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Execution Copy

Exhibit 10.68

Second Amended and Restated
Strategic Neurology Drug Discovery and Development Collaboration, Option and
License Agreement

Between

Ionis Pharmaceuticals, Inc.

And

Biogen MA Inc.

Dated October 17, 2018

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Table of Contents

 
Page
   
ARTICLE 1. RESEARCH AND DEVELOPMENT
2
     
1.1.
Collaboration Overview
2
 
1.2.
Research Programs
3
 
1.3.
Process for Designating High Interest Targets as Collaboration Targets or Biogen
Alternate Modality Targets
8
 
1.4.
Process for Designating Ionis Neurology Targets as Collaboration Targets
9
 
1.5.
Process for Designating ALS Targets as Collaboration Targets
9
 
1.6.
Consequences of Designating Collaboration Targets
10
 
1.7.
Consequences of Designating Biogen Alternate Modality Targets
11
 
1.8.
Deferring the Selection of a Collaboration Target or Biogen Alternate Modality
Target
11
 
1.9.
End of Research Term
13
 
1.10.
Ionis’ Research and Development Responsibilities
14
 
1.11.
Resource Allocations
27
 
1.12.
Research and Development Costs Paid by Ionis
28  
1.13.
Research and Development Costs Paid by Biogen
28
 
1.14.
Payment Mechanisms
29  
1.15.
Participation in Regulatory Meetings
31
 
1.16.
Participation in Meetings Sponsored by a Party’s Clinical Development Group
32  
1.17.
Impact of Accelerated Development Path
32
 
1.18.
Research and Development Management
33    
ARTICLE 2. EXCLUSIVITY COVENANTS
40      
2.1.
Exclusivity; Right of First Negotiation
40  
2.2.
Right of First Negotiation for Follow-On Compounds
44    
ARTICLE 3. EXCLUSIVE OPTION
46      
3.1.
Option
46  
3.2.
Changing or Adding Modalities
48  
3.3.
Restrictions on Ionis’ Right to Grant Diagnostic Rights; Right to Negotiate
Diagnostic Rights
52

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ARTICLE 4. LICENSE GRANTS
52      
4.1.
License Grants to Biogen
52  
4.2.
Assignment of Ionis Product-Specific Patents; Grant Back to Ionis
56  
4.3.
Enabling Licenses
56  
4.4.
Licenses to Ionis for Biogen Results
60  
4.5.
Right to Obtain Direct License from Biogen to Ionis Partner; Sublicensees of
Ionis
61  
4.6.
Ownership of and Assistance with Regulatory Filings
61
 
4.7.
Subcontracting
62  
4.8.
Technology Transfer
63    
ARTICLE 5. DEVELOPMENT, MANUFACTURING AND COMMERCIALIZATION
66      
5.1.
Biogen Diligence
66  
5.2.
Regulatory Matters; Global Safety Database; Pharmacovigilance Agreement
69  
5.3.
Research and Manufacturing Records
73  
5.4.
Product Development Plans for ALS Collaboration Programs and Biogen Conducted
Non-ALS Collaboration Programs
73    
ARTICLE 6. FINANCIAL PROVISIONS
73      
6.1.
Up-Front Fee
73
 
6.2.
Drug Discovery Milestone Payments
73
 
6.3.
Milestone Payments for Achievement of Milestone Events by Biogen Alternate
Modality Products
74  
6.4.
Non-ALS Collaboration Program Milestone Payments for Achievement of
Pre-Licensing Milestone Events
74
 
6.5.
ALS Collaboration Program Milestone Payments for Achievement of Pre-Licensing
Milestone Events
75  
6.6.
License Fee
76
 
6.7.
Milestone Payments for Achievement of Post-Licensing Milestone Events
76
 
6.8.
Limitations on Milestone Payments; Exceptions; Notice
77
 
6.9.
Royalty Payments to Ionis for Biogen Alternate Modality Products
78
 
6.10.
Royalty Payments to Ionis for Collaboration Products
79
 
6.11.
Limitation on Aggregate Reduction for Royalties for Collaboration Products
82
 
6.12.
Reverse Royalty Payments to Biogen for a Discontinued Collaboration Product
82
 
6.13.
Third Party Payment Obligations
83

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6.14.
Payments
84  
6.15.
Audits
86
 
