Document:

EXHIBIT 10.81

      

      

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

      

      

      December 31, 2020

      

      

      Biogen MA Inc.

      225 Binney Street

      Cambridge, MA 02142

      Attention: Chief Legal Officer

      Email: [***]@biogen.com

      

      

      Re:  [***] Collaboration Program

       

      Dear Anabella:

       

      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:

       

      	

            	a.	
              In Section 1.8.6 (Manufacturing and Supply for Collaboration Programs), the terms “ASO” and “API” will be deemed to exclude any [***] or [***] that

                is incorporated into any Compound, Development Candidate, or Product; and

            

       

      	

            	b.	
              In Section 4.8.2(c) (API and Product), the terms “bulk Development Candidate,” “API,” “Clinical Supplies” and “Finished Drug Product” will be deemed to include any ASO that is incorporated into the applicable Compound,
                Development Candidate or Product, whether alone or in combination with any [***] or [***].

            

       

      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:

       

      
        	 	
                Post-Option Development Milestone Event

              	 	
                Milestone Event Payment for

                 the first Product from 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:

       

      
        
          

      

      	 	
              Post-Option Development Milestone Event

            	 	
              Milestone Event Payment for 

              the first Product from the [***] 

              Collaboration Program

            
	 	
              [***]

            	 	
              $[***]

            
	 	
              [***]

            	 	
              $[***]

            
	 	
              [***]

            	 	
              $[***]

            

       

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

       

      	

            	a.	
              as between the Parties, Biogen is the sole owner of all rights, title, and interests in and to the Biogen [***], and the Biogen [***] will be considered
                Biogen [***] (and will not be considered [***], [***], or [***]);

            

       

      	

            	b.	
              all Patent Rights Controlled by Biogen directed to or claiming the Biogen [***] as a composition of matter in a manner acceptable to a recognized patent office (e.g.,
                the  United States Patent and Trademark Office, the European Patent Office, etc.), including by structure or sequence (the “Biogen [***] Patents”), will be solely owned by Biogen and will be considered Biogen [***] with respect to the [***]
                Collaboration Program (and will not be considered [***]).  For clarity, Patent Rights that are not Biogen [***] Patent Rights will not be considered Biogen [***], including Patent Rights solely directed to or solely claiming (i) [***] of Biogen [***] or (ii) [***] Biogen [***], and such Patent Rights will continue to be Biogen [***], [***] or

                [***], as applicable; and

            

       

      	

            	c.	
              without limiting Paragraph 10(a) of this letter agreement, all Know-How that was discovered, developed, invented or created by or on behalf of either Party or its Affiliates under the Agreement or this letter agreement that [***] Biogen [***] will be considered [***] (as applicable).

            

       

      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:

       

      	

            	a.	
              products that include an Oligonucleotide as an active pharmaceutical ingredient (other than products that (i) include an Oligonucleotide that is designed to bind to the RNA that encodes the same target as a product that is being
                developed or commercialized by Biogen, its Affiliates or Sublicensee pursuant to an Option or exclusive license granted from Ionis under this Agreement or any Ionis/Biogen Additional Agreement or (ii) incorporate any Biogen [***]); and

            

       

      

      
        
          

      

      	

            	b.	
              Gene-Editing Products that do not incorporate any Biogen [***].

            

       

      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.

       

      	

            	a.	
              Prosecution and Maintenance.

            

       

      	

            	i.	
              Prosecution and Maintenance of Biogen [***] Patents.  Notwithstanding any provision to the contrary set forth in Section

                  7.2 (Prosecution and Maintenance of Patents), Biogen will control and be responsible for all aspects of the Prosecution and Maintenance of all Biogen [***] Patents.

            

       

      	

            	ii.	
              Prosecution and Maintenance of Biogen [***] Patents.  Prosecution and Maintenance of all Patent Rights that claim
                any Biogen [***] (the “Biogen [***] Patents”)

                will be subject to the terms of Section 7.2 (Prosecution and Maintenance of Patents), to the extent applicable; provided, however, that
                notwithstanding any provision to the contrary set forth in Section 7.2.5 (Other Matters Pertaining to Prosecution and Maintenance of Patents) if (A) Ionis has the responsibility to Prosecute and Maintain any Biogen [***] Patents pursuant to Section 7.2 (Prosecution and Maintenance of Patents), (B) Biogen timely provides any comments with respect to any draft filing, communication, response, or strategy with
                respect to such Patent Rights in accordance with Section 7.2.5 (Other Matters Pertaining to Prosecution and Maintenance of Patents), and (C) Ionis decides not to incorporate any such comment timely provided by Biogen, then Biogen
                may refer the matter to Expert Resolution for resolution under Section 12.1.4 (Expert Resolution). If Biogen terminates the [***] Collaboration Program as described in Paragraph 14 or 15 of
                this letter agreement, then the terms of  Section 7.2 (Prosecution and Maintenance of Patents) and this Paragraph 13(a)(ii) will survive such termination solely with respect to the Prosecution and Maintenance of the Biogen [***] Patents.

