(a), and any financial obligations under such Third Party agreement will be paid solely by [***] as [***].

                      

              

            

            

            

            
              83

              
                

            

            
              
                	

                      	(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 6.11.2, 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
                                6.13.3(a) is Additional Core IP under Section 6.13.3(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 Oligonucleotides, 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 6.13.3(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 6.13.3(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 [***].

                      

              

            

            

            

            
              
                	

                      	6.13.4.	
                        Other Third Party Payments.

                      

              

            

            

            

            
              
                	

                      	(a)	
                        Ionis’ Third Party Agreements. Except as otherwise expressly agreed
                            to by Biogen under Section 6.13.2, after Biogen is granted the license under Section

                                4.1.1(a) or Section 4.1.1(b) for a particular Product, Biogen will be responsible for paying [***]% of the [***] arising under any
                            Third Party agreements entered into by Ionis where either [***].

                      

              

            

            

            

            
              
                	

                      	(b)	
                        Biogen’s Third Party Agreements. Without limiting any applicable
                            [***] under Section 6.13.3(b), Biogen will be responsible for paying [***]% of the [***] arising under any Third Party agreements entered into by
                            Biogen as they apply to Products.

                      

              

            

            

            

            
              
                	6.14.	
                        Payments.

                      

              

            

            

            

            
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                      	6.14.1.	
                        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, the exchange rate used and the type of
                            Product (i.e., whether it is a Collaboration Product or Biogen Alternate Modality Product) and the aggregate reduction to gross sales to arrive at Net
                            Sales. Following the end of the first full Calendar Quarter subsequent to 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, 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.

                      

              

            

            

            

            
              
                	

                      	6.14.2.	
                        Mode of Payment. All payments under this Agreement will be (i)
                            payable in full in U.S. dollars, regardless of the country(ies) in which sales are made, (ii) made by wire transfer of immediately available funds to an account designated by Ionis in writing, and (iii) 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.

                      

              

            

            

            

            
              
                	

                      	6.14.3.	
                        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.

                      

              

            

            

            

            
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                      	6.14.4.	
                        No Payments for non-ASOs for Pre-Existing Targets.  For the
                            avoidance of doubt, in no event shall any payments be due to Ionis under this Agreement with respect to any non-Oligonucleotide product developed or commercialized for a Pre-Existing Target.

                      

              

            

            

            

            
              
                	6.15.	
                        Audits. After Biogen is granted the license under Section 4.1.1(a) or Section 4.1.1(b) for a particular Product, 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 6.17. 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.

                      

              

            

            

            

            
              
                	6.16.	
                        Taxes.

                      

              

            

            

            

            
              
                	

                      	6.16.1.	
                        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.

                      

              

            

            

            

            
              
                	

                      	6.16.2.	
                        Withholding Tax.

                      

              

            

            

            

            
              
                	

                      	(a)	
                        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 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, interest or penalties 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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                      	(b)	
                        With respect to any commercial supply agreement entered between the Parties for the commercial supply of API under this Agreement, such supply agreement will (i)
                            provide that only Biogen will claim any tax benefit allowed under IRC Section 199 Income Attributable to Domestic Production Activities, and (ii) include compensation to Ionis reflecting the value of the reasonably anticipated
                            tax benefit under IRC Section 199 Income Attributable to Domestic Production Activities forfeited by Ionis.  If the IRS determines that Biogen is not entitled to the tax benefits under Section 199, Ionis is not required to
                            reimburse Biogen for this tax benefit unless Ionis receives a cash benefit on its federal tax return.   A cash benefit will include any utilization of net operating losses that were generated in a year in which Ionis claimed any
                            IRC Sec 199 deduction.  The reimbursement to Biogen would be an amount equal to the Section 199 deduction times thirty-five percent, less any administrative costs to compute the tax benefit.  The reimbursement would be due to
                            Biogen within 90 days after filing any original or amended federal tax return.  If the IRS determines that Ionis is not eligible for the tax benefit or determines the tax benefit should be a different amount, Biogen will pay
                            back to Ionis the amount of any adjustment.  Ionis will notify Biogen within 30 days of filing a return that claims such deduction or utilizes a related net operating loss.

                      

              

            

            

            

            
              
                	

                      	6.16.3.	
                        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 determine if any taxes are applicable to payments under this Agreement and 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 6.16.

                      

              

            

            

            

            
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            The provisions of this Section 6.16 are to be read
                in conjunction with the provisions of Section 12.4 below.

            

            

            
              
                	6.17.	
                        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 (i) 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 (ii) 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.

                      

              

            

            

            

            
              
                	

                      	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.”

                      

              

            

            

            

            
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                      	7.1.3.	
                        Joint Patent Committee.

                      

              

            

            

            

            
              
                	

                      	(a)	
                        The Parties will establish a “Joint Patent Committee”
                            or “JPC” promptly following the Effective Date.  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 Neurological Disease Research Plan 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, the Neurological Disease Research
                            Plan, (iii) making recommendations with respect to intellectual property considerations to be taken into account in each ASO Development Candidate Identification 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 JDC 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 Neurology 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 Research 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
                            Core Research Program and the Neurological Disease Research Program, promptly following the Second 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 Neurology 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 Neurology Plans or solely by a Third Party performing activities under the Neurology 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(f)) 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 under Section 6.11, if Collaborator IP (other than Additional Core IP arises from activities performed by a Third Party under the applicable Neurology Plan, 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 4.1.5 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, even after seeking the CSC’s input, 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.

                      

              

            

            

            

            
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                      	7.2.1.	
                        Patent Filings. Subject to Biogen’s right to provide reasonable
                            input and comment as set forth in Section 7.2.5(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.

                      

              

            

            

            

            
              
                	

                      	7.2.2.	
                        Licensed Patents and Biogen Patents.

                      

              

            

            

            

            
              
                	

                      	(a)	
                        Licensed Patents In General. Prior to the License Effective Date for
                            a Collaboration Program or Biogen Alternate Modality Program (as applicable) (a “Program”), and subject to Biogen’s
                            right to provide reasonable input and comment as set forth in Section 7.2.5(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 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 Program-by-Program, until the earlier of the License Effective Date with respect to such 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 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 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 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.

                      

              

            

            

            

            
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                      	7.2.3.	
                        Jointly-Owned Program Patents. Subject to Biogen’s right to provide
                            reasonable input and comment as set forth in Section 7.2.5(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 Program and subject to Biogen’s right to
                            provide reasonable input and comment as set forth in Section 7.2.5(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 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 Program.

                      

              

            

            

            

            
              
                	

                      	7.2.4.	
                        Prosecution of Multi-Indication Product-Specific Patents; Biogen Supremacy to
                                Enforce and Extend.  With respect to Product-Specific Patents related to Multi-Indication Products, the Parties will endeavor to prosecute such Patent Rights to claim inventions related to Neurological Diseases
                            separately from inventions related to Non-Neurological Indications. If there is an Ionis Product-Specific Patent that Covers both (a) a Multi-Indication Product licensed to Biogen under Section 4.1.1(a), and (b) a Multi-Indication Product of Ionis (each such Ionis Product-Specific Patent, a “Multi-Indication Product-Specific Patent”), then so long as Biogen is Developing and Commercializing such Multi-Indication Product pursuant to its license under Section 4.1.1(a), upon the grant of such license, Biogen will have the sole and exclusive right, but not the obligation, to institute and control any (i)
                            Proceeding related to the infringement of such Multi-Indication Product-Specific Patent, (ii) Prosecution and Maintenance of such Multi-Indication Product-Specific Patent and (iii) patent term extension related to such
                            Multi-Indication Product-Specific Patent.

                      

              

            

            

            

            
              
                	

                      	7.2.5.	
                        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 7.2.5,
                            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.

                      

              

            

            

            

            
              94

              
                

            

            
              
                	

                      	(b)	
                        Following the License Effective Date with respect to a particular 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 7.2.5, 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 will not be required to implement. Following the License Effective Date with respect
                            to a particular 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
                            Program, including any Proceeding related to the infringement of such Patent Rights and any patent term extensions related to such Patent Rights.

                      

              

            

            

            

            
              
                	

                      	(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 7.2.5(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 7.2.5(c),
                            then Ionis will have no obligation to notify Biogen if Ionis intends to abandon such Biogen-Prosecuted Patent.

                      

              

            

            

            

            
              95

              
                

            

            
              
                	

                      	(d)	
                        Notwithstanding Section 7.2.5(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

                                6.10.2(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 7.2.5(c) above to
                            file or prosecute the Conflicting Patent Right.

                      

              

            

            

            

            
              
                	

                      	(e)	
                        If, during the Agreement Term, Ionis intends not to file or 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 7.2.5(e), then Biogen will have no obligation to notify Ionis if
                            Biogen intends to abandon such Ionis Product-Specific Patent.

                      

              

            

            

            

            
              96

              
                

            

            
              
                	

                      	(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 7.2.5(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.

                      

              

            

            

            

            
              
                	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, titles and interests in and to such Jointly-Owned Program
                            Patents.

                      

              

            

            

            

            
              97

              
                

            

            
              
                	

                      	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 Program, Biogen will be solely responsible for Patent Costs arising from the Prosecution and Maintenance of the Ionis
                            Product-Specific Patents related to such 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 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 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 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.

                      

              

            

            

            

            
              98

              
                

            

            
              
                	

                      	7.4.2.	
                        Discontinued Collaboration 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 Collaboration 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).

                      

              

            

            

            

            
              99

              
                

            

            
              
                	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 (i) a product directed against the RNA that encodes a Collaboration Target in the Field, or (ii) a non-Oligonucleotide product that is designed to bind, mimic or
                            otherwise affect a protein or RNA that is encoded by a Biogen Alternate Modality Target (“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 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.

                      

              

            

            

            

            
              
                	

                      	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, Collaboration Target in the Field, then such Party 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.

                      

              

            

            

            

            
              100

              
                

            

            
              
                	

                      	7.5.4.	
                        Following License Grant. For any Competitive Infringement with
                            respect to a particular Product (except for a Discontinued Collaboration Product) occurring after the License Effective Date for the 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.

                      

              

            

            

            

            
              101

              
                

            

            
              
                	

                      	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:

                      

              

            

            

            

            
              
                	

                      	(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 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 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 such Section 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.

                      

              

            

            

            

            
              102

              
                

            

            
              
                	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.

                      

              

            

            

            

            
              
                	

                      	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.

                      

              

            

            

            

            
              103

              
                

            

            
              
                	

                      	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 Collaboration 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 Collaboration 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).

                      

              

            

            

            

            
              
                	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 6.13.2, (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.

                      

              

            

            

            

            
              104

              
                

            

          

          	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 Second 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;

                      

              

            

            

            

            
              
                	

                      	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

                      

              

            

            

            

            
              105

              
                

            

            
              
                	

                      	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(a) upon the exercise of the Option for a Collaboration 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 Collaboration 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 right, title and
                            interest in the Licensed Technology in a manner that conflicts with any rights granted to Biogen hereunder with respect to Collaboration Products.

                      

              

            

            

            

            
              
                	

                      	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) and Schedule 8.2.4(b)
                            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.

                      

              

            

            

            

            
              106

              
                

            

            
              
                	

                      	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 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 6.13.1 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(a) 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.  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 with respect to Collaboration Programs.

                      

              

            

            

            

            
              107

              
                

            

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

                      

              

            

            

            

            
              
                	

                      	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 a 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 right, title and interest 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 Collaboration 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.

                      

              

            

            

            

            
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                	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.

                      

              

            

            

            

            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 it’s or their respective directors, officers, employees and agents or other circumstance for which Ionis has an indemnity obligation pursuant to Section 9.2.

            

            

            
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                	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

                      

              

            

            

            

            
              
                	

                      	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 Collaboration 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 (i) inform the indemnifying Party in writing of a Claim as soon as reasonably practicable after
                            such Indemnitee receives notice of such Claim, (ii) 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 (A) 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 (B) the indemnifying Party first obtain the written consent of the Indemnitee with respect to such settlement, which
                            consent will not be unreasonably withheld), (iii) cooperate as reasonably requested (at the expense of the indemnifying Party) in the defense of the Claim, and (iv) 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.

                      

              

            

            

            

            
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                	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.

                      

              

            

            

            

            
              
                	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 10.4.4(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.