6.16.
Taxes
86
 
6.17.
Interest
88
   
ARTICLE 7. INTELLECTUAL PROPERTY
88
     
7.1.
Ownership
88
 
7.2.
Prosecution and Maintenance of Patents
92
 
7.3.
Patent Costs
97
 
7.4.
Defense of Claims Brought by Third Parties
98
 
7.5.
Enforcement of Patents Against Competitive Infringement
100  
7.6.
Other Infringement
103  
7.7.
Patent Listing
103
 
7.8.
Joint Research Agreement under the Leahy-Smith America Invents Act
104  
7.9.
Obligations to Third Parties
104
 
7.10.
Additional Right and Exceptions
104
 
7.11.
Patent Term Extension
105    
ARTICLE 8. REPRESENTATIONS AND WARRANTIES
105      
8.1.
Representations and Warranties of Both Parties
105  
8.2.
Representations and Warranties of Ionis
106  
8.3.
Ionis Covenants
108  
8.4.
DISCLAIMER
109
   
ARTICLE 9. INDEMNIFICATION; INSURANCE
109      
9.1.
Indemnification by Biogen
109  
9.2.
Indemnification by Ionis
110  
9.3.
Procedure
110  
9.4.
Insurance
111  
9.5.
LIMITATION OF CONSEQUENTIAL DAMAGES
111    
ARTICLE 10. TERM; TERMINATION
112      
10.1.
Agreement Term; Expiration
112  
10.2.
Termination of the Agreement
113

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10.3.
Alternative Remedies to Termination Available to Biogen Prior to License
Effective Date
117  
10.4.
Consequences of Expiration or Termination of the Agreement
119    
ARTICLE 11. CONFIDENTIALITY
132      
11.1.
Confidentiality; Exceptions
132  
11.2.
Prior Confidentiality Agreement Superseded
132  
11.3.
Authorized Disclosure
132  
11.4.
Press Release; Publications; Disclosure of Agreement
133    
ARTICLE 12. MISCELLANEOUS
138      
12.1.
Dispute Resolution
138  
12.2.
Governing Law; Jurisdiction; Venue; Service of Process
139  
12.3.
Remedies
140  
12.4.
Assignment and Successors
141  
12.5.
Change of Control
141  
12.6.
Protective Provisions
146  
12.7.
Force Majeure
146  
12.8.
Notices
147  
12.9.
Export Clause
148  
12.10.
Waiver
148  
12.11.
Severability
148  
12.12.
Entire Agreement
148  
12.13.
Independent Contractors
149  
12.14.
Interpretation
149  
12.15.
Books and Records
149  
12.16.
Further Actions
149
 
12.17.
Construction of Agreement
149  
12.18.
Supremacy
150
 
12.19.
Counterparts
150  
12.20.
Compliance with Laws
150

iv

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

This SECOND AMENDED AND RESTATED STRATEGIC NEUROLOGY DRUG DISCOVERY AND
DEVELOPMENT COLLABORATION, OPTION AND LICENSE AGREEMENT (the “Agreement”) is
entered into as of the 17th day of October, 2018 (the “Second Amendment Date”)
by and between Ionis Pharmaceuticals, Inc., a Delaware corporation, having its
principal place of business at 2855 Gazelle Court, Carlsbad, CA 92010 (“Ionis”),
and Biogen MA Inc., a Massachusetts corporation, having its principal place of
business at 225 Binney Street, Cambridge, MA 02142 (“Biogen”). Biogen and Ionis
each may be referred to herein individually as a “Party” or collectively as the
“Parties.” Capitalized terms used in this Agreement, whether used in the
singular or the plural, have the meaning set forth in Appendix 1. All attached
appendices and schedules are a part of this Agreement.