            

       

      

      
        
          

      

      	

            	iii.	
              Coordination.  Notwithstanding Biogen’s right to Prosecute and Maintain the Biogen [***] Patents or each Party’s right to Prosecute and Maintain the Biogen
                [***] Patents to the extent provided in Section 7.2 (Prosecution and Maintenance of Patents) and this letter agreement, the Parties will, and will cause their Affiliates to, cooperate and
                implement reasonable patent filing and prosecution strategies (including filing divisionals, continuations or otherwise) to ensure that, to the extent reasonable and feasible, Patent Rights claiming the Biogen [***] and Patent Rights claiming any [***] directed to [***] under the [***] Collaboration Program
                are pursued in a manner that are not detrimental to each such set of Patent Rights.

            

       

      	

            	b.	
              Enforcement.

            

       

      	

            	i.	
              Enforcement of Biogen [***] Patents.  Notwithstanding any provision to the contrary set forth in Section 7.5
                (Enforcement of Patents against Competitive Infringement), for any Competitive Infringement with respect to a Product to the extent involving any Biogen [***] Patent, Biogen will have the sole right,
                but not the obligation, to institute, prosecute, and control any Proceeding with respect thereto by counsel of its own choice at its own expense.

            

       

      	

            	ii.	
              Enforcement of Biogen [***] Patents.  Any Competitive Infringement with respect to a Product to the extent
                involving any Biogen [***] Patent will be subject to the terms of Section 7.5 (Enforcement of Patents against Competitive Infringement); provided, however, that notwithstanding any provision to the contrary set forth in Section 7.5 (Enforcement of Patents against Competitive Infringement), if (A) Ionis has the right to institute, prosecute,
                and control any Proceeding to the extent involving any such Biogen [***] Patent pursuant to Section 7.5 (Enforcement of Patents against Competitive Infringement), (B) Biogen timely provides
                any comments with respect to filings, submissions and communications related to such Proceeding in accordance with Section 7.5 (Enforcement of Patents against Competitive Infringement), and (C) Ionis decides not to incorporate any
                such comment timely provided by Biogen, then Biogen may refer the matter to Expert Resolution for resolution under Section 12.1.4 (Expert Resolution).

            

       

      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:

       

      

      
        
          

      

      	

            	a.	
              Biogen’s Option under Section 3.1 (Option) will expire with respect to such Collaboration Program;

            

       

      	

            	b.	
              Notwithstanding anything to the contrary set forth in Section 2.1.1 (Exclusivity Covenants) and regardless of whether Biogen has exercised an Option for another Collaboration Program directed to [***],
                Ionis will be free to Develop, Manufacture and Commercialize Terminated Strategy Product(s) with respect to such Collaboration Program, on its own or with a Third Party, provided, however, that Ionis will not, on its own or with any Third Party, change, use an alternate, or in any way modify, any Terminated Strategy Product, including any Biogen [***]
                included therein, that is incorporated into any Terminated Strategy Product, except for any Permitted Changes in  Form.  For clarity, the terms of Section 2.1.1 (Exclusivity Covenants) will continue to govern the Development and
                Commercialization by Ionis or its Affiliates of any Products directed to [***] that are not Terminated Strategy Products, to the extent applicable.

            

       

      	

            	c.	
              To the extent requested by Ionis, Biogen will promptly transfer to Ionis all data, results, and information (including Biogen’s Confidential Information and any regulatory documentation (including drafts)) related to the testing and
                Clinical Studies for such Terminated Strategy Products in the possession of Biogen or its contractors, to the extent such data, results, and information were generated by or on behalf of Biogen under the Agreement; and Ionis will pay all
                out-of-pocket direct Third Party costs and expenses in transferring such data, results and information together with the Biogen FTE Cost in transferring such data, results and information.

