Side Letter dated December 31, 2020 to the New Strategic Neurology Drug Discovery and Development Collaboration, Option and License Agreement by and between the Registrant and Biogen MA Inc. dated April 19, 2018. Portions of this exhibit have been omitted because they are both (i) not material and (ii) would be competitively harmful if publicly disclosed

Reference is hereby made to that certain New Strategic Neurology Drug Discovery and Development Collaboration, Option and License Agreement between Ionis Pharmaceuticals, Inc. (“Ionis”) and Biogen MA Inc. (“Biogen”) dated April 19, 2018, as supplemented or amended to date (the “Agreement”). Any capitalized terms not defined herein will have the meaning set forth in the Agreement.

WHEREAS, Biogen and Ionis have discussed the use of certain drug delivery technology, including [***] (each a “[***]”) and [***] (each, a “[***]”), in each case targeting the [***];

WHEREAS, Biogen has identified certain specific [***]and specific [***];

WHEREAS, as of the date hereof, the Neurology Target [***] is a High Interest Target;

WHEREAS, as of the date hereof, the Parties are pursuing a Collaboration Program consisting of a Strategy directed against [***] for [***] (such Strategy, the “[***] Strategy,” and such Collaboration Program, the “[***] Collaboration Program”); and

WHEREAS, the Parties desire to (i) designate an alternative Strategy directed to [***] pursuant to which the Parties would [***] (as defined below) with an [***] directed against [***] for [***] and (ii) designate such Strategy directed to [***] as an additional Collaboration Program under the Agreement (such Strategy, the “[***] Strategy,” and such Collaboration Program, the “[***] Collaboration Program”).

NOW, THEREFORE, for the promises set forth herein and valuable consideration (the receipt and adequacy of which is hereby acknowledged), solely with respect to [***], the Parties agree to modify the Agreement as follows:

1.    Selection of [***].  Each [***] or [***] provided by Biogen to Ionis under this letter agreement or the Agreement and identified by Biogen by sequence will be a “Biogen [***]” or “Biogen [***],” respectively (collectively, the “Biogen [***]”).  The Parties will select the final Biogen [***] for inclusion in the [***] Development Candidate and such selection will be reflected in the minutes of the Neurology JRC or Neurology JDC.

2.   Designation of [***] Collaboration Program; Target Designation Milestone Payment.  The Parties hereby (a) designate the [***] Strategy as an alternative Strategy directed to [***] and (b) designate the [***] Strategy as a Collaboration Program. Notwithstanding any provision to the contrary set forth in the Agreement, the Target Designation Milestone for the [***] Strategy will be [***].  Such payment will be due and payable no later than [***] ([***]) Business Days after the date of receipt an invoice therefor from Ionis.

3.   Supply of [***].  Notwithstanding any provision to the contrary set forth in the Agreement, including Section 1.8.6 (Manufacturing and Supply for Collaboration Programs), before the License Effective Date with respect to the [***] Strategy, to the extent necessary, Biogen, at its expense, will supply research-grade [***] to Ionis sufficient to (a) support the Research and Development activities under the [***] Strategy as set forth in the applicable Development Candidate Identification Plan, and (b) support IND-Enabling Toxicology Studies pursuant to the applicable Toxicology Strategy. Notwithstanding any provision to the contrary set forth in the Agreement, including Section 1.8.4 (IND-Enabling Toxicology Studies), unless the Neurology JDC agrees otherwise, Biogen will conduct and lead, all IND-Enabling Toxicology Studies for all Development Candidates under the [***] Collaboration Program, in accordance with the applicable IND-Enabling Toxicology Study design and Toxicology Strategy (that are each approved pursuant to Section 1.8.4 (IND-Enabling Toxicology Studies)) and the other terms of the Agreement.