                      

              

            

            

            

            
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            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 Collaboration 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 Collaboration Products) in all
                            countries pursuant to Section 10.1.1;

                      

              

            

            

            

            
              
                	

                      	10.1.3.	
                        where there are no Collaboration Targets and no Biogen Alternate Modality Targets designated by the expiration of the Research Term as described in Section 1.9;

                      

              

            

            

            

            
              
                	

                      	10.1.4.	
                        where there are no Biogen Alternate Modality Targets designated by the expiration of the Research Term as described in Section 1.9, and no Development Candidates designated by the expiration of the ASO Development Candidate Identification Term as described in Section 1.10.1(d); and

                      

              

            

            

            

            
              
                	

                      	10.1.5.	
                        where there are no Biogen Alternate Modality Targets designated by the expiration of the Research Term as described in Section 1.9, and 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 6.6 by the Option Deadline, or as a result of Section 1.10.2(g)
                            or Section 10.4.3.

                      

              

            

            

            

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

            

            

            
              112

              
                

            

            
              
                	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 or Biogen Alternate Modality Target, for convenience by providing 90 days written notice to Ionis of such termination.  

                      

              

            

            

            

            
              
                	

                      	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 Collaboration Product or Competitive Collaboration 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 Collaboration Product or engaged in a Competitive Collaboration Program, as set forth in Section 12.5.3, 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 proposed Program under Section 1.7,
                            Section 3.1.3 or Section 3.2.5 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 the applicable proposed 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 proposed 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
                            proposed Program, as applicable.

                      

              

            

            

            

            
              113

              
                

            

            
              
                	

                      	(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 (y) [***] or (z) [***].

            

            

            
              
                	

                      	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 ARTICLE 1, 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 Neurology Target or 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 Neurology Target or Collaboration Program affected by such breach.

                      

              

            

            

            

            
              
                	

                      	(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 [***]-month 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 Neurology Target or 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 ARTICLE 1 prior to the date Biogen is granted a license under Section 4.1.1(a) or Section 4.1.1(b) (as applicable) with respect to a particular High Interest Target or 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 ARTICLE 1. Following such a meeting, if Ionis fails to use Commercially Reasonable Efforts as contemplated by ARTICLE 1 with respect to such High Interest Target or 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 High Interest Target or Collaboration Program or, (ii) if the
                            breach involves a Collaboration Program prior to the applicable License Effective Date, 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 ARTICLE 1 prior to the date Biogen is granted a license under Section 4.1.1(a) or Section 4.1.1(b) (as applicable).

                      

              

            

            

            

            
              
                	

                      	(b)	
                        If Biogen, in Ionis’ reasonable determination, fails to use Commercially Reasonable Efforts under Section

                                5.1 with respect to a Collaboration Program, 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, 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 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:

                      

              

            

            

            

            
              116

              
                

            

            
              
                	

                      	(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.

                      

              

            

            

            

            
              
                	10.3.	
                        Alternative Remedies to Termination Available to Biogen Prior to 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 Collaboration Product under the applicable Collaboration Program or participate in the Neurology
                            JRC, the applicable Neurology JDC, 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 JRC, the applicable Neurology JDC, 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;

                      

              

            

            

            

            
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                      	(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(a)
                            for the applicable Collaboration Program;

                      

              

            

            

            

            
              
                	

                      	(d)	
                        Biogen may exclude Ionis from all discussions with Regulatory Authorities regarding the applicable Collaboration 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 Collaboration Products pursuant to this Agreement
                            (including pursuant to Section 4.8 and Section 5.2.7) will terminate, other than reports required by Section 6.14.1, Section 10.4.4 (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 Collaboration 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 Collaboration
                            Products in an efficient and orderly manner; and

                      

              

            

            

            

            
              
                	

                      	(g)	
                        If such Collaboration Program is not an ALS Collaboration Program 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 6.6 for the applicable Collaboration Product will be [***]. Such [***] will be due within 90 days after [***] and Biogen’s [***]. 

                         

                          

                        

                        The milestone provisions of Section 6.7 and the royalty provisions
                            of Section 6.10 will [***].

                      

              

            

            

            

            
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                	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 Biogen Alternate Modality Product or
                            Collaboration Product (as applicable) 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 for a surviving Product. 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)	
                        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.

                      

              

            

            

            

            
              
                	

                      	(c)	
                        Survival. The following provisions of this Agreement will survive
                            the expiration or termination of this Agreement: Section 1.9 (End of Research Term), Section

                                1.10.1(d) (End of ASO Development Candidate Identification Term), Section 2.1.1(f) (Failure to Defer or Designate a High Interest
                            Target a Collaboration Target or Biogen Alternate Modality Target), Section 3.1.3 (Option and Option Deadline) (but only with respect to Biogen’s
                            transfer obligations thereunder), Section 4.1.3 (Effect of Termination on Sublicenses), Section 4.2.2 (Grant Back to Ionis), Section 4.3.3
                            (Enabling License to Biogen), Section 4.3.4 (Enabling License to Ionis),
                            Section 4.4 (Licenses to Ionis for Biogen Results), Section 4.5 (Right to Obtain Direct License from Biogen to Ionis Partner;
                            Sublicensees of Ionis), Section 4.8.2 (Technology Transfer after License
                            Effective Date) (but only to the extent necessary to satisfy the requirements of Section 10.4.4), Section 6.12 (Reverse Royalty Payments to Biogen for a Discontinued Collaboration Product), Section 6.14.3 (Records
                            Retention), Section 6.15 (Audits), Section 7.1.1 (Ionis Technology and
                            Biogen Technology), Section 7.1.2 (Agreement Technology), 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 10.4.5 (Remedies Available to Biogen for Ionis’ Material Breach After 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).

                      

              

            

            

            

            
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                      	10.4.2.	
                        Natural Expiration. If this Agreement expires in accordance with Section 10.1.1 or Section 10.1.2, the following terms will apply to any
                            Biogen Alternate Modality Product or Collaboration Product (as applicable) that is the subject of such expiration:

                      

              

            

            

            

            
              
                	

                      	(a)	
                        Perpetual, Royalty-Free Non-Exclusive License. If Biogen has been
                            granted a license under Section 4.1.1(a) or Section 4.1.1(b) (as
                            applicable) for a particular Product, then upon expiration of the Biogen Alternate Modality Royalty Period or Reduced Royalty Period, as the case may be, in all countries in which the applicable Products are being or have been
                            sold, Ionis will and hereby does grant to Biogen a perpetual, non-exclusive, worldwide, royalty-free, fully paid-up, sublicensable license under the Ionis Know-How to Manufacture, Develop and Commercialize the applicable
                            Product.

                      

              

            

            

            

            
              
                	

                      	10.4.3.	
                        Termination Prior to License Effective Date. If this Agreement expires or is terminated by a Party
                            in accordance with this ARTICLE 10 before the License Effective Date for a particular Program, then, in addition to the terms set forth in Section 10.4.1, the following terms will apply to each Product, Neurology Target, High Interest Target or Collaboration Program that is the subject of such
                            expiration or termination:

                      

              

            

            

            

            
              
                	

                      	(a)	
                        Biogen’s right to designate High Interest Targets as Collaboration Targets or Biogen Alternate Modality Targets under this Agreement 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.

                      

              

            

            

            

            
              120

              
                

            

            
              
                	

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

                      

              

            

            

            

            
              
                	

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

                      

              

            

            

            

            
              
                	

                      	(d)	
                        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.

                      

              

            

            

            

            
              
                	

                      	(e)	
                        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 the License Effective Date for such Collaboration Program, then Biogen will
                            [***].

                      

              

            

            

            

            
              
                	

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

                      

              

            

            

            

            
              
                	

                      	(g)	
                        If Biogen terminates this Agreement for convenience with respect to a Collaboration Program that is not an ALS Collaboration Program or a Biogen Conducted Non-ALS
                            Collaboration Program, then solely with respect to such Collaboration Program:

                      

              

            

            

            

            
              
                	

                      	(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 Collaboration Product(s) solely as necessary to Develop, make, have made, use, sell, offer for sale, have sold, import and otherwise Commercialize
                            the applicable Discontinued Collaboration Product(s) in the Field (such license will be sublicensable by Ionis in accordance with Section 4.1.2, mutatis mutandis); and

                      

              

            

            

            

            
              121

              
                

            

            
              
                	

                      	(ii)	
                        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 IND and orphan drug designation that relate to the applicable Discontinued Collaboration Product(s), provided

                              that, (A) 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 (other than any Gene-Editing Product or messenger RNA) as an active pharmaceutical
                            ingredient, provided, further that, for such products that do not include such an Oligonucleotide as an active pharmaceutical ingredient,
                            such excerpts or portions shall not include any Confidential Information of Ionis, and (B) 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 (A) 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.

                      

              

            

            

            

            
              
                	

                      	(h)	
                        If Biogen terminates this Agreement for convenience with respect to an ALS Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program, then solely
                            with respect to such Collaboration Program:

                      

              

            

            

            

            
              122

              
                

            

            
              
                	

                      	(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 Collaboration Product(s) solely as necessary to Develop, make, have made, use, sell, offer for sale, have sold, import and otherwise Commercialize
                            the applicable Discontinued Collaboration Product(s) in the Field (such license will be sublicensable by Ionis in accordance with Section 4.1.2, mutatis mutandis);

                      

              

            

            

            

            
              
                	

                      	(ii)	
                        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 Collaboration 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
                            Collaboration 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(h)(i);

                      

              

            

            

            

            
              
                	

                      	(iii)	
                        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 IND and orphan drug designation that relate to the applicable Discontinued Collaboration 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 (other than any Gene-Editing Product or messenger RNA) as an active pharmaceutical
                            ingredient, provided, further that, for such products that do not include such 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; and

                      

              

            

            

            

            
              123

              
                

            

            
              
                	

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

                      

              

            

            

            

            
              
                	

                      	10.4.4.	
                        Termination After License Effective Date. If this Agreement is terminated by a Party in accordance with this ARTICLE 10
                            after the License Effective Date for a particular Product, then, in addition to the terms set forth in Section 10.4.1, the following terms will apply
                            to any Product or Collaboration Program that is the subject of such termination:

                      

              

            

            

            

            
              
                	

                      	(a)	
                        The applicable licenses granted by Ionis to Biogen under this Agreement will terminate. 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 10.4.6.

                      

              

            

            

            

            
              
                	

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

                      

              

            

            

            

            
              
                	

                      	(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 Products
                            and/or Collaboration Program(s):

                      

              

            

            

            

            
              124

              
                

            

            
              
                	

                      	(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 Collaboration Product(s) solely as necessary to Develop, make, have made, use, sell, offer for sale, have sold, import and otherwise Commercialize
                            the applicable Discontinued Collaboration Product(s) in the Field (such license will be sublicensable by Ionis in accordance with Section 4.1.2, mutatis mutandis);

                      

              

            

            

            

            
              
                	

                      	(ii)	
                        Within [***] days following the date of the termination, Biogen will assign back to Ionis any Product-Specific Patent Rights and Ionis’ interest in any Program
                            Patents that relate to the applicable Biogen Alternate Modality Product(s) and/or Discontinued Collaboration 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 solely for use with respect to the Development and Commercialization of the
                            applicable Discontinued Collaboration 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
                            Collaboration 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 10.4.4(d)(i), except as otherwise provided in Section 10.4.4(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;

                      

              

            

            

            

            
              125

              
                

            

            
              
                	

                      	(v)	
                        Biogen will, and does hereby, exclusively license to Ionis any trademarks that are specific to a Discontinued Collaboration Product(s) solely for use with such
                            Discontinued Collaboration Product(s), in accordance with Section 4.1.6, mutatis mutandis; provided, however, 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 Product
                            and/or 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, 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 6.12 with
                            respect to the applicable Discontinued Collaboration Product(s).  Such payments will be governed by the financial provisions in Section 6.14, and the
                            definition of Net Sales will apply to sales of Discontinued Collaboration Product(s) by Ionis, in each case mutatis mutandis.

                      

              

            

            

            

            
              126

              
                

            

            
              
                	

                      	(e)	
                        With respect to Discontinued Collaboration Products, if Ionis terminates this Agreement due to Biogen’s material breach or Biogen terminates this Agreement for
                            convenience, 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
                            Collaboration Products and identified by Ionis to which Biogen is a party.

                      

              

            

            

            

            
              
                	

                      	(g)	
                        If Biogen under Section 10.2.1 or Section 10.2.2 voluntarily terminates its license under Section 4.1.1(b) with respect to a High Interest Target Biogen
                            designated as a Biogen Alternate Modality Target then Section 2.1.1(f) will apply.

                      

              

            

            

            

            
              
                	

                      	10.4.5.	
                        Remedies Available to Biogen for Ionis’ Material Breach After License Effective Date.

                      

              

            

            

            

            
              
                	

                      	(a)	
                        Termination of Committees and Information Sharing. If, after the
                            License Effective Date with respect to 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 CSC, Neurology JRC, the applicable Neurology JDC, 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;

                      

              

            

            

            

            
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                      	(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 Collaboration 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
                            Collaboration Products, including pursuant to Section 4.8 and Section 5.2.7, other than reports required by Section 6.14.1, Section 10.4.4 (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 ASO Development Candidate Identification Plan and Initial
                            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.