            

       

      	

            	d.	
              The provisions of Section 10.6.3(h) will apply solely with respect to such Terminated Strategy Products (and for clarity, not with respect to other Discontinued Products that are the subject of such Collaboration Program), mutatis mutandis, and solely for the purposes of Section 10.6.3(h), [***] will be considered a Terminated Target thereunder, provided, however, that the terms of Section 10.6.3(h)(v) will not apply to, and Biogen will not be required to provide to Ionis, any Regulatory Materials that solely
                relate to the Biogen [***] incorporated into the Terminated Strategy Product, unless requested by a Regulatory Authority, in which case Biogen will provide such information to Ionis, solely for the purposes of submitting such information to such Regulatory Authority, subject to Article 11 (Confidentiality).

            

       

      

      
        
          

      

      	

            	e.	
              For the purposes of this letter agreement, “Terminated Strategy Products” means, with respect to the [***] Collaboration Program or the
                [***] Collaboration Program (as applicable), all Products that (i) are the subject of such Collaboration Program and that are in existence as of the effective date of termination of the Agreement with
                respect to such Collaboration Program, (ii) only utilize the Strategy of such Collaboration Program (i.e., as such Strategy is defined in the recitals to this letter agreement), and (iii) are either
                in the form that such Products exist as of such effective date of termination or are any Permitted Changes in Form.

            

       

      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:

       

      	

            	a.	
              The applicable licenses granted by Ionis to Biogen under the Agreement will terminate with respect to such Collaboration Program.  Biogen, its Affiliates and Sublicensees will cease selling the Products that are the subject of such
                Collaboration Program, unless Ionis elects to have Biogen continue to sell such Products as part of the Transition Services to the extent provided in Section 10.6.6 (Transition Services).

            

       

      	

            	b.	
              Notwithstanding anything to the contrary set forth in Section 2.1.1 (Exclusivity Covenants) and regardless of whether Biogen has exercised an Option for another Collaboration Program directed to [***],
                Ionis will be free to Develop, Manufacture and Commercialize Terminated Strategy Product(s) with respect to such Collaboration Program, on its own or with a Third Party, provided, however, that Ionis will not, on its own or with any Third Party, change, use an alternate, or in any way modify, any Terminated Strategy Product, including any Biogen [***]
                included therein, that is incorporated into any Terminated Strategy Product, except for any Permitted Changes in Form.  For clarity, the terms of Section 2.1.1 (Exclusivity Covenants) will continue to govern the Development and
                Commercialization by Ionis or its Affiliates of any Products directed to [***] that are not Terminated Strategy Products, to the extent applicable.

            

       

      

      
        
          

      

      	

            	c.	
              The provisions of Section 10.6.4(d), Section 10.6.4(e) and Section 10.6.4(f) will apply solely with respect to such Terminated Strategy Products (and for clarity, not with respect to other Discontinued Products
                that are the subject of such Collaboration Program), mutatis mutandis, and solely for the purposes of Section 10.6.4(d), Section 10.6.4(e) and Section 10.6.4(f), [***] will be considered a Terminated Target thereunder, provided, however, that (i) for the purposes of Section
                  10.6.4(f), to the extent requested by Ionis, Biogen will only be required to assign to Ionis any manufacturing agreements to the extent solely related to the Terminated Strategy Products (and, for clarity, will not be obligated to
                assign to Ionis any manufacturing agreements that relate to [***] generally), (ii) following the assignment back by Biogen to Ionis of the Product-Specific Patents described in Section
                  10.6.4(d)(v), Ionis will and hereby does grant to Biogen a worldwide, non-exclusive, sublicensable license under such Patent Rights to research, Develop, Manufacture, have Manufactured, register, market, and Commercialize any Biogen [***], whether alone or in combination with any other compound or conjugate, but excluding Terminated Strategy Products, and (iii) the terms of Section 10.6.4(d)(ix) will not apply to the
                Prosecution and Maintenance of any Biogen [***] Patents (and for clarity, the terms of Paragraph 13(a)(ii) of this letter agreement will apply to the Prosecution and Maintenance of such Patent
                Rights).

            

       

      	

            	16.	
              Disputes Regarding Biogen Notification of [***] Terminated Strategy Products.  If Ionis disputes Biogen’s determination under clause (B) of Paragraph 14 or clause (B) of Paragraph 15 of this
                letter agreement that any further Research, Development, Manufacture, and Commercialization of Terminated Strategy Products that are the subject of a terminated [***] Collaboration Program [***], then Ionis may refer the matter to Expert Resolution for resolution under Section 12.1.4 (Expert Resolution).