RECITALS

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

WHEREAS, Biogen has expertise in developing and commercializing human
therapeutics, and is interested in entering into a strategic relationship with
Ionis to explore potential targets for the treatment of neurological and
neuromuscular diseases and to create antisense and other drugs to such targets;

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

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

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

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

WHEREAS, Biogen and Ionis seek to amend and restate the First Amended and
Restated Agreement in its entirety as set forth herein;

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

ARTICLE 1.
RESEARCH AND DEVELOPMENT

1.1.
Collaboration Overview.

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

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

2

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

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

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

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

1.1.7.
The purpose of this Section 1.1 is to provide a high-level overview of the
roles, responsibilities, rights and obligations of each Party under this
Agreement, and therefore this Section 1.1 is qualified in its entirety by the
more detailed provisions of this Agreement set forth below.

1.2.
Research Programs. Subject to and in accordance with the terms of this
Agreement, during the Research Term, Ionis and Biogen will conduct two research
programs, each under a separate mutually agreed plan. The first research program
will cover research focused on enhancing the Parties’ knowledge of ASO
pharmacokinetics and pharmacodynamics in the central and peripheral nervous
systems (such program, the “Core Research Program” and the plan for such
program, the “Core Research Plan”). The second research program will focus on
the identification and validation of High Interest Targets, and the
identification of ALS Targets, that are eligible to become Collaboration Targets
(such program, the “Neurological Disease Research Program” and the plan for such
program, the “Neurological Disease Research Plan”).  Drafts of the Core Research
Plan and the initial Neurological Disease Research Plan have been mutually
agreed upon by the Parties in writing on or prior to the Effective Date. The
Parties will finalize these initially agreed draft plans within [***] days after
the Effective Date. Thereafter, the Parties will update such plans at least once
before the beginning of each Calendar Year, and submit them to the Neurology JRC
for its review and approval.  Each update to the Neurological Disease Research
Plan will include, at a minimum (a) the activities to support Target Sanction in
the Calendar Year covered by such Neurological Disease Research Plan, (b) any
Neurological Disease research to support Collaboration Programs, and (c) any
ongoing work on High Interest Targets from prior Calendar Years. 
Notwithstanding the foregoing, neither Party will be required to complete any
activities under the Core Research Plan or Neurological Disease Research Plan if
such Party in good faith believes that such activities are not technically
feasible given the then-current state of the art.

3

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

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

 
1.2.3.
Neurological Disease Research Program. The Neurological Disease Research Program
activities will focus primarily on identifying and validating novel Neurology
Targets and prioritizing a list of High Interest Targets (defined below),
including ALS Targets.

4

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

5

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

(c)
Target Validation Under the Neurological Disease Research Program. The Neurology
JRC will agree on an update to the Neurological Disease Research Plan annually.
The first [***] years of the Research Term are planned to focus on validating
the role of novel Neurology Targets that are not ALS Targets in Neurological
Disease, with the goal of achieving Target Sanction for High Interest Targets,
and providing for all pre-clinical development work under the Neurological
Disease Research Plan required to validate such High Interest Targets. Biogen
will have final decision-making authority with respect to [***]. The Neurology
JRC will determine the number of High Interest Targets for which activities to
support Target Sanction will be conducted during each Calendar Year of the
Research Term, which number will reflect the number of targets the Neurology JRC
determines that Ionis can, in the exercise of Commercially Reasonable Efforts,
(i) [***], (ii) [***], (iii) [***], and taking into account resources that may
be used for ALS Targets, in each case using the number of FTEs provided for
under Section 1.11.  Prior to the initiation of any activities to support Target
Sanction with respect to any High Interest Target, Biogen will notify Ionis if
such High Interest Target is a Neurology Target with respect to which Biogen has
[***] intended for a neurology indication (a “Pre-Existing Target”).  Ionis will
use Commercially Reasonable Efforts to conduct such activities to support Target
Sanction on such High Interest Targets each year during the Research Term.  The
Neurological Disease Research Plan will identify which Party will be responsible
for the activities related to validation of such targets. It is anticipated that
Biogen will perform the [***] required under the Neurological Disease Research
Plan where Biogen, at such time, already has in place at Biogen or through its
collaborators the appropriate [***] and the ability to conduct such [***]; and
that all other such [***] will be conducted by Ionis. Each Party will be
responsible for the cost of the work it conducts under the Neurological Disease
Research Program as more specifically detailed in Section 1.12 and Section
1.13.  Neither Party will be required to conduct work using [***] that are not
similar in cost or technical feasibility to the [***] such Party has obtained
from Third Parties and uses for its other programs.