                      

              

            

            

            

            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.

            

            

            
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                      	(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 Ionis Breach Event
                            [***] (the “Setoff Amount”). If Biogen exercises its setoff right under this Section 10.4.5(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 10.4.5(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 10.4.5(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 10.4.5(b) the Advisory Panel will determine (1) 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 (2) 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 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 Ionis the amount of such
                            excess, plus interest on such amount as provided for in Section 6.17 (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: (X) appoint a member of the Advisory Panel to the extent required in
                            Section 2 of Schedule 10.4.5(b); (Y) meet with
                            the Advisory Panel as required in Section 3 of Schedule
                                10.4.5(b); or (Z) 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 10.4.5(b) and Schedule 10.4.5(b) with respect to any and all Setoff Disputes.

                      

              

            

            

            

            
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                      	10.4.6.	
                        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 (Remedies for Failure to Use Commercially Reasonable Efforts) with respect to one or more Products, the terms of this Section 10.4.6 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 the termination of the applicable
                            Product. As such, Ionis may request Biogen perform transition services as listed on Schedule 10.4.6 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 the
                            termination of this Agreement with respect to the applicable Product, transition the responsibilities under all Approvals and ongoing Clinical Studies for the applicable Product to Ionis or its designee and (iii) following
                            termination of this Agreement with respect to the applicable Collaboration Target, 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 10.4.6(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 10.4.6(b), 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 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 10.4.6, 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 10.4.6 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: (i) 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; (ii) 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; (iii) 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; (iv) 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 (v) 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 Initial Development Plan for any Collaboration Program for which Biogen has not yet been granted a license under Section 4.1.1(a)
                            or Section 4.1.1(b) (as applicable) with respect to a Product, the Neurology JDC for such Collaboration Program 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 (a) 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 and (b) if the applicable Neurology JDC cannot
                            agree upon the designation of a Communications Lead, such matter shall be submitted to the CSC for resolution. 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.

                      

              

            

            

            

            
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                      	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.

                      

              

            

            

            

            
              
                	

                      	11.4.5.	
                        Prior to License Grant. Prior to the date Biogen has been granted a
                            license under Section 4.1.1(a) or Section 4.1.1(b) (as applicable) 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 1.10.2(d) 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, (i) Ionis will submit such proposed communication to Biogen for review at least two Business Days in advance of such proposed public disclosure, (ii) Biogen will have the right to review and recommend changes to such
                            communication, and (iii) 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(a) or Section 4.1.1(b) (as applicable) 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 License Grant. After the date Biogen has been granted a
                            license under Section 4.1.1(a) or Section 4.1.1(b) (as applicable) 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 CSC 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 CSC 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 Collaboration 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 Collaboration Product, the Parties acknowledge that scientific
                            lead time is a key element of the value of the Collaboration 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(a) or Section 4.1.1(b) (as applicable) 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(a) or Section 4.1.1(b)
                            (as applicable) 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 11.4.7 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 11.4.7 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 11.4.7 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.

                      

              

            

            

            

            
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                      	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.

                      

              

            

            

            

            
              
                	

                      	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 Collaboration 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.

                      

              

            

            

            

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

                      

              

            

            

            

            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 Operating 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 CSC 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 CSC 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 10.4.5(b) and Schedule 10.4.5(b).

                      

              

            

            

            

            
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                      	12.1.4.	
                        Expert Resolution. In the event that a matter is referred for expert resolution under this Section 12.1.4 pursuant to Section 1.10.2(d) or under Appendix 3, the matter
                            will be resolved by a panel of three (3) industry experts experienced in the issues comprising such dispute.  One expert will be chosen by Ionis, one expert will be chosen by Biogen and the third expert will be chosen by mutual
                            agreement of the experts chosen by Ionis and Biogen.  The place of such expert resolution will be in Chicago, Illinois. Within [***] days after the selection of the third expert (which will occur not later than [***] days after
                            a Party notifies the other Party that it elects to have a dispute resolved pursuant to this Section 12.1.4), the Parties will each simultaneously
                            submit to the expert panel and one another a written statement of their respective positions on the relevant dispute.  Each Party will have [***] days from receipt of the other Party’s submission to submit a written response
                            thereto, which will include any scientific and technical information in support thereof.  The expert panel will conduct at least one hearing at which each Party will have the opportunity to advocate its position before the other
                            Party and the expert panel.  The expert panel will have the right to further meet with both Parties together, as necessary to make a determination.  There will be no ex parte communications between an individual Party and either the expert panel or one or more experts.  All documents submitted will be in the English language.  Further, the expert panel will have
                            the right to request information and materials and to require and facilitate discovery as it will determine is appropriate in the circumstances, taking into account the needs of the Parties and the desirability of making
                            discovery expeditious and cost-effective determinations.  No later than 90 days after the designation of the third expert or as otherwise agreed by the Parties, the expert panel will make a determination.  The expert panel will
                            provide the Parties with a written statement setting forth the basis of the determination in connection therewith.  The decision of the expert panel will be final, binding and conclusive, absent manifest error.  Each Party will
                            bear its attorneys’ fees, costs and disbursements (including, for example, expert witness fees and expenses, photocopy charges, travel expenses, etc.) and the Parties will share equally (50/50) the fees and costs of the expert
                            panel.  Judgment upon any award rendered pursuant to this Section 12.1.4 may be entered by any court having jurisdiction over the Parties’ assets. 
                            Except to the extent necessary to confirm or enforce an award or as may be required by law, neither Party nor any of the experts may disclose the existence, content or results of any proceeding under this Section 12.1.4 without the prior written consent of both Parties.

                      

              

            

            

            

            
              
                	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.

                      

              

            

            

            

            
              139

              
                

            

            
              
                	

                      	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.

                      

              

            

            

            

            
              
                	

                      	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 6.13.3(c)).  Except for the offsets and credits explicitly set forth in
                            Section 1.8.3, Section 6.15, Section 6.13.3(b), Section 6.13.3(d) and Section

                                10.4.5(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.

                      

              

            

            

            

            
              140

              
                

            

            
              
                	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,
                            if Biogen transfers or assigns this Agreement to [***] described in this Agreement, then Biogen (or such Affiliate), will [***] due Ionis under ARTICLE 6
                            for the [***] 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 [***], Ionis will provide Biogen with Ionis’ Annual tax returns (federal and state) and, in years in which Ionis utilizes [***], supporting documentation
                for such [***]. Notwithstanding the foregoing, if the [***].

            

            

            
              
                	12.5.	
                        Change of Control.

                      

              

            

            

            

            
              
                	

                      	12.5.1.	
                        Research Activities. If, at any time during the Research Term, a Change of Control of Ionis occurs, then at any time prior to the [***] anniversary of the closing of such Change of Control, upon written
                            notice to Ionis, Biogen may either:

                      

              

            

            

            

            
              
                	

                      	(a)	
                        Extend the Research Term until such time as Ionis has completed target validating activities that are Ionis Activities under the Neurological Disease Research Plan
                            for a total of [***] High Interest Targets;

                      

              

            

            

            

            
              141

              
                

            

            
              
                	

                      	(b)	
                        Terminate the Research Term, in which case: (i) Ionis will complete all ongoing target validation work that are Ionis Activities under the Neurological Disease
                            Research Plan and advance each such target to Target Sanction (but for clarity, no target validation work will be initiated for any new target under the Neurological Disease Research Plan); (ii) Ionis will complete all ongoing
                            Ionis Activities under the Core Research Plan (but for clarity, no new work will be initiated under the Core Research Plan); (iii) for each Collaboration Target that is not an ALS Target that reaches Target Sanction or each ALS
                            Target designated a Collaboration Target, an ASO Development Candidate Identification Plan will be prepared and Ionis will carry out its obligations under such plan, all in accordance with Section 1.10.1; (iv) Ionis will continue to perform its obligations under each ongoing ASO Development Candidate Identification Plan until the end of the applicable ASO
                            Development Candidate Identification Term and under each ongoing Initial Development Plan until completion of all Ionis Activities thereunder; (v) for each Collaboration Program for which a Development Candidate is identified as
                            provided herein, Biogen may, upon written notice to Ionis, such notice to be delivered within [***] days after designating a Development Candidate for the applicable Collaboration Program, elect to either (A) exercise the
                            applicable Option by notifying Ionis in writing of Biogen’s election to license the Collaboration Product [***] and will be paid to Ionis within [***] days after Biogen’s election under clause (A) of this Section 12.5.1(b), and after such exercise, Biogen will not be obligated [***], or (B) establish an Initial Development Plan for such Collaboration Program
                            pursuant to Section 1.10.2(d), in which case Ionis and Biogen will continue to exercise their rights and perform their respective obligations with
                            respect to the applicable Collaboration Program under the terms of this Agreement; (vi) the Research Term will end upon Ionis’ completion of all Ionis Activities under clauses (i), (ii) and (iii) above; and (vii) within [***]
                            days after the end of the Research Term, Ionis will [***]; or

                      

              

            

            

            

            
              
                	

                      	(c)	
                        Allow such [***] period to lapse without providing any such notice of election under this Section
                                12.5.1, in which case Ionis and Biogen will continue to exercise their rights and perform their respective obligations under the terms of this Agreement.

                      

              

            

            

            

            
              
                	

                      	12.5.2.	
                        Pre-Existing Competitive Collaboration 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 Collaboration Product within the Field (such pre-existing Competitive Collaboration Products
                            and Competitive Indication Products, each, a “Pre-Existing Competitive Collaboration Product”) or (B) is engaged in a (1) Competitive Collaboration Program or (2) Competitive Indication Program (such pre-existing Competitive
                            Collaboration Programs and Competitive Indication Collaboration Programs, each, a “Pre-Existing Competitive Collaboration
                              Program,” and such Person being hereinafter referred to as a “Competing Collaboration Acquirer”), then in each
                            case ((A) and (B)):

                      

              

            

            

            

            
              142

              
                

            

            
              
                	

                      	(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 Collaboration Product or Pre-Existing Competitive Collaboration 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 Collaboration Competitive Product(s) and
                            Pre-Existing Competitive Collaboration Program(s);

                      

              

            

            

            

            
              
                	

                      	(d)	
                        the research, development, manufacture or commercialization of any Pre-Existing Competitive Collaboration 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 12.5.3(a) will not apply to any such Pre-Existing Competitive
                            Collaboration Product or Pre-Existing Competitive Collaboration Program; provided that the conditions of Section 12.5.2(a) and Section 12.5.2(c) are satisfied.

                      

              

            

            

            

            
              
                	

                      	12.5.3.	
                        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 Collaboration Product within the Field or is engaged in a Competitive Collaboration
                            Program, in each case that would violate the provisions of ARTICLE 2 if conducted by such Party (such acquired Competitive Collaboration Product an “Acquired Competitive Product” and such acquired Competitive Collaboration 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 12.5.3(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 12.5.3(a)(i) through 12.5.3(a)(iv) are met:

                      

              

            

            

            

            
              143

              
                

            

            
              
                	

                      	(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 12.5.3(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 [***].

                      

              

            

            

            

            
              144

              
                

            

            
              
                	

                      	(c)	
                        In addition, without limiting Section 12.5.3(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
                            Collaboration Product, or (B) is engaged in [***] (an “Associated Program”) or a Competitive Indication Collaboration
                            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 Collaboration Product or Competitive Collaboration Program is
                            directed and with respect to any Collaboration Program intended for the same indication as the Competitive Indication Collaboration Product or the Competitive Indication Collaboration 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 Collaboration Product, Competitive Collaboration Program,
                            Competitive Indication Collaboration Product or Competitive Indication Collaboration Program.