4.    Materials.  To facilitate the conduct of activities under the [***] Collaboration Program or the performance of other activities for such Collaboration Program under the Agreement or this letter agreement, Biogen may provide to Ionis or its Affiliates certain compositions of matter, biological materials, or chemical compounds Controlled by Biogen, including the Biogen [***], for use by Ionis (such materials or compounds and any progeny and derivatives thereof, collectively, “Materials”). Except as otherwise set forth in this Agreement, all such Materials will remain the sole property of Biogen, will be used only in the fulfillment of obligations or exercise of rights under the Agreement expressly in accordance with the applicable Neurology Plan or other written agreement by the Parties as to the use thereof, subject to any limitations specified in writing by Biogen in connection with such provision, which restrictions will not further limit Ionis’ rights under this letter agreement or the Agreement, will not be used or delivered to or for the benefit of any Third Party without the prior written consent of Biogen (except as expressly permitted under the applicable Neurology Plan), and will not be used in research or testing involving human subjects, unless expressly agreed by Biogen.  Without limiting the foregoing, Ionis will not reverse engineer, disassemble, modify, create, or engineer any type of [***] from, any Biogen [***], Biogen [***], Biogen [***], or Biogen [***] provided to Ionis under the Agreement or this letter agreement.  Except as otherwise set forth in the Agreement or in this letter agreement, THE MATERIALS ARE PROVIDED “AS IS” AND WITHOUT ANY REPRESENTATION OR WARRANTY, EXPRESS OR IMPLIED, INCLUDING ANY IMPLIED WARRANTY OF MERCHANTABILITY OR OF FITNESS FOR ANY PARTICULAR PURPOSE OR ANY WARRANTY THAT THE USE OF THE MATERIALS WILL NOT INFRINGE OR VIOLATE ANY PATENT RIGHT OR OTHER PROPRIETARY RIGHTS OF ANY THIRD PARTY.

5.   Interpretation.  Solely with respect to the [***] Collaboration Program, Section 1.8.6 (Manufacturing and Supply for Collaboration Programs) and Section 4.8.2(c) (API and Product) of the Agreement are hereby amended as follows:

6.   Initiation of IND-Enabling Toxicology Study.  There will be [***] under Section 6.3 (Milestone Payments for First Initiation of IND-Enabling Toxicology Studies) for the [***] Milestone with respect to the [***] Collaboration Program.

7.    License Fee.  Notwithstanding any provision to the contrary set forth in the Agreement, including Section 6.4 (License Fee), the Option Fee for the [***] Collaboration Program will be $[***].

8.    [***] Post-Option Development Milestone Payments.  If a Product under the [***] Collaboration Program is classified as a [***] under the Agreement in accordance with Section 6.5 (Collaboration Program Asset Size Determination), then [***] the milestone payments under Section 6.7 (Post-Option Development Milestone Payments), Biogen will pay to Ionis the milestone payments as set forth below when a Post-Option Development Milestone Event listed below is first achieved by Biogen, or its Affiliates or Sublicensees for such Product under the [***] Collaboration Program:

9.    [***] Post-Option Development Milestone Payments.  If a Product under the [***] Collaboration Program is classified as a [***] under the Agreement in accordance with Section 6.5 (Collaboration Program Asset Size Determination), then [***] the milestone payments under Section 6.7 (Post-Option Development Milestone Payments), Biogen will pay to Ionis the milestone payments as set forth below when a Post-Option Development Milestone Event listed below is first achieved by Biogen, its Affiliates or Sublicensees for such Product under the [***] Collaboration Program:

10.  Ownership of [***] and [***].  Notwithstanding any provision to the contrary set forth in the Agreement, the Parties agree that:

11.  Biogen [***] Patent License.  Subject to the terms and conditions of the Agreement (including Ionis’ exclusivity covenants under Section 2.1.1 (Exclusivity Covenants)), Biogen hereby grants Ionis an irrevocable, perpetual, worldwide non-exclusive, sublicensable (subject to the restrictions set forth in Section 4.3.4(c)), royalty-free license under any Biogen [***] Patent Controlled by Biogen or its Affiliates at any time during the Agreement Term to research, develop, manufacture, have manufactured and commercialize any:

12.  Third Party Obligations for [***].  Notwithstanding Section 6.11 (Third Party Rights and Payment Obligations), so long as Biogen has an Option with respect to the [***] Strategy or a license under Section 4.1 (License Grants to Biogen) with respect to the [***] Collaboration Program, [***] will have the sole right and discretion, at its sole cost and expense, to acquire rights (whether by purchase, assignment, license, or otherwise) or other access to Patent Rights that are [***] the Biogen [***] that is incorporated into any Product under the [***] Collaboration Program and [***] will have no right of offset under Section 6.11 (Third Party Rights and Payment Obligations) for such Product Specific Payments, provided, however, the foregoing will not apply to any payments and other obligations to Third Parties to acquire rights (whether by purchase, assignment, license, or otherwise) or other access to Patent Rights that are [***] (a) [***] any Biogen [***], or (b) [***] any Biogen [***] (and such Product-Specific Payments, in each case ((a) and (b)), will remain subject to the terms of Article 6 (Financial Provisions), to the extent applicable).

13.   Prosecution and Maintenance, Defense, and Enforcement of Patents.

14.  Consequences of Termination or Failure to Designate a Development Candidate Prior to License Effective Date.  If (A) the Agreement with respect to the [***] Collaboration Program or the [***] Collaboration Program is terminated by Biogen pursuant to Section 10.3.2 (Biogen’s Termination for Convenience) before the License Effective Date for such Collaboration Program or the Option with respect to such Collaboration Program expires unexercised, (B) Biogen has not reasonably determined (and Biogen has not so notified Ionis in writing of such determination and the rationale therefor, which such notice must be delivered (I) in the event Biogen so terminates such Collaboration Program, then together with such notice of termination, or (II) in the event the Option with respect to such Collaboration Program expires unexercised, then prior to the expiration of the Option (each of (I) and (II), the “Reversion Notification Deadline”)) that any further Research, Development, Manufacture, and Commercialization of Terminated Strategy Products that are the subject of such Collaboration Program [***] (subject to Paragraph 16 of this letter agreement), and (C) such termination of the Agreement is not due to [***] that are reasonably demonstrated by Biogen to Ionis on or prior to the applicable Reversion Notification Deadline, then, in addition to the terms set forth in Section 10.6.1 (In General), the following terms will apply:

15.  Consequences of Termination After License Effective Date.  If (A) the Agreement with respect to the [***] Collaboration Program or the [***] Collaboration Program is terminated by Biogen under Section 10.3.2 (Biogen’s Termination for Convenience) after the License Effective Date for such Collaboration Program, (B) Biogen has not reasonably determined (and Biogen has not so notified Ionis in writing of such determination and the rationale therefor, which such notice must be delivered on or prior to the applicable Reversion Notification Deadline) that any further Research, Development, Manufacture, and Commercialization of Terminated Strategy Products that are the subject of such Collaboration Program [***] (subject to Paragraph 16 of this letter agreement), and (C) such termination of the Agreement is not due to [***] that are reasonably demonstrated by Biogen to Ionis on or prior to the applicable Reversion Notification Deadline, then, in addition to the terms set forth in Section 10.6.1 (In General), the following terms will apply:

The terms of Section 12.14 (Interpretation) will govern the terms of this letter agreement.  Except as otherwise expressly set forth herein, the provisions of the Agreement will remain in full force and effect and each Party reserves its rights thereunder.  In the event of any express conflict or inconsistency between this letter agreement and the Agreement, the terms of this letter agreement will apply.

If you accept the terms and conditions set forth in this letter agreement, please so indicate by executing a copy of this letter agreement and returning it to Ionis. This letter agreement may be executed in counterparts, each of which will be deemed an original, notwithstanding variations in format or file designation which may result from electronic transmission, store and printing of copies of this letter agreement from separate computers or printers. Facsimile signatures and signatures transmitted via electronic mail in PDF format will be treated as original signatures.