6

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

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

7

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

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

8

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

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

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1.6.
Consequences of Designating Collaboration Targets.

1.6.1.
Subject to and in accordance with the terms of this Agreement, for each
Collaboration Target designated under Section 1.3, Section 1.4, Section 1.5,
Section 1.8, Section 3.2.1 or Section 3.2.4.1, Ionis and Biogen will be
responsible for conducting collaboration programs in accordance with this
Agreement to discover, Develop and Manufacture Collaboration Products and, upon
Biogen’s exercise of the applicable Option, Biogen will be responsible for
Commercializing Collaboration Products (each, a “Collaboration Program”).  For
each Collaboration Target, an ASO Development Candidate Identification Plan and
Initial Development Plan will be established pursuant to Section 1.10.1 and
Section 1.10.2(d), respectively. For each Collaboration Program, Ionis will use
its Commercially Reasonable Efforts to (i) conduct drug discovery activities,
according to the applicable ASO Development Candidate Identification Plan to
identify a Development Candidate for the applicable Collaboration Target, and
(ii) for each Collaboration Program that is not an ALS Collaboration Program or
a Biogen Conducted Non-ALS Collaboration Program, conduct drug development
activities for each Development Candidate through completion of the first PoC
Trial in accordance with the applicable Initial Development Plan; provided that,
in each case unless the Neurology JRC unanimously agrees under Section 1.11 to
re-allocate resources to support additional Collaboration Programs and, except
for any activities Ionis conducts for Collaboration Targets designated under
that certain side letter between the Parties, dated as of October 28, 2016 (the
“ALS Letter Agreement”) attached hereto as Schedule 1.6.1, Ionis will not be
required to commence work on more than [***] Collaboration Programs in any
rolling [***] month period; provided, further, that, if Biogen has designated
more than [***] High Interest Targets as Collaboration Targets pursuant to
Section 1.3 in any rolling [***] month period, such excess targets will be
treated the same as “Deferred Targets” hereunder until the earlier of (a) such
time as Ionis has agreed to commence work on such excess targets, (b) such time
as Ionis is otherwise obligated to commence such work hereunder because Ionis
has commenced work on fewer than [***] targets in a rolling [***] month period
and (c) the expiration of the Research Term and, notwithstanding the provisions
of Section 6.2.1, Biogen will not be obligated to make the payment under Section
6.2.1 with respect to such target until such time. For each ALS Collaboration
Program and each Biogen Conducted Non-ALS Collaboration Program, Biogen will use
its Commercially Reasonable Efforts to conduct drug development activities for
each Development Candidate through completion of the [***] in accordance with
the applicable Initial Development Plan.

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

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

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

1.8.1.
Right to Defer. If under Section 1.3 Biogen provides Ionis a notice (each, a
“Deferral Notice”) electing to defer selecting a High Interest Target as a
Collaboration Target or a Biogen Alternate Modality Target (each, a “Deferred
Target”), and there is at least [***] at the time of Deferral Notice, then
Biogen may defer selecting such High Interest Target as a Collaboration Target
or a Biogen Alternate Modality Target for a period of up to the shorter of (i)
(A) with respect to any High Interest Target for which the best therapeutic
modality was determined to be an ASO, [***] or (B) with respect to any High
Interest Target for which the best therapeutic modality was determined to be an
Alternate Modality, [***], or (ii) the end of the Research Term (the “Deferral
Period”); provided, however, Biogen may only defer up to [***] High Interest
Targets under this Section 1.8.1 at any given time. For the avoidance of doubt,
the limitation in the preceding proviso will not apply with respect to any
Collaboration Target that is treated the same as a Deferred Target pursuant to
Section 1.6.1.