                      

              

            

            

            

            
              
                	

                      	12.5.4.	
                        Biogen Alternate Modality Programs. On a Biogen Alternate Modality Product-by-Biogen Alternate Modality Product basis, if, at any time during the Agreement Term, a Change of Control occurs involving
                            Ionis and a Person that, at the time of the closing of such Change of Control, is developing in human clinical trials or commercializing a Directly Competitive Biogen Alternate Modality Product within the Field or is engaged in
                            a Directly Competitive Biogen Alternate Modality Program or, at any time during the Agreement Term after such closing of the Change of Control, develops or acquires a Directly Competitive Biogen Alternate Modality Product or
                            begins a Directly Competitive Biogen Alternate Modality Program (such Person being hereinafter referred to as a “Competing
                              Alternate Modality Acquirer”) and such Competing Alternate Modality Acquirer has not, within [***] of either (i) closing of the Change of Control in the event the Directly Competitive Biogen Alternate Modality Product
                            is being developed in human clinical trials or commercialized, or the Directly Competitive Biogen Alternate Modality Program exists, as of such closing date or (ii) the date of first development or acquisition of such Directly
                            Competitive Biogen Alternate Modality Product or the date on which such Competing Alternate Modality Acquirer begins such Directly Competitive Biogen Alternate Modality Program (the “Alternate Modality Divestiture Period”) divested itself of the Directly Competitive Biogen Alternate Modality Product or Directly Competitive Biogen Alternate
                            Modality Program, terminated development and commercialization of such Directly Competitive Biogen Alternate Modality Product or such Biogen Alternate Modality Program or assigned this Agreement pursuant to Section 12.4 to a Third Party that is not itself developing or commercializing a Directly Competitive Collaboration Product or engaged in a Directly
                            Competitive Biogen Alternate Modality Program, then (i) Ionis will provide written notice to Biogen of the closing of such Change of Control or Alternate Modality Divestiture Period, as applicable, and (ii) [***].  For clarity,
                            Biogen’s rights as set forth in this Section 12.5.4 shall be Biogen’s exclusive remedies for the failure of a Competing Alternate Modality Acquirer to
                            divest or terminate development and commercialization of a Directly Competitive Biogen Alternate Modality Product or Directly Competitive Collaboration Program or assigned this Agreement to an applicable Third Party, in each
                            case, during the Alternate Modality Divestiture Period in accordance with this Section 12.5.4.

                      

              

            

            

            

            
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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 or Competing Alternate Modality 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 Collaboration Product, Competitive Collaboration Program, Directly Competitive Biogen Alternate Modality Product or Directly Competitive
                            Biogen Alternate Modality 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
                            or Competing Alternate Modality 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 Collaboration Product or Directly Competitive Biogen Alternate Modality 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 Operating 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: Mark Bellomy, Esq.

                  
	 	
                    Email: mark.bellomy@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.

            

            

            
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                	12.9.	
                        Export Clause. Each Party acknowledges that the Laws 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.

                      

              

            

            

            

            
              
                	12.10.	
                        Waiver. Neither Party may waive or release any of its rights or
                            interest 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 ALS Letter Agreement), amends and restates the First Amended and Restated Agreement, is a comprehensive and integrated statement of the agreement between the Parties with respect to the subject
                            matter hereof and fully supersedes the the First Amended and Restated Agreement for the period commencing on the Second Amendment Date and continuing thereafter. 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. 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.

                      

              

            

            

            

            
              148

              
                

            

            
              
                	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, (h) unless otherwise specified, “$” is in reference to United States dollars and (i) 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.

                      

              

            

            

            

            
              
                	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 GAAP (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.

                      

              

            

            

            

            
              149

              
                

            

            
              
                	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 and good laboratory and clinical practices and cGMP in exercising its rights and fulfilling its obligations under this Agreement.

                      

              

            

            

            

            [SIGNATURE PAGE FOLLOWS]

            

            

            * - * - * - *

            

            

            
              150

              
                

            

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

            

            

            	
                    BIOGEN MA INC.

                  
	 
	
                    By:

                  	
                    /s/ Michael Ehlers

                  	 
	
                    Name: Michael Ehlers

                  
	
                    Title: EVP, Research & Development

                  

            
               

              

              Signature Page to Second Amended and Restated Strategic Neurology Drug Discovery and Development Collaboration,
                Option and License Agreement

               

              

            

            
              
                

            

            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 P. Monia

                  	 

            	
                    Name:

                  	
                     Brett P. Monia

                  	 

            	
                    Title:

                  	
                    Chief Operating Officer/SVP Translational Medicine

                  	 

            
               

              

              Signature Page to Second Amended and Restated Strategic Neurology Drug Discovery and Development Collaboration,
                Option and License Agreement

              

              

            

            
              
                

            

            List of Appendices and Schedules

            

            

            Appendix 1 – Definitions

            

            

            Appendix 2 – Development Candidate Checklist

            

            

            Appendix 3 – Multi-Indication Target Process

            

            

            Appendix 4 – Form of Side Letter

            

            

            Schedule 1.1.4 – Biogen Conducted Non-ALS
                Targets

            

            

            Schedule 1.2.4 – Terms and Conditions for
                Provision of Research ASOs to Biogen

            

            

            Schedule 1.6.1 – ALS Letter Agreement

            

            

            Schedule 1.10.2(c) – Ionis’ Standard IND-Enabling Toxicology Studies

            

            

            Schedule 1.10.2(d) – Initial Development Plan Requirements

            

            

            Schedule 1.10.2(d)(v) – Study Synopsis Requirements

            

            

            Schedule 1.10.2(e) – Apportionment of Certain Milestone Payments and Biogen-Approved Costs

            

            

            Schedule 1.10.6 – Ionis API Supply for ALS
                Collaboration Programs and Biogen Conducted Non-ALS Collaboration Programs

            

            

            Schedule 1.18.1 – Collaboration Steering Committee Governance

            

            

            Schedule 1.18.2 – Neurology JRC Governance

            

            

            Schedule 1.18.3 – Neurology JDC Governance

            

            

            Schedule 1.18.6 – Alliance Management
                Activities

            

            

            Schedule 4.3.1(a) – Drug Substance Process and Formulation Development Activities

            

            

            Schedule 4.8.2(c) – Ionis’ Fully Absorbed Cost of Goods Methodology

            

            

            Schedule 5.1.4 – Biogen’s Development and Commercialization Activities

            

            

            Schedule 5.1.6 – Integrated Development Plan
                Content

            

            

            Schedule 6.10.2(e) – Royalty Calculation Examples

            

            

            Schedule 6.10.2(f) – Allocation of Net Sales

            

            

            Schedule 6.13.1 – 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 10.4.5(b) – Advisory Panel Regarding Setoff Disputes

            

            

            Schedule 10.4.6 – Transition Services

            

            

            Schedule 12.1.2 – Mediation

            

            

            Schedule 12.5 – Applicable License Fee Payments in Change of Control for Collaboration Products, and [***]

            

            

            
              153

              
                

            

            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 1.8.4.

            

            

            “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 European 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 12.5.3(a).

            

            

            “Acquired Competitive Program” has the
                meaning set forth in Section 12.5.3(a).

            

            

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

            

            

            “Actual Biogen-Approved Costs” has the
                meaning set forth in Section 1.14.1(e).

            

            

            “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 [***].

            

            

            “Advisory Panel” has the meaning in Schedule 10.4.5(b) of this Agreement.

            

            

            “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 (i) 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 (ii) 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.

            

            

            
              154

              
                

            

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

            

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

            

            

            “Alliance Manager” has the meaning set
                forth in Section 1.18.6.

            

            

            “ALS” means the disease amyotrophic
                lateral sclerosis.

            

            

            “ALS Collaboration Program” means a
                Collaboration Program focused on an ALS Target.

            

            

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

            

            

            “ALS Pre-Licensing Milestone Event” has
                the meaning set forth in Section 6.5.

            

            

            “ALS Target” means the initial
                ALS-associated High Interest Targets identified as ALS Targets on Schedule
                    1.2.3(a) on the Effective Date, plus any ALS-associated High Interest Target that is designated as an ALS Target in accordance with Section 1.2.3(a).

            

            

            “ALS Target List” means the list of
                ALS-associated High Interest Targets identified as ALS Targets on the High Interest Target List.  For clarity, at any given time, if a gene target is not on the ALS Target List at such time, then such gene target is not an ALS Target.

            

            

            “Alternate Modality” means a
                therapeutic approach for a gene target that is not an Oligonucleotide approach.

            

            

            “Alternate Modality Divestiture Period”
                has the meaning set forth in Section 12.5.4.

            

            

            “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 Collaboration 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.

            

            

            
              155

              
                

            

            “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.

            

            

            “ASO Development Candidate Identification
                  Plan” has the meaning set forth in Section 1.10.1(a).

            

            

            “ASO Development Candidate Identification
                  Term” has the meaning set forth in Section 1.10.1(b).

            

            

            “Associated Product” has the meaning
                set forth in Section 12.5.3(c).

            

            

            “Associated Program” has the meaning
                set forth in Section 12.5.3(c).

            

            

            “Audit Report” has the meaning set
                forth in Section 6.15.

            

            

            “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.

            

            

            “Biogen Activities” means, under any
                Neurology 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 Neurology Plan it approves.

            

            

            “Biogen Alternate Modality Milestone Event”
                has the meaning set forth in Section 6.3.

            

            

            “Biogen Alternate Modality Product”
                means a finished drug product that contains a molecule that is (i) not an Oligonucleotide, (ii) designed to bind, mimic or otherwise affect a protein or RNA that is encoded by a Biogen Alternate Modality Target, and (iii) discovered by
                Biogen or its Affiliates or any Third Party acting on their behalf.

            

            

            “Biogen Alternate Modality Program”
                means a program to discover, Develop, Manufacture and Commercialize a Biogen Alternate Modality Product.

            

            

            
              156

              
                

            

            “Biogen Alternate Modality Royalty”
                has the meaning set forth in Section 6.9.1.

            

            

            “Biogen Alternate Modality Royalty Period”
                has the meaning set forth in Section 6.9.2.

            

            

            “Biogen Alternate Modality Target” is
                either (i) a High Interest Target that is designated as a Biogen Alternate Modality Target under Section 1.3, Section 1.4 or Section 1.8, (ii) a Collaboration Target that is changed to a Biogen Alternate Modality Target under Section 3.2.2, or (v) a Collaboration Target that is added as a Biogen Alternate Modality Target under Section 3.2.4.2.

                  

            

            

            “Biogen-Approved Changes” means any
                changes (including number of subjects, duration of dosing, additional studies, additional endpoints, additional analysis, etc.) to the applicable Neurology Plan for a Product that are requested by either Party after the Parties have set the
                initial Cost Estimates for such Neurology Plan under Section 1.10.2(e), 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 1.14.1

            

            

            “Biogen Conducted Non-ALS Collaboration
                  Program” means a Collaboration Program focused on a Biogen Conducted Non-ALS Target.

            

            

            “Biogen Conducted Non-ALS Option Deadline” has the meaning set forth in Section 3.1.3.

            

            

            “Biogen Conducted Non-ALS Target”
                means each of the High Interest Targets listed on Schedule 1.1.4, which may be updated by mutual written agreement of the Parties to
                include additional High Interest Targets relating to [***].

            

            

            “Biogen Full Royalty” has the meaning
                set forth in Section 6.10.1.

            

            

            “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 Patents”
                has the meaning set forth in Section 4.8.3.

            

            

            “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 7.2.5(c).

            

            

            
              157

              
                

            

            “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 to [***], other than (i) reports required by Section 5.2.7, Section 6.14.1 and Section
                    10.4.4 (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.

            

            

            “Biogen Reduced Royalty” has the
                meaning set forth in Section 6.10.2(c).

            

            

            “Biogen Results” has the meaning set
                forth in Section 4.8.3.

            

            

            “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 4.1.6, owned, used, developed by, or
                licensed to Biogen or its Affiliates that is necessary or useful to Develop, register, Manufacture or Commercialize a Product.

            

            

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

            

            

            “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 2013, the Effective Date) and ending on December 31.

            

            

            “Carryover Development Candidate” has
                the meaning set forth in Section 1.10.1(e).

            

            

            “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.

            

            

            
              158

              
                

            

            “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
                such Party’s outstanding securities, (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 its 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.

            

            

            “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 Collaboration Product for use in a Clinical Study.

            

            

            “CMC” has the meaning set forth in Section 1.13.1(c).

            

            

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

            

            

            “Collaboration” means the conduct of
                the Neurology Plans in accordance with this Agreement.

            

            

            “Collaboration Divestiture Period” has
                the meaning set forth in Section 12.5.3(a)(ii).

            

            

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

            

            

            “Collaboration Program” has the
                meaning set forth in Section 1.6.1.

            

            

            “Collaboration Target” means a gene
                target for which the Parties wish to start an ASO drug discovery program that is either (i) a High Interest Target that is not an ALS Target and is designated as a Collaboration Target under Section 1.3 or Section 1.8, (ii) an ALS Target designated as a Collaboration Target under Section 1.5, (iii) an Ionis Neurology Target designated as a Collaboration Target under Section 1.4, (iv) a
                Biogen Alternate Modality Target that is changed to a Collaboration Target under Section 3.2.1, or (v) a Neurology Target that is added as a Collaboration Target
                under Section 3.2.4(a).  As of the Effective Date SOD-1 is a Collaboration Target that is an ALS Target and is not a Multi-Indication Target.