            

       

      	

            	17.	
              Publications Prior to License Effective Date.  Notwithstanding any provision to the contrary set forth in Section 11.4 (Press Release; Publications; Disclosure of Agreement):

            

       

      	

            	a.	
              Solely with respect to the [***] Collaboration Program, the terms of Section 11.4.4 (Prior to License Effective Date) are hereby amended and replaced with the following: “prior to the
                License Effective Date for the [***] Collaboration Program, neither Party will have sole right to issue press releases, publish, present or otherwise disclose the progress and results regarding such
                Products to the public without the prior written consent of the other Party”; and

            

       

      	

            	b.	
              Biogen will have the sole right to issue press releases, publish, present, or otherwise disclose the progress and results regarding the Biogen [***] if such press release, publication,
                presentation, or other disclosure does not disclose any progress or results regarding any [***] that is incorporated into any Product under the [***] Collaboration

                Program.

            

       

      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.

      

      

      [SIGNATURE PAGE FOLLOWS]

       

      

      
        
          

      

      	 	
              Sincerely,

            
	 	 
	 	
              /s/Brett Monia

            
	 	
              Brett Monia

            
	 	
              Chief Executive Officer

            
	 	
              Ionis Pharmaceuticals, Inc.

            

      

      

      AGREED AND CONFIRMED ON BEHALF OF BIOGEN MA INC.:

       

      	
              By:

            	
              /s/Anabella Villalobos

            
	
              Name:

            	
              Anabella Villalobos

            
	
              Title:

            	
              Senior Vice President, Biotherapeutics & Medicinal Sciences

            
	
              Date:

            	
              December 31, 2020Document

EXHIBIT 4.4    

DESCRIPTION OF THE REGISTRANT’S SECURITIES REGISTERED
PURSUANT TO SECTION 12 OF THE SECURITIES EXCHANGE ACT OF 1934
As of December 31, 2020, Upwork Inc. (“we,” “us,” or “our”) had one class of securities registered under Section 12 of the Securities Exchange Act of 1934, as amended: our common stock. 
The following summary of the terms of our common stock is based upon our restated certificate of incorporation, our amended and restated bylaws, and applicable provisions of the Delaware General Corporation Law (the “DGCL”). The summary is not complete, and is qualified by reference to our restated certificate of incorporation and our amended and restated bylaws, which are filed as exhibits to this Annual Report on Form 10-K and are incorporated by reference herein. We encourage you to read our restated certificate of incorporation, our amended and restated bylaws, and the applicable provisions of the DGCL for additional information.
Capitalization
Our authorized capital stock consists of 500,000,000 shares of capital stock, including 490,000,000 shares of common stock, $0.0001 par value per share, and 10,000,000 shares of undesignated preferred stock, $0.0001 par value per share. 
Common Stock 
Dividend Rights 
Subject to preferences that may apply to any shares of preferred stock outstanding at the time, the holders of our common stock are entitled to receive dividends out of funds legally available if our board of directors, in its discretion, determines to issue dividends and then only at the times and in the amounts that our board of directors may determine.
Voting Rights
Holders of our common stock are entitled to one vote for each share of common stock held on all matters submitted to a vote of stockholders. Our restated certificate of incorporation does not provide for cumulative voting for the election of directors. As a result, the holders of a majority of our voting shares can elect all of the directors then standing for election. Our restated certificate of incorporation establishes a classified board of directors that is divided into three classes with staggered three-year terms. Only one class of directors will be elected at each annual meeting of our stockholders, with the other classes continuing for the remainder of their respective three-year terms.
No Preemptive or Similar Rights 
Our common stock is not entitled to preemptive rights, and is not subject to redemption or sinking fund provisions.
Right to Receive Liquidation Distributions 
Upon our liquidation, dissolution, or winding-up, the assets legally available for distribution to our stockholders would be distributable ratably among the holders of our common stock and any participating preferred stock outstanding at that time, subject to prior satisfaction of all outstanding debt and liabilities and the preferential rights of and the payment of liquidation preferences, if any, on any outstanding shares of preferred stock.
Preferred Stock 
Our board of directors is authorized, subject to limitations prescribed by Delaware law, to issue preferred stock in one or more series, to establish from time to time the number of shares to be included in each series, and to fix the designation, powers, preferences, and rights of the shares of each series and any of its qualifications, limitations, or restrictions, in each case without further vote or action by our stockholders. Our board of directors can also increase or decrease the number of shares of any series of preferred stock, but not below the number of shares of that series then outstanding, without any further vote or action by our stockholders. Our board of directors may authorize the issuance of preferred stock with voting or conversion rights that could adversely affect the voting power or other rights of the holders of our common stock. The issuance of preferred stock, while providing flexibility in connection with possible acquisitions and other corporate purposes, could, among other things, have the 
effect of delaying, deferring, or preventing a change in our control and might adversely affect the market price of our common stock and the voting and other rights of the holders of our common stock. 
Anti-Takeover Provisions 
The provisions of Delaware law, our restated certificate of incorporation, and our amended and restated bylaws could have the effect of delaying, deferring, or discouraging another person from acquiring control of our company. These provisions, which are summarized below, may have the effect of discouraging takeover bids. 
Delaware Law 
We are subject to the provisions of Section 203 of the DGCL regulating corporate takeovers. In general, DGCL Section 203 prohibits a publicly held Delaware corporation from engaging in a business combination with an interested stockholder for a period of three years following the date on which the person became an interested stockholder unless: 
•prior to the date of the transaction, the board of directors of the corporation approved either the business combination or the transaction which resulted in the stockholder becoming an interested stockholder; 
•the interested stockholder owned at least 85% of the voting stock of the corporation outstanding at the time the transaction commenced, excluding for purposes of determining the voting stock outstanding, but not the outstanding voting stock owned by the interested stockholder, (i) shares owned by persons who are directors and also officers and (ii) shares owned by employee stock plans in which employee participants do not have the right to determine confidentially whether shares held subject to the plan will be tendered in a tender or exchange offer; or
•at or subsequent to the date of the transaction, the business combination is approved by the board of directors of the corporation and authorized at an annual or special meeting of stockholders, and not by written consent, by the affirmative vote of at least 66.67% of the outstanding voting stock that is not owned by the interested stockholder. 
Generally, a business combination includes a merger, asset or stock sale, or other transaction or series of transactions together resulting in a financial benefit to the interested stockholder. An interested stockholder is a person who, together with affiliates and associates, owns or, within three years prior to the determination of interested stockholder status, did own 15% or more of a corporation’s outstanding voting stock. We expect the existence of this provision to have an anti-takeover effect with respect to transactions our board of directors does not approve in advance. We also anticipate that DGCL Section 203 may also discourage attempts that might result in a premium over the market price for the shares of common stock held by stockholders.
Restated Certificate of Incorporation and Amended and Restated Bylaws Provisions 
Our restated certificate of incorporation and our amended and restated bylaws include a number of provisions that could deter hostile takeovers or delay or prevent changes in control of our management team, including the following: 
•Board of Directors Vacancies. Our amended and restated bylaws and our restated certificate of incorporation authorize only our board of directors to fill vacant directorships resulting from any cause or created by the expansion of our board of directors. In addition, the number of directors constituting our board of directors may be set only by resolution adopted by a majority vote of our entire board of directors. These provisions prevent a stockholder from increasing the size of our board of directors and gaining control of our board of directors by filling the resulting vacancies with its own nominees. This makes it more difficult to change the composition of our board of directors but promotes continuity of management.