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

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

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

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

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

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

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1.10.
Ionis’ Research and Development Responsibilities.

1.10.1.
Development Candidate Identification.

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

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

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

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

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(e)
Carryover Development Candidates. If, by the end of the ASO Development
Candidate Identification Term for a particular Collaboration Program, Ionis has
not designated a Development Candidate for such Collaboration Program, and at
any time during the [***] period after the end of the applicable ASO Development
Candidate Identification Term Ionis’ RMC designates an ASO discovered by Ionis
that is designed to bind to the RNA that encodes the Collaboration Target for
such Collaboration Program as a development candidate ready to start
IND-Enabling Toxicology Studies (such ASO, a “Carryover Development Candidate”),
then, Ionis will notify Biogen and will provide Biogen with the data package
presented to Ionis’ RMC to approve such Carryover Development Candidate. Biogen
will then have [***] days from its receipt of such package to elect to enter
into an amendment to this Agreement under the same terms as set forth in this
Agreement (except that no additional upfront payment under Section 6.1 will be
due). If, within [***] days after Biogen’s receipt of such notice from Ionis,
Biogen provides Ionis with written notice that it accepts such offer from Ionis
for such Carryover Development Candidate, the Parties will execute an amendment
to this Agreement regarding such Carryover Development Candidate on such terms.
Otherwise, Ionis will have no further obligations and Biogen will have no
further rights with respect to such Carryover Development Candidate.

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

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

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

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(c)
IND-Enabling Toxicology Studies.

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

(ii)
For each ALS Collaboration Program and each Biogen Conducted Non-ALS
Collaboration Program, the applicable Neurology JDC will agree upon a high level
pre-clinical toxicology strategy no later than [***] days following its receipt
of the applicable Development Candidate Data Package.  In addition, the
applicable Neurology JDC will approve any study protocols for the IND-Enabling
Toxicology Studies at least [***] months prior to the anticipated commencement
of such IND-Enabling Toxicology Studies. If the Neurology JDC is unable to agree
on such high level pre-clinical toxicology strategy or study protocols for a
particular ALS Collaboration Program or Biogen Conducted Non-ALS Collaboration
Program within the applicable time period as set forth above in this Section
1.10.2(c)(ii), the matter will be referred to the CSC for resolution. If the CSC
cannot agree on such a high level pre-clinical toxicology strategy within [***]
days after the matter is so referred, or on any such study protocol within [***]
days after the matter is so referred, as applicable, then Biogen will have final
decision-making authority with respect thereto for IND-Enabling Toxicology
Studies conducted by Biogen. Solely with respect to the first ALS Collaboration
Program to have a Development Candidate, Ionis will conduct the IND-Enabling
Toxicology Studies utilizing the same mechanics as set forth in Section
1.10.2(c)(i), and upon Initiation of such IND-Enabling Toxicology Studies Biogen
will pay Ionis the applicable milestone payment under Section 6.5, which
IND-Enabling Toxicology Studies are complete as of the First Amendment Date for
the Collaboration Program for SOD-1.  Biogen will conduct, [***], all other
IND-Enabling Toxicology Studies for the ALS Collaboration Programs and the
Biogen Conducted Non-ALS Collaboration Programs, provided that Ionis may perform
study analyses with respect to the Biogen Conducted Non-ALS Collaboration
Programs if mutually agreed by the Parties.  If, with respect to a particular
ALS Collaboration Program or a particular Biogen Conducted Non-ALS Collaboration
Program, Biogen desires Ionis to provide consulting or advisory services, and
Ionis agrees to perform such services, Biogen will pay the costs of performing
such services using the payment mechanisms set forth in Section 1.14.1.