            

            

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

            

            

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

            

            

            
              159

              
                

            

            “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 Collaboration 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 (i) any Biogen Activities in a Neurology Plan, and (ii) the “General Activities” described in Schedule 5.1.4, 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 Neurology Plan.

            

            

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

            

            

            “Competing Alternate Modality Acquirer”
                has the meaning set forth in Section 12.5.4.

            

            

            “Competing Collaboration Acquirer” has
                the meaning set forth in Section 12.5.2.

            

            

            “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 Collaboration 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.

            

            

            
              160

              
                

            

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

            

            

            “Competitive Collaboration 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 Collaboration Product for which drug discovery
                activities have been initiated.

            

            

            “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 any Neurology Plan, including each
                Development Candidate under any 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;

                      

              

            

            

            

            
              
                	

                      	(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 7.2.5(d).

            

            

            “Contracting Party” has the meaning
                set forth in Section 1.10.7.

            

            

            “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 applicable Third Party Compensation. Notwithstanding anything to the contrary under this Agreement, with respect
                to any Third Party acquirer of a Party that becomes an Affiliate of a Party after the Effective Date, no intellectual property of such Third Party acquirer will be included in the licenses granted hereunder by virtue of such Third Party
                becoming an Affiliate of such Party.

            

            

            
              161

              
                

            

            “Core Research Plan” has the meaning
                set forth in Section 1.2.

            

            

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

            

            

            “Cost Estimate” has the meaning set
                forth in Section 1.10.2(e).

            

            

            “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.

            

            

            “CSC” has the meaning set forth in Section 1.18.1.

            

            

            “CTD” has the meaning set forth in Section 4.4.

            

            

            “Deferral Notice” has the meaning set
                forth in Section 1.8.1.

            

            

            “Deferral Period” has the meaning set
                forth in Section 1.8.1.

            

            

            “Deferred Target” has the meaning set
                forth in Section 1.8.1.

            

            

            “Deferred Target Development Candidate” means a Development Candidate identified in accordance with Section 1.8.4.

            

            

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

            

            

            “Design Notice” has the meaning set
                forth in Section 6.2.1.

            

            

            “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 such 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 such Product to seek Approval for additional indications
                for such Product.

            

            

            “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; provided, however, that with respect to any Primarily Neuro Multi-Indication Target, such Compound will be reasonably selected by Biogen (giving good faith consideration to the input of
                Ionis’ representatives on the Neurology JRC) as a Development Candidate from the body of work Ionis used to determine the applicable Compound Ionis believes is 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.

            

            

            
              162

              
                

            

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

            

            

            “Diagnostic Option” has the meaning
                set forth in Section 3.3.1.

            

            

            “Directly Competitive Biogen Alternate
                  Modality Product” means with respect to a Biogen Alternate Modality Product, a product designed to bind to or directly modulate the Biogen Alternate Modality Target targeted by such Biogen Alternate Modality Program, other than a
                Biogen Alternate Modality Product that is being pursued under this Agreement.

            

            

            “Directly Competitive Biogen Alternate
                  Modality Program” means any internal research program for which [***] or [***], with the goal of discovering and developing a Directly Competitive Biogen Alternate Modality Product for which drug discovery activities have been
                initiated.

            

            

            “Directly Competitive Collaboration Product”
                means with respect to a Collaboration Product, any product, other than such Collaboration Product, that is designed to bind to or directly modulate the Collaboration Target targeted by such Collaboration Product.

            

            

            “Directly Competitive Collaboration Program”
                means any internal research program for which [***] or [***], with the goal of discovering and developing a Directly Competitive Collaboration Product for which drug discovery activities have been initiated.

            

            

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

            

            

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

            

            

            “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 completion of the first Phase 2 PoC Trial under a Collaboration Program in accordance with the applicable Initial Development Plan for all Collaboration
                Programs under this Agreement.

            

            

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

            

            

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

            

            

            
              163

              
                

            

            “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.

            

            

            “Equal Multi-Indication Target” has
                the meaning set forth in Appendix 3.

            

            

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

            

            

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

            

            

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

            

            

            “Excluded Payments” means (i) royalty
                or profit sharing payments, or any other type of payment based on periodic sales of a Collaboration Product or Deferred Target Development Candidate; (ii) payments made in consideration of Ionis’ or Ionis’ Affiliate’s equity or debt
                securities at fair market value; (iii) payments made to pay for or reimburse Ionis or Ionis’ Affiliate for the fully-burdened cost of research and development; (iv) payments made to pay for or reimburse Ionis or Ionis’ Affiliate for the
                cost of prosecuting, maintaining or defending Patent Rights; and (v) 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.

            

            

            “[***]” means any form of the [***].

            

            

            “[***] Collaboration Program” means an
                [***] Collaboration Program solely and exclusively focused on [***].

            

            

            “Field” means, except as may be
                limited under Section 4.1.5, 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 Amended and Restated Agreement” has the meaning set forth in the Preamble of this Agreement.

            

            

            
              164

              
                

            

            “First Amendment Date” has the meaning set forth in the Preamble of 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 2.2.1.

            

            

            “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 2.2.1.

            

            

            “Follow-On Negotiation Notice” has the
                meaning set forth in Section 2.2.1.

            

            

            “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 1.14.1.

            

            

            “FTE Rate” means $[***] for the
                Calendar Year 2013. The FTE Rate will be increased each Calendar Year thereafter by the [***].

            

            

            “Full Royalty Period” has the meaning
                set forth in Section 6.10.2(a).

            

            

            “Fully Absorbed Cost of Goods” means
                the costs incurred by Ionis as determined using the methodology set forth in Schedule 4.8.2(c) fairly applied and as employed on a consistent basis throughout Ionis’ operations.

            

            

            “GAAP” means generally accepted
                accounting principles in the United States, consistently applied.

            

            

            “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 Collaboration Product, one or more Third Party product(s) (i) having the same active pharmaceutical ingredient as such
                Collaboration Product and for which in the U.S. an ANDA has been filed naming such Collaboration Product as the reference listed drug or outside of the U.S., an equivalent process where bioequivalence to such Collaboration Product has been
                asserted, and (ii) 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 Collaboration Product taken in the aggregate, as provided by IMS) during the applicable Calendar Quarter in such country of at least [***]%.

            

            

            
              165

              
                

            

            “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 1.2.3(a).  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 List” has the
                meaning set forth in Section 1.2.3(a).

            

            

            “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.

            

            

            “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.

            

            

            “Initial Development Plan” has the
                meaning set forth in Section 1.10.2(d).

            

            

            “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 5.1.6.

            

            

            
              166

              
                

            

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

            

            

            “Ionis Activities” means the research,
                pre-clinical and/or clinical activities for which Ionis is designated as responsible under any Neurology Plan.

            

            

            “Ionis Activities Data” has the
                meaning set forth in Section 1.10.2(d)(i).

            

            

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

            

            

            “Ionis/Biogen Additional Agreements” means the (i) SMN Agreement, (ii) DMPK Agreement, (iii) the Neurology Drug Discovery and Development Collaboration, Option and License Agreement between the Parties dated December 10, 2012, (iv) the Research Collaboration, Option and License Agreement between the
                Parties dated December 19, 2017 and (v) the Neurology III Agreement, in each case, as amended and/or restated from time to time

            

            

            “Ionis Breach Event” has the meaning
                set forth in Section 10.4.5(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 6.13.1(a).

            

            

            “Ionis Internal ASO Safety Database”
                has the meaning set forth in Section 5.2.7.

            

            

            “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 they related to ASOs 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.

            

            

            
              167

              
                

            

            “Ionis Multi-Indication Compound” has
                the meaning set forth in Appendix 3.

            

            

            “Ionis Neurology Target” means a
                Neurology Target that (1) is not (i) a High Interest Target for which target validating activities are planned under the then-current Neurological Disease Research Plan, (ii) an ALS Target, (iii) a Collaboration Target, or (iv) a Biogen
                Alternate Modality Target and (2) has a Neurological Disease as its primary disease association.

            

            

            “Ionis Non-Exclusive Product” has the
                meaning set forth in Section 2.1.1(c).

            

            

            “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.

            

            

            “Ionis Results” has the meaning set
                forth in Section 4.8.3.

            

            

            “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, and in each case that are unpatented.

            

            

            
              168

              
                

            

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

            

            

            “License Effective Date” means, on an
                Option-by-Option and Program-by-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 6.6 (in the event Biogen wishes to exercise its Option for a Collaboration Program) or Section 6.2.2  (in the event Biogen wishes to exercise its Option for a Biogen Alternate Modality Program) for
                such 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.  For clarity, Licensed Patents that are jointly-owned by Ionis and Biogen will count toward the calculation of the Full Royalty
                Period in a particular country if the use or sale of a Product by an unauthorized Third Party in such country would infringe a Valid Claim of such Licensed Patent.

            

            

            “Licensed Technology” means, on a 
                Program-by- Program basis, any and all Licensed Patents, Licensed Know-How, and any trademarks described in Section 4.1.6, 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.

            

            

            “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 the bulk active
                pharmaceutical ingredient for a Biogen Alternate Modality Product, or a Collaboration Product or Biogen Alternate Modality Product in finished form.

            

            

            “Manufacturing Process Development Terms”
                means Section 4.1.3(b), Section 4.3.1(a), Section 4.3.2, Section 4.4, Section 4.5, Section 4.7.2 and Section

                  4.8.3 of this Agreement.

            

            

            
              169

              
                

            

            “Measurement Period” has the meaning
                set forth in Section 1.14.1(c) or Section 1.14.1(d), as applicable.

            

            

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

            

            

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

            

            

            “[***]” means a disease that has, as
                its [***].

            

            

            “Multi-Indication Product” means a
                product for a Non-Neurological Indication associated with a Multi-Indication Target.

            

            

            “Multi-Indication Product-Specific Patent”
                has the meaning set forth in Section 7.2.4.

            

            

            “Multi-Indication Target” has the
                meaning set forth in Section 1.2.3(b).

            

            

            “Multi-Indication Target Notice” has
                the meaning set forth in Section 1.2.3(b).

            

            

            “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 2.2.2.

            

            

            “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 (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 Affiliate 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 will 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.

            

            

            
              170

              
                

            

            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.

            

            

            “Neurological Disease Research Plan”
                has the meaning set forth in Section 1.2.

            

            

            “Neurological Disease Research Program”
                has the meaning set forth in Section 1.2.

            

            

            “Neurology III Agreement” means that
                certain New Strategic Neurology Drug Discovery and Development Collaboration, Option and License Agreement between the Parties dated April 19, 2018, as amended or restated from time to time.

            

            

            “Neurology JDC” has the meaning set
                forth in Section 1.18.3.

            

            

            “Neurology JRC” has the meaning set
                forth in Section 1.18.2.

            

            

            “Neurology Plan” means any of the
                following plans: (i) the Core Research Plan, (ii) the Neurological Disease Research Plan, (iii) any ASO Development Candidate Identification Plans, or (iv) any Initial Development Plans.

            

            

            “Neurology Target” means any gene
                target that (i) as of the Effective Date, (y) has not been encumbered by Ionis under an agreement with a Third Party that would prevent Ionis from granting Biogen the license under Section 4.1.1 of this Agreement with respect to such gene target, and (z) has not yet achieved Target Sanction status, and (ii) as of the Effective Date or during the Research Term, the expression or activity of the
                gene in neurons is demonstrated to have an association to any one of the following (each of (a) through (e) below, a “Neurological Disease”):

            

            

            [***].

            

            

            For purposes of clarity, [***] are expressly excluded from the above-listed [***] and therefore any gene target that has as its primary disease
                association an association to [***] will not be a Neurology Target, and any [***] will not be a Product under this Agreement. In addition, [***] or [***] are expressly excluded from the above-listed [***] and therefore any gene target that
                has as its [***] will not be a Neurology Target.  For purposes of further clarity, a gene target that has as its [***] would not be considered a Neurology Target.

            

            

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

            

            

            
              171

              
                

            

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

            

            

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

            

            

            “NPV” has the meaning set forth in Appendix 3.

            

            

            “[***]” means diseases that have, as
                their [***].

            

            

            “Oligonucleotide” means a synthetic
                compound that comprises or consists of at least 5 linked nucleosides (including any analog, variant, mimic, or mimetic thereof). For clarity, the [***] of Oligonucleotides [***].  Oligonucleotides [***].  Oligonucleotides may be
                single-stranded or multi-stranded.

            

            

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

            

            

            “Option Acceleration Deadline” has the meaning set forth in Section 1.10.2(g).

            

            

            “Option Acceleration Notice” has the meaning set forth in Section 1.10.2(g).

