Amended and Restated Strategic Neurology Drug Discovery and Development Collaboration, Option and License Agreement Between Ionis Pharmaceuticals, Inc. And Biogen MA Inc.

Collaboration Overview.

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.

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.

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.

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.

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

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.

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.

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 (i) the activities to support Target Sanction in the Calendar Year covered by such Neurological Disease Research Plan, (ii) any Neurological Disease research to support Collaboration Programs, and (iii) 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.

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

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.

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.

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 (1) [***], (2) such gene target is not eligible to become a High Interest Target hereunder [***], or (3) 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 so long as such Ionis Neurology Target is more 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 (a) 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, (b) [***] is not a Multi-Indication Target (as defined below) and (c) [***] is deemed to be a Pre-Existing Target (as defined below) for purposes of this Agreement.

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 ▇▇▇▇▇ 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 ▇▇▇▇▇ 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.

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.

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.

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.

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.

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 (x) [***] days following such meeting of the Neurology JRC or (y) [***] 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 (A) such High Interest Target (I) will not be designated a Collaboration Target or Biogen Alternate Modality Target and (II) will no longer be a Neurology Target under this Agreement and (B) 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 (X) 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 (Y) the provisions of clause (x) (but not clause (y)) of Section 2.1.1(f) will apply with respect to such target.

Process for Designating Ionis Neurology Targets as Collaboration Targets.  If, during 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 ▇▇▇▇▇ 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.

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.

Consequences of Designating Collaboration Targets.

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 ▇▇▇▇▇ 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.

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.

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.

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

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.

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 [***] year 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).

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.

Accelerating the Deferral Period with a Deferred Target Development Candidate.

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).

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 ▇▇▇▇▇ has reimbursed Biogen for [***]% of the last annual deferral fee paid to Ionis under Section 1.8.2 for such Deferred Target.

End of Research Term. At the end of the Research Term, (i) neither Ionis nor Biogen will have an obligation to perform any activities under the Core Research Program or the Neurological Disease Research Program; (ii) 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; (iii) 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; and (iv) at Ionis’ 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 4.3.2. For clarity, the expiration of the Research Term will not affect Biogen’s rights or Ionis’ obligations with respect to Collaboration Programs or Biogen Alternate Modality 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.

Ionis’ Research and Development Responsibilities.

Development Candidate Identification.

ASO Development Candidate Identification Plans. For each Collaboration Program, within [***] days after the designation of the applicable Collaboration Target, Ionis will provide 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.

Biomarker Work. If the Neurology JRC agrees to include biomarker work in the ASO Development Candidate Identification Plan, the [***] is responsible for performing such biomarker work taking into consideration [***].

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, ▇▇▇▇▇ 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 ▇▇▇▇▇’ 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.

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; and (iv) upon Ionis’ request, Biogen will provide to Ionis any data generated under the Collaboration Program and licensed to Ionis under Section 4.3.2. 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.

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 ▇▇▇▇▇ 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.

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.

Development Candidate Data Package. For each Collaboration Program, ▇▇▇▇▇ 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.

IND-Enabling Toxicology Studies.

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.

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 Amendment Date for the Collaboration Program for [***].  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.

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, ▇▇▇▇▇ 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 Option exercise.

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.

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 $[***].

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.

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 following Option exercise, 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).

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.

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, ▇▇▇▇▇ 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.

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.

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.

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.

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

Drug Development.

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, ▇▇▇▇▇ 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 ▇▇▇▇▇’ 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 ▇▇▇▇▇’ 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.

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.

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.

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.

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

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.

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.

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 (i) the Neurological Disease Research Program and progress toward achieving Target Sanction for each High Interest Target and progress related to ALS Targets; (ii) activities conducted under the Core Research Program; (iii) progress under each ASO Development Candidate Identification Plan toward designating a Development Candidate; (iv) activities on the Deferred Targets conducted pursuant to Section 1.8.4, and (v) 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.

Clinical Supplies by ▇▇▇▇▇. 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 Option exercise. 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.

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 designated, (i) 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 (ii) so long as the other Party provides the Contracting Party such comments within [***] days of 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.

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 ▇▇▇▇▇’ 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 ▇▇▇▇▇.

Research Programs. During the Research Term, ▇▇▇▇▇ 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.

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.

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.

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.

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 Option exercise, and ▇▇▇▇▇ 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.

After Option Exercise. After Option exercise, 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 ▇▇▇▇▇ at Biogen’s request, and all supply chain planning and decision-making.

Payment Mechanisms.

Payment Mechanics for Additional Activities Approved by Biogen.  Biogen will pay Ionis (1) 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 (2) 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 ▇▇▇▇▇) 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 (i) this Section 1.14.1 will not be used to establish the initial milestone payments under Section 1.10.2(e), and (ii) 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.

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.

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 [***].

For any Biogen-Approved Cost that (x) has an Estimated Biogen-Approved Cost of less than $[***] and (y) 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 [***].

For any Biogen-Approved Costs that (x) has an Estimated Biogen-Approved Cost of $[***] or more and (y) 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 [***], 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 [***].

Within [***] days after the end of the applicable Measurement Period, Ionis will provide Biogen with a written statement (1) 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 (2) 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.

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.

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 ▇▇▇▇▇ to attend and participate in any meetings organized by a 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.

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 an [***] 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 an [***] 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).

Research and Development Management.

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 ▇▇▇▇▇ 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.

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:

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

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

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;

establishing the Initial Development Plan in the event of a Neurology JDC dispute as described in Section 1.10.2(d);

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

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

reviewing and assessing reports provided by the Neurology JRC and the Neurology JDCs;

providing input to the JPC as appropriate;

reviewing and providing input on the CTDs and IDPs as appropriate;

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

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

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 ▇▇▇▇▇ 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.

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:

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;

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;

review and approve amendments to the Core Research Plan and the Neurological Disease Research Plan as described in Sections 1.2.2 and 1.2.3;

allocate resources under Section 1.11;

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

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

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;

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

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;

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

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

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

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;

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

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

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;

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

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

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 ▇▇▇▇▇ 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.

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:

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

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

approve Biogen-Approved Costs pursuant to Section 1.14.1;

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);

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);

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

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

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

Decision Making.

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.

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 Option exercise, (i) Ionis will have the final decision-making authority regarding [***] and (ii) Biogen will have the final decision-making authority regarding [***]. After Option exercise for 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.

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 ▇▇▇▇▇’ request.

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.

Exclusivity; Right of First Negotiation.

Exclusivity Covenants.

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.