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For each ALS Collaboration Program and each Biogen Conducted Non-ALS
Collaboration Program (other than the Collaboration Program for [***]), provided
Ionis has delivered the API to support the IND-Enabling Toxicology Studies for
such Collaboration Program to Biogen under Section 1.10.6 at least [***] days
prior to the anticipated commencement of IND-Enabling Toxicology Studies for
such Collaboration Program (subject to Biogen’s timely delivery of an order for
such API), Biogen will Initiate the first IND-Enabling Toxicology Study for such
Collaboration Program within [***] days following Biogen’s receipt of the
applicable Development Candidate Data Package. If Biogen does not Initiate the
first IND-Enabling Toxicology Study for such Collaboration Program within [***]
days following Biogen’s receipt of the applicable Development Candidate Data
Package, if Ionis delivered the API to support the IND-Enabling Toxicology
Studies for such Collaboration Program to Biogen under Section 1.10.6 at least
[***] days prior to the anticipated commencement of IND-Enabling Toxicology
Studies for such Collaboration Program, then Biogen will be deemed to have
terminated this Agreement under Section 10.2.1 solely with respect to such
Collaboration Program; provided, however, that if there is a delay in Initiating
such IND-Enabling Toxicology Study caused by a condition outside of Biogen’s
control (including a delay by a Third Party vendor or a delay in supply of API
from Ionis from the timeline described in this Section 1.10.2(c)(ii)), Biogen
shall be excused from Initiating such IND-Enabling Toxicology Study for so long
as such condition continues, and this Agreement shall not be deemed to be
terminated with respect to such Collaboration Program, for so long as such
condition continues.

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

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

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(i)
The Party responsible for conducting the Clinical Studies under a Collaboration
Program will file and maintain the IND and other communications with Regulatory
Authorities for each Collaboration Program consistent with Section 5.2.1. 
Notwithstanding the foregoing, with respect to each Collaboration Program for
which Biogen is responsible for conducting the Clinical Studies, including each
ALS Collaboration Program and each Biogen Conducted Non-ALS Collaboration
Program, Ionis shall provide such reports and/or data as reasonably requested by
Biogen generated from Ionis’ activities performed under the applicable Initial
Development Plan (“Ionis Activities Data”) that may be useful in support of the
IND for the Development Candidate under such Collaboration Program; provided,
that, if, after receiving the Ionis Activities Data, Biogen requests that Ionis
provide Biogen with additional information outside of the scope of the Ionis
Activities Data that Biogen reasonably believes is necessary or useful to
support the IND, then, to the extent such additional information is in Ionis’
possession and delivering such data to Biogen will not breach any obligation
Ionis owes to a Third Party, Ionis will promptly deliver such additional
information to Biogen solely for Biogen to use to support the IND.  [***] will
bear the cost of the transfer of such additional information to Biogen pursuant
to the preceding sentence; provided, that if [***] would incur out-of-pocket
costs in excess of $[***] or FTE Costs in excess of the equivalent of [***] for
one FTE at the then-applicable Ionis FTE Rate in connection with the delivery of
such additional information, then [***] shall reimburse [***] for such excess.

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

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(iii)
If the Initial Development Plan relates to an ALS Collaboration Program or a
Biogen Conducted Non-ALS Collaboration Program, then Biogen will conduct the
Phase 1 Trial and will pay Ionis a milestone payment in the amount as set forth
in Table 2 of Section 6.5 or Table 1 of Section 6.4, as applicable.