            

            

            “Option Deadline” means the Standard
                Option Deadline, the ALS Option Deadline or the Biogen Conducted Non-ALS Option Deadline, as applicable.

            

            

            “Option Period” means, with respect to
                a Collaboration Program, the period beginning on the date a Neurology Target is designated as a Collaboration Program hereunder and ending on the License Effective Date or the expiration or earlier termination of the Option with respect to
                such Collaboration Program.

            

            

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

            

            

            “Panel Decision” has the meaning set
                forth in Section 10.4.5(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).

            

            

            
              172

              
                

            

            “Permitted Licenses” means (1)
                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 (a) use Oligonucleotides (or supply Oligonucleotides to end users) solely to conduct pre-clinical research, or (b) enable such Third Party to manufacture or formulate Oligonucleotides, where (i) 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 (ii) Ionis does not assist such Third Party to identify,
                discover or make a Compound or Product; and (2) material transfer agreements with academic collaborators or non-profit institutions solely to conduct non-commercial 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 5.2.2.

            

            

            “Phase 1 Trial” means the first
                clinical study in human beings Initiated by Ionis or Biogen under the applicable Initial 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 for a given Development Candidate, 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 Initial 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 JDC).

            

            

            “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.

            

            

            
              173

              
                

            

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

            

            

            “Post-Licensing Milestone Event” has
                the meaning set forth in Section 6.7.

            

            

            “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 Collaboration
                  Product” has the meaning set forth in Section 12.5.2.

            

            

            “Pre-Existing Competitive Collaboration
                  Program” has the meaning set forth in Section 12.5.2.

            

            

            “Pre-Existing Target” has the meaning set forth in Section 1.2.3(c).

            

            

            “Pre-Licensing Milestone Event” means
                an ALS Pre-Licensing Milestone Event or a Standard Pre-Licensing Milestone Event, as applicable.

            

            

            “Primarily Neuro Multi-Indication Target”
                has the meaning set forth in Appendix 3.

            

            

            “Primarily Other Multi-Indication Target”
                has the meaning set forth in Appendix 3.

            

            

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

            

            

            “Proceeding” means an action, suit or
                proceeding.

            

            

            “Product” means (i) a Biogen Alternate
                Modality Product, or (ii) a Collaboration Product.

            

            

            “Product-Specific Patents” means, with
                respect to a Product, 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 such Product, (b) methods of using such
                Product as a prophylactic or therapeutic or (c) the specific method of manufacture of such Product (unless in the case of (c), such Patent Rights also claim any other product or services of Ionis); provided however, Patent Rights Controlled by Ionis or any of its Affiliates that (i) include claims that are directed to subject matter applicable to ASOs or products 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 (or similarly, a non-ASO molecule that binds, mimics or otherwise
                affects a protein or RNA that is encoded by a Biogen Alternate Modality Target and the RNA of a gene that does not encode a Biogen Alternate Modality 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.

            

            

            
              174

              
                

            

            “Program” has the meaning set forth in
                Section 7.2.2.

            

            

            “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.

            

            

            “[***]” means a [***].

            

            

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

            

            

            “Reduced Royalty Period” has the
                meaning set forth in Section 6.10.2(d).

            

            

            “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.

            

            

            “Regulatory Materials” means, with
                respect to a Product, any regulatory submissions, notifications, registrations, approvals 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.

            

            

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

            

            

            “Research Term” has the meaning set
                forth in Section 1.2.1.

            

            

            
              175

              
                

            

            “Results” has the meaning set forth in
                Section 4.8.3.

            

            

            “Reverse Royalties” has the meaning
                set forth in Section 6.12.1.

            

            

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

            

            

            “ROFN Period” has the meaning set
                forth in Section 2.2.

            

            

            “Royalty Quotient” has the meaning set
                forth in Section 6.10.2(c).

            

            

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

            

            

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

            

            

            “Setoff Amount” has the meaning set
                forth in Section 10.4.5(b).

            

            

            “Setoff Dispute” has the meaning set
                forth in Section 10.4.5(b).

            

            

            “Setoff Dispute Notice” has the
                meaning set forth in Section 10.4.5(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 Events”
                has the meaning set forth in Section 5.1.4.

            

            

            “[***]” means the form of the [***].

            

            

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

            

            

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

            

            

            “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.

            

            

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

            

            

            “Superior Patent Right” has the
                meaning set forth in Section 7.2.5(d).

            

            

            “Target Related Biogen Program Claim”
                has the meaning set forth in Section 4.3.4.

            

            

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

            

            

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

            

            

            
              176

              
                

            

            “Target Sanction Data Package” means,
                with respect to a Neurology Target, the data package Ionis presented to its RMC to obtain approval to justify expending resources to identify a human Development Candidate, all in accordance with Ionis’ standard processes; provided such package contains the same level of detail as the data packages Ionis currently presents to its Research Management Committee to approve
                Ionis’ own internal gene targets.

            

            

            “Technical Failure” has the meaning
                set forth in Section 1.10.1(b).

            

            

            “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, Biogen Alternate Modality
                Target 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 10.4.6.

            

            

            “Trial Court” has the meaning set
                forth in Section 10.4.5(b).

            

            

            “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.

            

            

            
              177

              
                

            

            Appendix 2

            

            

            Development Candidate Checklist

            

            

            [***]

            

            

            
              178

              
                

            

            
            Appendix 3

            

            

            Multi-Indication Target Process

            

            

            Neurology Targets with
                    Broader Therapeutic Benefit.

            

            

            
              
                	

                      	(a)	
                        If, pursuant to Section 1.2.3(d), the
                            CSC is unable to agree upon whether a Multi-Indication Target is a Primarily Neuro Multi-Indication Target, Equal Multi-Indication Target or Primarily Other Multi-Indication Target, the Parties will engage an expert panel under
                            Section 12.1.4 to make such determination. Such expert panel will first determine the net present value (“NPV”) of a therapeutic targeting such Multi-Indication Target and allocate such NPV between the markets for Neurological Disease
                            indications and for Non-Neurological Indications, where such NPV calculations and allocations will take into consideration, and risk-adjust for, the relevant market sizes, competitive landscapes, scientific rationale for each
                            market and any other factors deemed relevant by such expert panel.  Based on such NPV calculations and allocations, Multi-Indication Targets will be classified as either “Primarily Neuro Multi-Indication Targets”; “Equal

                              Multi-Indication Targets” or “Primarily Other Multi-Indication Targets”, where (1) a
                            Multi-Indication Target with [***]% or more of its NPV allocated to the market for Neurological Disease indications will be a Primarily Neuro Multi-Indication Target, (2) a Multi-Indication Target with less than [***]% but more
                            than [***]% of its NPV allocated to the market for Neurological Disease indications will be an Equal Multi-Indication Target, and (3) a Multi-Indication Target with [***]% or less of its NPV allocated to the market for
                            Neurological Disease indications will be Primarily Other Multi-Indication Target.

                      

              

            

          

          
            
              
                

                

                
                  179

                  
                    

                

                	

                      	 (b)	
                        Primarily Neuro Multi-Indication
                                Targets.  If a Multi-Indication Target is classified as a Primarily Neuro Multi-Indication Target, then within
                            [***] days of such classification, Biogen will send Ionis a written notice either (1) electing to negotiate in good faith with Ionis a development plan and [***] (i.e., [***]) for the Non-Neurological Indications if Developed and Commercialized under this Agreement, which plan and provisions will be recommended to the CSC for approval; (2) granting Ionis and
                            its Affiliates the right to work on their own or with a Third Party to discover, develop and commercialize an Oligonucleotide against such Multi-Indication Target for primarily Non-Neurological Indications (an “Ionis Multi-Indication Compound”); or (3) precluding Ionis and its Affiliates from working on their own or with a
                            Third Party to discover, develop commercialize an Ionis Multi-Indication Compound.  If under this clause (b) Ionis or any of its Affiliates or licensees Commercializes a product incorporating an Ionis Multi-Indication Compound,
                            and Biogen has paid the applicable license fee under Section 6.6 for the applicable Collaboration Program, then until the earlier of (i) the
                            [***] anniversary of the date of First Commercial Sale of such product or (ii) the date Biogen, its Affiliates and Sublicensees stop Commercializing the Product related to such Multi-Indication Target, Ionis will pay Biogen a
                            royalty of [***]% of Annual worldwide Net Sales of such product sold by Ionis, its Affiliates or Sublicensees. The definition of Net Sales in Appendix 1 and the other provisions contained in Sections 6.14, 6.15, 6.16, and 6.17 governing payment of
                            royalties from Biogen to Ionis will govern the payment of such royalty from Ionis to Biogen under this clause (b), mutatis mutandis. 

                            If within [***] days of Biogen making an election under clause (1) of this clause (b) to pursue the Non-Neurological Indication, the CSC has not agreed on a development plan and enhanced economic provisions to be paid by Biogen
                            for the Non-Neurological Indication, then (I) Ionis and its Affiliates will not work on their own or with a Third Party to discover, develop and commercialize in the Field an Ionis Multi-Indication Compound unless otherwise
                            permitted under this Agreement and (II) Biogen and its Affiliates will not work on their own or with a Third Party to discover, develop or commercialize Compounds related to such Multi-Indication Target for Non-Neurological
                            Indications.

                      

                 

                

              

            

            
              
                	

                      	(c)	
                        Equal Multi-Indication Targets.
                            If a Multi-Indication Target is classified as an Equal Multi-Indication Target, neither Party nor its respective Affiliates, licensees or Sublicensees may develop or commercialize a product targeting such Multi-Indication Target
                            for any indication unless and until Ionis and Biogen have agreed on (i) a development plan and enhanced economic provisions to be paid by Biogen (i.e.,
                            multi-indication filing and approval milestone payments, but not additional license fees) for the Non-Neurological Indications, and (ii) the restrictions under which Ionis or Biogen (as applicable) would develop or commercialize
                            a product targeting such Multi-Indication Target (which terms may include the requirements set forth under clause (d)(2) below).

                      

              

            

            

            

            
              180

              
                

            

            
              
                	

                      	(d)	
                        Primarily Other Multi-Indication
                                Targets.  If a Multi-Indication Target is classified as a Primarily Other Multi-Indication Target, then (A)
                            Biogen may continue to Develop and Commercialize Products for Neurological Disease indications pursuant to the terms of this Agreement, and (B) within [***] days of such classification, Biogen will send Ionis a written notice
                            either (1) electing to negotiate in good faith with Ionis and agree on a development plan and [***] (i.e., [***]) for the Non-Neurological
                            Indications if Developed and Commercialized under this Agreement, which plan and provisions will be recommended to the CSC for approval; or (2) granting Ionis and its Affiliates the right to work on their own or with a Third
                            Party to discover, develop and commercialize an Ionis Multi-Indication Compound so long as such Ionis Multi-Indication Compound [***], provided,
                            in addition to the foregoing provisions, if the Development Candidate targeting such Multi-Indication Target being Developed or Commercialized by Biogen, its Affiliates or Sublicensees under this Agreement is [***], Ionis cannot
                            develop or commercialize such Ionis Multi-Indication Compound for [***].

                      

              

            

            

            

            
              
                	

                      	(e)	
                        If within [***] days of Biogen making an election under clause (b)(1) of this Appendix 3 to pursue the Non-Neurological Indication, the CSC has not agreed on a development plan and [***] (i.e., [***]) for the Non-Neurological Indications, then Ionis and its Affiliates will have the right to work on their own or with a Third Party to discover, develop and commercialize
                            an Ionis Multi-Indication Compound so long as such Ionis Multi-Indication Compound [***].

                      

              

            

            

            

            
              181

              
                

            

             
              	
                      

                    

            

             

            
            Appendix 4

             

                  

            Form of Side Letter

            

            

            [Date]

            

            

            Ionis Pharmaceuticals, Inc.

            2855 Gazelle Court

            Carlsbad, CA 92010

            Attention:  Chief Operating Officer

            E-mail: [***]

            

            

            Re:  Establishment of Cost Estimates and Milestone Payments

             

              

            Dear [Chief Operating Officer]:

              

                

            Reference is hereby made to that
                  certain Second Amended and Restated Strategic Neurology Drug Discovery and Development Collaboration, Option and License Agreement by and
                  between Ionis and Biogen dated _________ ___, [2018] (the “Neurology II Agreement”), as supplemented and/or amended to date.  Any capitalized terms not defined herein will have the meaning set forth in the Neurology II 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 applicable Neurology JDC in accordance with Section 1.10.2(e) of the Neurology II 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 applicable
                  Neurology JDC 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:

                      

                  	 	 
	 	 	 
	
                    [***]

                  	 	 

            

            

            
              184

              
                

            

             
              	
                      

                    

            

             

                

            [Date]

            

            

            Ionis Pharmaceuticals, Inc.