•Classified Board of Directors. Our restated certificate of incorporation provides that our board of directors is classified into three classes of directors, with directors in each class serving for a term of three years. The existence of a classified board of directors could delay a successful tender offeror from obtaining majority control of our board of directors, and the prospect of that delay might deter a potential offeror. 
•Directors Removed Only for Cause. Our restated certificate of incorporation provides that stockholders may remove directors only for cause and only with the affirmative vote of the holders of at least two-thirds of the voting power of the then-outstanding shares of our outstanding common stock.
•Supermajority Requirements for Amendments of Our Restated Certificate of Incorporation and Amended and Restated Bylaws. Our restated certificate of incorporation further provides that the affirmative vote of holders of at least two-thirds of the voting power of our outstanding common stock will be required to amend certain provisions of our restated certificate of incorporation. The affirmative vote of holders of at least two-thirds of the voting power of our outstanding common stock is required to amend or repeal our amended and restated bylaws, although our amended and restated bylaws may be amended by a majority vote of our board of directors.
•Stockholder Action; Special Meeting of Stockholders. Our restated certificate of incorporation provides that our stockholders may not take action by written consent, but may only take action at annual or special meetings of our stockholders. As a result, holders of our capital stock would not be able to amend our amended and restated bylaws or remove directors without holding a meeting of our stockholders called in accordance with our amended and restated bylaws. Our restated certificate of incorporation and our amended and restated bylaws provide that special meetings of our stockholders may be called only by a majority of our board of directors, the Chairperson of our board of directors, our Chief Executive Officer, our President, or our Lead Independent Director, thus prohibiting a stockholder from calling a special meeting. These provisions might delay the ability of our stockholders to force consideration of a proposal or for stockholders to take any action, including the removal of directors.
•Advance Notice Requirements for Stockholder Proposals and Director Nominations. Our amended and restated bylaws provide advance notice procedures for stockholders seeking to bring business before our annual meeting of stockholders or to nominate candidates for election as directors at our annual meeting of stockholders. Our amended and restated bylaws also specify certain requirements regarding the form and content of a stockholder’s notice. These provisions might preclude our stockholders from bringing matters before our annual meeting of stockholders or from making nominations for directors at our annual meeting of stockholders if the proper procedures are not followed. We expect that these provisions might also discourage or deter a potential acquirer from conducting a solicitation of proxies to elect the acquirer’s own slate of directors or otherwise attempting to obtain control of our company.
•Proxy Access. Our amended and restated bylaws provide that, in certain circumstances, a stockholder or group of up to 20 stockholders may include director candidates that they have nominated in our annual meeting proxy materials. Such stockholder or group of stockholders need to own 3% or more of our outstanding common stock continuously for at least three years. The number of stockholder-nominated candidates appearing in any of our annual meeting proxy materials cannot exceed the greater of two individuals or 20% of our board of directors. The nominating stockholder or group of stockholders is also required to deliver certain information, and each nominee is required to meet certain qualifications, as described in more detail in the amended and restated bylaws.
•No Cumulative Voting. The DGCL provides that stockholders are not entitled to the right to cumulate votes in the election of directors unless a corporation’s certificate of incorporation provides otherwise. Our restated certificate of incorporation and amended and restated bylaws do not provide for cumulative voting.
•Issuance of Undesignated Preferred Stock. Our board of directors has the authority, without further action by the stockholders, to issue up to 10,000,000 shares of undesignated preferred stock with rights and preferences, including voting rights, designated from time to time by our board of directors. The existence of authorized but unissued shares of preferred stock enables our board of directors to render more difficult or to discourage an attempt to obtain control of us by means of a merger, tender offer, proxy contest, or other means.
•Choice of Forum. Our restated certificate of incorporation provides that the Court of Chancery of the State of Delaware is the sole and exclusive forum for: (i) any derivative action or proceeding brought on our behalf; (ii) any action asserting a claim of breach of a fiduciary duty owed to us by or our stockholders, or other wrongdoing by, any of our directors, officers, stockholders, employees, or agents; (iii) any action 
asserting a claim against us arising pursuant to any provision the DGCL, our restated certificate of incorporation, or our amended and restated bylaws or as to which the DGCL confers jurisdiction on the Court of Chancery of the State of Delaware; (iv) any action to interpret, apply, enforce or determine the validity of our restated certificate of incorporation or our amended and restated bylaws; or (v) any action asserting a claim against us that is governed by the internal affairs doctrine. Our amended and restated bylaws also provide that the federal district courts of the United States would be the exclusive forum for resolving any complaint asserting a cause of action arising under the Securities Act of 1933, as amended (the “Federal Forum Provision”).  In December 2018, the Delaware Court of Chancery found that provisions such as the Federal Forum Provision are not valid under Delaware law. In light of this decision of the Delaware Court of Chancery, we do not intend to enforce the Federal Forum Provision in our amended and restated bylaws unless and until there is a final determination by the Delaware Supreme Court regarding the validity of provisions such as the Federal Forum Provision. To the extent the Delaware Supreme Court makes a final determination that provisions such as the Federal Forum Provision are not valid as a matter of Delaware law, our board of directors intends to amend our amended and restated bylaws to remove the Federal Forum Provision.
Exchange Listing 
Our common stock is listed on The Nasdaq Global Select Market under the symbol “UPWK.” 
Transfer Agent and Registrar 
The transfer agent and registrar for our common stock is Computershare Trust Company, N.A. 

1

Source: [{"source": "alea-institute/alea-institute/kl3m-data-edgar-agreements/train-00322-of-00352.parquet"}, [{"source": "alea-institute/alea-institute/kl3m-data-edgar-agreements/train-00322-of-00352.parquet"}]]