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

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

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(e)
Cost Estimates. After designation of a Development Candidate under a
Collaboration Program that is not an ALS Collaboration Program or a Biogen
Conducted Non-ALS Collaboration Program, the applicable Neurology JDC will agree
on an initial estimate of the expected cost for Ionis to conduct the work [***]
specified in the applicable Initial Development Plan, including Ionis’ expected
[***] and [***] costs (each, a “Cost Estimate”). The initial Cost Estimate [***]
shall be agreed on by the applicable Neurology JDC no later than [***] months
prior to the anticipated [***]. Based on the Cost Estimates, the Neurology JDC
will establish the [***] and [***] milestone payments for such Collaboration
Program, which payments will be equal to (i) [***]; plus (ii) [***]. The Parties
will promptly negotiate in good faith using the Ionis/Biogen Additional
Agreements as a basis for Cost Estimates and, if the total milestone payment
[***] is more than $[***], the Parties will apportion such total milestone
payment into smaller milestone payments in accordance with Schedule 1.10.2(e);
provided, however, that if [***], then the Neurology JDC shall determine whether
and how to apportion such total milestone payment into smaller milestone
payments. Each such smaller milestone payment shall be payable by Biogen within
[***] days after receipt of the applicable invoice by Biogen following the event
that triggered such milestone payment. If the total milestone payment [***] is
$[***] or less, then such milestone payment shall become due in its entirety
upon [***], and shall be payable by Biogen within [***] days after receipt of
the applicable invoice by Biogen following [***]. As part of this process, Ionis
will provide the Neurology JDC with a good faith estimate of the cost to conduct
the work necessary to develop such Development Candidates under the applicable
Initial Development Plan using a similar methodology as used under the
Ionis/Biogen Additional Agreements. [***] months prior to the [***], using the
process set forth above, the Neurology JDC will re-assess the total cost of such
[***] and, if the cost has changed from the initial Cost Estimate, the Neurology
JDC will adjust the applicable milestone payment accordingly, with any such
adjustment to be agreed in writing to no later than the date that is [***]
months prior to the [***]. Once there is less than [***] months prior to the
[***], or such [***], if there are any changes to such [***] in accordance with
this Agreement that result in an increase to the cost of such [***], then (A) if
such cost is increased by more than [***], such increased costs will constitute
an additional milestone payment to be paid in accordance with the provisions of
this Section 1.10.2(e), or (B) if such cost is increased by [***], such increase
will not affect the milestone payments for such [***] established under this
Section 1.10.2(e), but instead will be handled in accordance with Section
1.14.1.  For clarity, with respect to any increase in the cost of a [***] by
more than [***]% under clause (A) of the preceding sentence, if such increased
costs total $[***] or less and such [***], then such increased costs shall
become due in their entirety immediately, and shall be payable by Biogen within
[***] days after receipt of the applicable invoice by Biogen. If the Neurology
JDC cannot agree on the Cost Estimates within [***] days of receiving the
proposed Cost Estimate, the matter will be referred to the CSC for resolution.
Once the Neurology JDC has agreed on a Cost Estimate and/or the [***] milestone
payments for such Collaboration Program are established under this Section
1.10.2(e) or Section 1.14.1, such agreement will be documented in a written side
letter, in the form and format attached hereto as Appendix 4, which shall be
executed by both Parties.

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(f)
Obligation to Start Development Activities. Ionis will not be required to
conduct any Development activities for a Development Candidate if the Initial
Development Plan, Specific Performance Milestone Events and the corresponding
Cost Estimates have not been agreed to pursuant to this Section 1.10.2.  Prior
to such time as the Parties mutually agree on such Cost Estimate and/or the
applicable [***] milestone payments and have executed a written side letter with
respect to the foregoing in accordance with Section 1.10.2(e), Ionis may, in its
discretion, commence Development activities for which it is responsible under
this Agreement; provided, however, that Biogen will not be responsible for any
costs of such Development activities if commenced by Ionis prior to the
execution of any such side letter unless and until such a side letter has been
executed by the Parties, and in no event will Biogen be responsible for any
amounts incurred by Ionis for such Development activities in excess of amounts
set forth in the side letter executed by the Parties with respect to such
Development activities.

(g)
Option Acceleration. If the PoC Trial for a Collaboration Program that is not an
ALS Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program
will be [***] or more, or require more than [***], then, if Ionis provides to
Biogen the notice described in the following sentence, Ionis will not be
required to conduct such PoC Trial for such Collaboration Program.  Ionis will
notify Biogen within [***] after finalization of the initial PoC Trial Design
pursuant to Section 1.10.2(d) (or each time there is a material change thereto)
for a Collaboration Program that is not an ALS Collaboration Program or a Biogen
Conducted Non-ALS Collaboration Program if Ionis elects not to conduct such PoC
Trial for such Collaboration Program (such notice, an “Option Acceleration
Notice”). If Ionis has delivered an Option Acceleration Notice as provided in
this Section 1.10.2(g), Biogen will have [***] from its receipt of the data
generated under the [***] for the first Phase 1 Trial for such Collaboration
Program (an “Option Acceleration Deadline”) to exercise its Option for the
applicable Collaboration Program.  If Biogen does not exercise its Option for
the applicable Collaboration Program by the applicable Option Acceleration
Deadline, Biogen’s Option under Section 3.1 with respect to such Collaboration
Program will expire and such Collaboration Program will terminate.