            2855 Gazelle Court

            Carlsbad, CA 92010

            Attention:  Chief Operating Officer

            E-mail: [***]

            

            

            Re:  Establishment of Biogen-Approved Costs

             

              

            Dear [Chief Operating Officer]:

              

                

            Reference is hereby made to that
                  certain Second Amended and Restated Strategic Neurology Drug Discovery and Development Collaboration, Option and License Agreement
                by and between Ionis and Biogen dated _________ ___, 2018 (the “Neurology II Agreement”), as supplemented and/or amended to date.  Any capitalized terms not defined herein will have the meaning set forth in the Neurology II 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 applicable Neurology JDC) in accordance with Section 1.14.1 of the Neurology II 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 1.14.1(a)

                    [***]

                  
	 	 	 
	 	 	 
	 	 	 

            

            

            
              187

              
                

            

            Schedule 1.1.4

             

                  

            Biogen Conducted Non-ALS Targets

            

            

            
              
                	 	1.	
                        [***]

                      

                 

                

              

            

            
              
                	

                      	2.	
                        [***]

                      

                 

                

              

            

            
              
                	

                      	3.	
                        [***]

                      

                 

                

              

            

            
              
                	

                      	4.	
                        [***]

                      

              

            

            

            
              188

              
                

            

            Schedule 1.2.3(a)

             

                  

            ALS Targets

             

              

            
              
                	

                      	1.	
                        SOD-1

                      

                 

                

              

            

            
              
                	

                      	2.	
                        [***]

                      

                 

                

              

            

            
              
                	

                      	3.	
                        [***]

                      

                 

                

              

            

            
              
                	

                      	4.	
                        [***]

                      

                 

                

              

            

            
              
                	

                      	5.	
                        [***]

                      

                 

                

              

            

            
              
                	

                      	6.	
                        [***]

                      

              

            

            

            

            
              189

              
                

            

            Schedule 1.2.4

            

            

            Terms and Conditions for Provision of Research ASOs to Biogen

            

            

            ARTICLE 1

            DEFINITIONS

            

            

            The terms used in this Schedule 1.2.4 with
                initial letters capitalized, whether used in the singular or the plural, will have the meaning set forth in Attachment 1, or if not
                listed in Attachment 1, the meaning designated in places throughout the Agreement (or Appendix 1 to the Agreement).

            

            

            ARTICLE 2

            PROVISION OF RESEARCH ASOS OUTSIDE OF THE DISEASE RESEARCH PROGRAM

            

            

            2.1. Scope of Collaboration.

            

            

            
              
                
                  	 	
                          a)

                        	
                          Ionis will generate Research ASOs for Accepted Gene Targets in accordance with the terms and conditions of this Schedule 1.2.4.

                        

                

              

            

            

            

            
              
                	

                      	b)	
                        Each Party will devote commercially reasonable efforts to performing its obligations under the Target Validation Plan.

                      

              

            

            

            

            ARTICLE 3

            CONDUCT OF THE TARGET VALIDATION OUTSIDE OF THE DISEASE RESEARCH PROGRAM

            

            

            3.1. Selection of Biogen TV Targets; Target Validation Activities.

            

            
              
                	

                      	a)	
                        During the Research Term, Biogen will have the right to propose gene targets that are the focus of Biogen programs that are not part of the Collaboration (each, a “Biogen TV Target”) for up to a total of [***] Accepted Gene Targets per [***] period. Biogen will propose such Biogen TV
                            Targets by written notice to the Ionis Alliance Manager.

                      

              

            

            

            

            
              
                	

                      	b)	
                        Ionis may reject a proposed Biogen TV Target if, at the time of such proposal, [***].

                      

              

            

            

            

            
              
                	

                      	c)	
                        Each Biogen TV Target that is not rejected by Ionis will be an “Accepted Gene Target.” During the Research Term, Ionis and Biogen will use Commercially Reasonable Efforts to perform the activities outlined in the Target Validation Plan on each Accepted Gene Target.

                      

              

            

            

            

            
              190

              
                

            

            3.2. Biogen’s Use of Research ASOs and Information.

            

            

            
              
                	

                      	a)	
                        The Research ASOs and any related Confidential Information provided to Biogen by Ionis hereunder are proprietary to Ionis.  Biogen will not distribute or release
                            the Research ASOs to any Person other than its employees, academic collaborators, Affiliates, agents or (sub)contractors, solely for purposes of performing work in support of Biogen’s drug discovery activities. Subject to the
                            terms and conditions of this Schedule 1.2.4, Ionis hereby grants Biogen a non-exclusive, fully paid, license to use the
                            Ionis Confidential Information (including data generated by Ionis with Research ASOs in the performance of the Target Validation Plan) and Research ASOs solely for use in support of Biogen' drug discovery purposes. In exercising
                            its rights under this Schedule 1.2.4, Biogen may use data generated by Biogen using the Research ASOs (the “Biogen Data”) to support Patent Rights filed by or on behalf of Biogen, including Patent Rights that claim methods of
                            treating disease by modulating the applicable Accepted Gene Target. The claims of any such Biogen Patent Right using such Biogen Data that generically claims methods of treating disease by modulating the applicable Accepted Gene
                            Target, but are not directed to specific compounds or agents, are referred to as the “Biogen Licensed Claims.”
                            Notwithstanding the foregoing, Biogen will not use such Biogen Data to support claims directed to one or more Oligonucleotides as a composition of matter or one or more Oligonucleotides as a pharmaceutical product, without the
                            prior written consent of Ionis. In addition, Biogen may not use Ionis data disclosed to Biogen in connection with this Schedule 1.2.4
                            or the Research ASOs to make products that incorporate Oligonucleotides.

                      

              

            

            

            

            
              
                	

                      	b)	
                        Biogen hereby grants Ionis a non-exclusive, fully-paid sublicensable license under any Biogen Licensed Claims solely for the purpose of discovering, developing or
                            commercializing an Oligonucleotide(s) as a pharmaceutical product, provided, however, that such license will only be sublicensable by
                            Ionis to a Third Party licensee in connection with the grant of an exclusive license to such Third Party under other Ionis intellectual property with respect to such Oligonucleotide. No other license is granted to Ionis under
                            any Biogen-owned or controlled Patent Right or other intellectual property under this Schedule 1.2.4.  For avoidance of
                            doubt, no rights are granted by Biogen to Ionis under this Schedule 1.2.4 (expressly or by implication or otherwise) with
                            respect to any compounds, materials or agents (or any method of use or manufacture thereof).

                      

              

            

            

            

            
              
                	

                      	c)	
                        Ionis hereby grants Biogen a non-exclusive, fully-paid sublicensable license under any Ionis Licensed Claims solely for the purpose of discovering, developing or
                            commercializing a non-Oligonucleotide compound(s) as a pharmaceutical product, provided, however, that such license will only be
                            sublicensable by Biogen to a Third Party licensee in connection with the grant of an exclusive license to such Third Party under other Biogen intellectual property with respect to any such non‐Oligonucleotide compound. “Ionis Licensed Claims” means the claims of any Ionis Invention that generically claims methods of treating disease by
                            modulating an Accepted Gene Target, but are not directed to any specific compound or agent (including any Oligonucleotide).  Except as set forth in Section
                                3.2(a) and (c), no other license is granted to Biogen under any Ionis-owned or controlled Patent Right or other intellectual property
                            under this Schedule 1.2.4.

                      

              

            

            

            

            3.3. Non-exclusive Collaboration.

            

            

            
              
                	

                      	a)	
                        Ionis will perform target validation activities and will provide Research ASOs to Biogen as set forth in the Target Validation Plan on a non-exclusive basis. Ionis
                            may collaborate with Third Parties for target validation studies on any gene targets, including Accepted Gene Targets. In addition, this Schedule

                                1.2.4 will not limit Ionis from conducting research, discovery and development work on any and all Oligonucleotides, for itself or with or on behalf of a Third Party.

                      

              

            

            

            

            
              
                	

                      	b)	
                        If an Oligonucleotide to an Accepted Gene Target hereunder becomes a drug development candidate of Ionis or a Third Party collaborator of Ionis, Ionis will notify
                            Biogen. Upon receipt of such notice from Ionis, Biogen will return to Ionis all unused quantities of applicable TV Compound within [***] days after the date on which Biogen received such notice.  After such time, Ionis will not
                            have any obligation to provide additional quantities of the originally supplied TV Compound to Biogen under this Schedule 1.2.4.

                      

              

            

            

            

            
              191

              
                

            

            
              
                	 	c)	
                        If Ionis achieves Target Sanction for an Accepted Gene Target, and Ionis does not at such time have any obligations to any Third Party with respect to such Accepted
                            Gene Target that would conflict with Ionis’ compliance with this Section 3.3(c), Ionis will provide to Biogen a Target Sanction Data Package for such
                            Accepted Gene Target (an “AGT Target Sanction Data Package”) and Biogen will have [***] days following receipt of such
                            AGT Target Sanction Data Package to decide whether to negotiate with Ionis regarding an agreement with respect to such Accepted Gene Target (an “AGT Agreement”).  Following delivery of an AGT Target Sanction Data Package, Ionis will not initiate negotiations regarding or enter into an AGT Agreement with any Third Party until the earlier to
                            occur of: (1) Biogen notifying Ionis that it declines the opportunity to negotiate with Ionis regarding such AGT Agreement; (2) Biogen not responding to Ionis within [***] days after receipt of such AGT Target Sanction Data
                            Package; or (3) the AGT Negotiation Period expiring before Biogen and Ionis have entered into such AGT Agreement.  If Biogen or one of its Affiliates responds within 30 days after its receipt of the AGT Target Sanction Data
                            Package indicating that Biogen or one of its Affiliates desires to negotiate with Ionis regarding the proposed AGT Agreement, Ionis and Biogen or one of its Affiliates will negotiate in good faith for 180 days thereafter (or
                            such other period as mutually agreed by the Parties) (the “AGT Negotiation Period”) regarding a mutually satisfactory AGT Agreement. During the AGT Negotiation Period, Biogen or its Affiliate will make the first written proposal to
                            Ionis setting forth all material business and legal terms on which Biogen or its Affiliate would be willing to enter into the proposed AGT Agreement with Ionis; provided that neither Party will have any obligation to enter into an AGT Agreement. If the AGT Negotiation Period expires before Biogen or its Affiliate and Ionis have entered into such AGT
                            Agreement, Ionis will have no further obligation to negotiate with Biogen or its Affiliates with respect to such AGT Agreement and Ionis will be free to negotiate and enter an agreement with a Third Party with respect to an AGT
                            Agreement [***]; provided, however, that Ionis will not enter into any such AGT Agreement with any Third Party unless the terms and
                            pricing of such AGT Agreement, [***].

                      

              

            

            

            

            3.4. Biogen Materials.

            

            

            Any materials provided by Biogen to Ionis in connection with a Biogen TV Target or Accepted Gene Target, including any biological materials with
                respect to screening assays, including any progeny, expression products, mutants, replicates, derivatives and modifications thereof, (such materials being individually and collectively referred to as the “Biogen Materials”) will be used by Ionis solely for purposes of performing activities in accordance with the  Target Validation Plan and any remaining Biogen
                Materials will be returned to Biogen (or destroyed as may be requested by Biogen in writing) promptly following the end of the applicable activities under the Target Validation Plan or earlier upon request by Biogen. All information related
                to such Biogen Materials will be Biogen Confidential Information. All such materials must be used with prudence and appropriate caution in any experimental work, since all of their characteristics may not be known.

            

            

            ARTICLE 4

            INTELLECTUAL PROPERTY

            

            

            4.1. Ownership of Inventions.

            

            

            
              
                	

                      	a)	
                        Title to any inventions, technology, discoveries, or other proprietary property made or discovered (as determined by the U.S. laws of inventorship) by employees of
                            or consultants or contractors of a Party pursuant to the performance Target Validation Plan (collectively, “Inventions”)

                            are retained by the Party that is the employer of the inventor (or, in the case of consultants or contractors, the Party for which such consultant or contractor is providing services). Ionis will own Inventions invented solely
                            by employees or consultants or contractors of Ionis and any Patent Rights claiming such Invention (collectively, the “Ionis
                              Inventions”). Biogen will own Inventions invented solely by employees or consultants or contractors of Biogen and any Patent Rights claiming such Invention.

                      

              

            

            

            

            
              192

              
                

            

            
              
                	

                      	b)	
                        Except as provided otherwise herein, Ionis and Biogen will jointly hold title to all Inventions, made or discovered (as determined by the U.S. laws of inventorship)
                            jointly by employees or consultants or contractors of Ionis and Biogen (“Joint Inventions”). Patent Rights claiming
                            such Joint Inventions will be “Joint Patents.”  Ionis and Biogen will promptly provide each other with notice whenever
                            a Joint Invention is made or discovered.

                      

              

            

            

            

            
              
                	

                      	c)	
                        The Parties agree, upon reasonable request, to execute any documents reasonably necessary to effect and perfect each other’s ownership of any Invention or Patent
                            Right claiming such Invention.

                      

              

            

            

            

            4.2. Patent Prosecution; Infringement of Joint Patents.

            

            

            
              
                	

                      	a)	
                        Each Party has the right to file, prosecute, maintain, enforce and defend Patent Rights on Inventions owned by such Party, at its own expense.

                      

              

            

            

            

            
              
                	

                      	b)	
                        Ionis and Biogen will mutually agree on the filing, prosecution and maintenance of any Joint Patents and the expenses of such prosecution and maintenance will be
                            shared equally. If either Party elects not to participate in the filing, prosecution or maintenance of a Joint Patent, it will notify the other Party of such election not later than [***] days before the applicable deadline for
                            filing, prosecution or maintenance, and the other Party will thereafter have the right to undertake such filing, prosecution or maintenance, at its own expense.

                      

              

            

            

            

            
              
                	

                      	c)	
                        A Party whose rights in a Joint Patent are impacted by the infringement of such Joint Patent by a Third Party will have the right to enforce that Joint Patent at
                            its own discretion and at its own expense. The non-enforcing Party agrees to provide the enforcing Party all reasonable assistance (including joining such action as a Party plaintiff), at the enforcing Party’s expense. Any
                            damages or other recovery, whether by settlement or otherwise, from an action hereunder to enforce a Joint Patent will be paid first to each Party to reimburse the costs of enforcement and then prorated to the Party(ies) based
                            on damages incurred.

                      

              

            

            

            

            ARTICLE 5

            TERM AND TERMINATION

            

            

            5.1. Agreement Term.

            

            

            Unless the Agreement is earlier terminated (in which case this Schedule 1.2.4 will also terminate), this Schedule 1.2.4 will remain in effect until the end
                of the Research Term (the “Term”), at which time it will expire.

            

            

            5.2. Survival.

            

            

            Section 3.2 (Biogen’s Use of Research ASOs and
                Information), Section 5.2 (Survival) and ARTICLE 4 (Intellectual Property) will
                survive the expiration or termination of this Schedule 1.2.4.

            

            

            
              193

              
                

            

            Attachment 1 to Schedule 1.2.4

            

            

            Definitions

            

            

            “Accepted Gene Target” has the meaning
                set forth in Section 3.1(c).

            

            

            “AGT Agreement” has the meaning set forth
                in Section 3.3(c).

            

            

            “AGT Negotiation Period” has the meaning
                set forth in Section 3.3(c).

            

            

            “AGT Target Sanction Data Package” has
                the meaning set forth in Section 3.3(c).

            

            

            “Biogen Data” has the meaning set forth
                in Section 3.2(a).

            

            

            “Biogen Licensed Claims” has the meaning
                set forth in Section 3.2(a).

            

            

            “Biogen Materials” has the meaning set
                forth in Section 3.4.

            

            

            “Biogen TV Target” has the meaning set
                forth in Section 3.1(a).

            

            

            “Inventions” has the meaning set forth in
                Section 4.1(a).

            

            

            “Ionis Inventions” has the meaning set
                forth in Section 4.1(a).

            

            

            “Ionis Licensed Claims” has the meaning
                set forth in Section 3.2(c).

            

            

            “Joint Invention” has the meaning set
                forth in Section 4.1(b).

            

            

            “Joint Patents” has the meaning set forth
                in Section 4.1(b).

            

            

            “Target Validation Plan” means the
                collaborative Target Validation Plan undertaken by the Parties pursuant to this Schedule 1.2.4, as further described in Attachment 2.

            

            

            “Term” has the meaning set forth in Section 5.1.

            

            

            “TV Compound” means an Oligonucleotide
                delivered to Biogen by Ionis under this Schedule 1.2.4 directed to an Accepted Gene Target.

            

            

            
              194

              
                

            

            Attachment 2 to Schedule 1.2.4

            

            

            Target Validation Plan

            

            

            [***]

            

            

            
              195

              
                

            

            Schedule 1.6.1

            

            

            ALS Letter Agreement

            

            

            [***]

            

            

            
              196

              
                

            

            Schedule 1.10.2(c)

            

            

            Ionis’ Standard IND-Enabling Toxicology Studies

            

            

            [***]

            

            

            
              197

              
                

            

            Schedule 1.10.2(d)

            

            

            Initial Development Plan Requirements

            

            

            [***]

            

            

            
              198

              
                

            

            Schedule 1.10.2(d)(v)

            

            

            Study Synopsis Requirements

            

            

            [***]

            

            

            
              199

              
                

            

            Schedule 1.10.2(e)

            

            

            Apportionment of Certain Milestone Payments and Biogen-Approved Costs

            

            

            In the event that either (I) a milestone payment established under Section
                    1.10.2(e) or (II) Biogen-Approved Costs resulting from [***], such milestone payment or Biogen-Approved Costs, as applicable, shall be apportioned into smaller milestone payments and paid by Biogen to Ionis as follows:

            

            

            [***].

            

            

            Each payment due under this Schedule 1.10.2(e) shall be payable by Biogen within [***] days after receipt of the applicable invoice by Biogen following the event that triggered such milestone payment.

            

            

            
              200

              
                

            

            Schedule 1.10.6

            

            

            Ionis API Supply for ALS Collaboration Programs and Biogen Conducted Non-ALS Collaboration Programs

            

            

            [***]

             

              

            
              201

              
                

            

            Schedule 1.18.1

            

            

            Collaboration Steering Committee Governance

            

            

            CSC Representatives

            

            

            Ionis

            

            

            Lynne Parshall, Senior Strategic Advisor

            

            

            Frank Bennett, SVP, Head of Research

            

            

            Richard Geary, SVP, Head of Development

            

            

            Biogen

            

            

            Michael Ehlers, EVP, Research and Development

            

            

            Katherine Dawson, VP, Late Stage Clinical Development

            

            

            Anabella Villalobos, SVP, Biotherapeutic and Medicinal Sciences

            

            

            Daniel Karp, EVP Corporate Development

            

            

            
              202

              
                

            

            Schedule 1.18.2

            

            

            Neurology JRC Governance

            

            

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

                      

              

            

            

            

            
              
                	(b)	
                        The Neurology JRC may hold meetings in person or by audio or video conference as determined by the Neurology JRC; 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 JRC 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 JRC meetings, including any subject matter expert(s) with valuable knowledge of High Interest Targets or Collaboration Targets (as applicable) or the
                            diseases associated with such targets.

                      

              

            

            

            

            
              
                	(c)	
                        The co-chairs will be responsible for ensuring that activities occur as set forth in this Agreement, including ensuring that Neurology JRC meetings occur, Neurology
                            JRC recommendations are properly reflected in the minutes, and any dispute is given prompt attention and resolved in accordance with Section 1.18.2, Section 7.1.3 and Section 12.1, as applicable.

                      

              

            

            

            

            
              
                	(d)	
                        The Neurology JRC members from the same Party will collectively have one vote. The Neurology JRC 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 JRC meeting.

                      

              

            

            

            

            
              
                	
                        (e)

                      	
                        The Neurology JRC 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 JRC dissolves.

                      

              

            

            

            

            
              203

              
                

            

            Schedule 1.18.3

            

            

            Neurology JDC Governance

            

            

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

                      

              

            

            

            

            
              
                	(b)	
                        The Neurology JDC may hold meetings in person or by audio or video conference as determined by the Neurology JDC; 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 JDC 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 JDC meetings, including any subject matter expert(s) with valuable knowledge of the applicable or Collaboration Target or the diseases associated with
                            such target.

                      

              

            

            

            

            
              
                	(c)	
                        The co-chairs will be responsible for ensuring that activities occur as set forth in this Agreement, including ensuring that Neurology JDC meetings occur, Neurology
                            JDC recommendations are properly reflected in the minutes, and any dispute is given prompt attention and resolved in accordance with Section 1.18.3, Section 7.1.3 and Section 12.1, as applicable.

                      

              

            

            

            

            
              
                	(d)	
                        Neurology JDC members from the same Party will collectively have one vote. The Neurology JDC 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 JDC meeting.

                      

              

            

            

            

            
              
                	
                        (e)

                      	
                        The Neurology JDC 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 JDC dissolves.

                      

              

            

            

            

            
              204

              
                

            

            Schedule 1.18.6

            

            

            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;

                      

              

            

            

            

            
              
                	(c)	
                        Organizing CSC, Neurology JRC and Neurology JDC meetings, including agendas, drafting minutes, and publishing final minutes;

                      

              

            

            

            

            
              
                	(d)	
                        Supporting the co-chairs of the CSC, Neurology JRC and Neurology JDC 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 CSC, Neurology JRC and Neurology JDC;

                      

              

            

            

            

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

                      

              

            

            

            

            
              
                	(g)	
                        Manage and coordinate the target validation activities under Schedule
                                1.2.4;

                      

              

            

            

            

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

                      

              

            

            

            

            
              
                	(i)	
                        Determining an appropriate format for summaries of resource and FTE utilization, and ensuring such summarized are timely provided to the Neurology JRC as outlined
                            in Section 1.11.

                      

              

            

            

            

            
              205

              
                

            

            Schedule 4.3.1(a)

            

            

            Drug Substance Process and Formulation Development Activities

            

            

            [***]

             

              

            
              206

              
                

            

            Schedule 4.8.2(c)

            

            

            Ionis’ Fully Absorbed Cost of Goods Methodology

            Cost Estimate of API Cost per Kilogram

            (OOO’s)

            

            

            [***]

             

              

            
              207

              
                

            

            Schedule 5.1.4

             

                  

            Biogen’s Development and Commercialization Activities

             

              

            [***]

            

            

            
              208

              
                

            

            Schedule 5.1.6

             

              

            Integrated Development Plan Content

            

            

            	
                    [***]

                  	
                    [***]

                  	
                    [***]

                  	
                    [***]

                  
	
                    [***]

                  	 

                  	
                    [***]

                  	

                  	
                    [***]

                  	 

                  	
                    [***]

                  
	
                    [***]

                  	 	
                    [***]

                  	
                            

                    

                  	
                    [***]

                  	 	 
	
                    [***]

                  	 

                  	
                    [***]

                  	
                              

                    

                  	
                    [***]

                  
	
                    [***]

                  	 

                  	
                    [***]

                  	
                             

                    

                  	
                    [***]

                  

            

            

            
              209

              
                

            

            Schedule 6.10.2(e)

            Royalty Calculation Examples

            [***]

            	
                    [***]

                  	
                    [***]

                  	
                    [***]

                  	
                    [***]

                  	
                    [***]

                  	
                    [***]

                  	
                    [***]

                  	
                    [***]

                  	
                    [***]

                  
	
                    [***]

                  	
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            [***]

             

                

            
              210

              
                

            

            Schedule 6.10.2(f)

             

                  

            Allocation of Net Sales

             

              

            [***]

             

              

            
              211

              
                

            

            Schedule  6.13.1

             

                  

            Certain Ionis In-License Agreements

             

              

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

             

              

            [***]

            

            

            
              212

              
                

            

            Schedule  8.2.4(a)

             

                  

            Ionis Core Technology Patents

            

            

            	 	
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              213

              
                

            

            Schedule 8.2.4(b)

            

            

            Ionis Manufacturing and Analytical Patents

            

            

            	
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              214

              
                

            

            Schedule 8.2.4(c)

             

                  

            Ionis Product-Specific Patents

            

            

            	
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            Schedule 8.2.8

             

                  

            Prior Agreements

            

            

            [***]

             

              

            
              
                

            

            Schedule 10.4.5(b)

            

            

            Advisory Panel Regarding Setoff Disputes

             

              

            [***]

            

            

            
              
                

            

            Schedule 10.4.6

            

            

            Transition Services

            

            

            [***]

             

              

            
              
                

            

            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).

            

            

            
              
                

            

            Schedule 12.5

             

                  

            Table A

            Applicable License Fee Payments in Change of Control for Collaboration Products

            

            

            	
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            Schedule 12.5

            

            

            Table B

            Applicable [***] under Section 12.5.1(b) in Change of Control

            

            

            	
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Source: [{"source": "alea-institute/alea-institute/kl3m-data-edgar-agreements/train-00292-of-00352.parquet"}, [{"source": "alea-institute/alea-institute/kl3m-data-edgar-agreements/train-00292-of-00352.parquet"}]]