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

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

1.10.3.
Development Term. The term for the conduct of the Drug Development Program will
begin on the designation of the first Development Candidate and will end upon
the earlier of (a) completion of the Initial Development Plans under all
Collaboration Programs, which the Parties estimate will be approximately [***]
years after the Effective Date, (b) exercise by Biogen of its Option for all
Collaboration Programs, (c) the termination of the last Collaboration Program
and (d) mutual agreement of the Parties to terminate the Drug Development
Program.

1.10.4.
Drug Development.

(a)
Collaboration Programs Other than ALS Collaboration Programs and Biogen
Conducted Non-ALS Collaboration Programs.  For each Collaboration Program that
is not an ALS Collaboration Program or a Biogen Conducted Non-ALS Collaboration
Program, Ionis will use Commercially Reasonable Efforts to conduct all
activities under each Initial Development Plan on the timeline set forth in the
applicable Initial Development Plan. For each Biogen Conducted Non-ALS
Collaboration Program, Ionis will use Commercially Reasonable Efforts to conduct
all activities allocated to Ionis under each Initial Development Plan on the
timeline set forth in the applicable Initial Development Plan. Without limiting
the foregoing, Ionis may discontinue Development under an Initial Development
Plan if after having consulted, and having given good faith consideration to the
recommendations of the Neurology JDC and a mutually-agreed Third Party expert,
Ionis in good faith believes that continuing such Development would (i) pose an
unacceptable risk or threat of harm in humans, or (ii) violate any Applicable
Law, ethical principles, or principles of scientific integrity. Prior to
discontinuing Development under an Initial Development Plan, Ionis will provide
Biogen with reasonable advance notice of such discontinuation, including the
grounds for Ionis’ determination. If Ionis elects to discontinue Development
under an Initial Development Plan pursuant to this Section 1.10.4(a), Biogen
may, in its discretion, elect to continue Development of the applicable
Development Candidate by providing Ionis with written notice of Biogen’s
exercise of the Option within [***] after Ionis’ written notice to Biogen of
such discontinuation and [***]. If Biogen does not timely exercise its Option
under this Section 1.10.4(a), then the Option will expire.

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(b)
Phase 1 Trials. Each Phase 1 Trial will be conducted in accordance with the
applicable Phase 1 Trial Design set forth in the applicable Initial Development
Plan.

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

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

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

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

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

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

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1.10.6.
Clinical Supplies by Ionis. For Collaboration Programs that are not ALS
Collaboration Programs or Biogen Conducted Non-ALS Collaboration Programs,
Ionis, at its expense, will supply API (on its own or through a CMO approved by
Biogen) and Clinical Supplies to support the Research and Development activities
under each Neurology Plan through the License Effective Date with respect to a
Collaboration Program. If Biogen exercises an Option for a Collaboration Program
that is not an ALS Collaboration Program or a Biogen Conducted Non-ALS
Collaboration Program at least [***] prior to the planned Initiation of the PoC
Trial for the applicable Collaboration Program, Biogen may elect to either have
(a) Ionis supply Clinical Supplies for such PoC Trial (on its own or through a
CMO approved by Biogen), in which case Biogen will pay Ionis an amount equal to
[***] or (b) a CMO supply Clinical Supplies for such PoC Trial in accordance
with the Manufacturing Agreement entered into with such CMO. If Biogen exercises
an Option for a Collaboration Program that is not an ALS Collaboration Program
or a Biogen Conducted Non-ALS Collaboration Program prior to, but less than
[***] before, the planned Initiation of the PoC Trial for the applicable
Collaboration Program, Ionis will supply Clinical Supplies for such PoC Trial
(on its own or through a CMO approved by Biogen) and Biogen will pay Ionis an
amount equal to [***]. For ALS Collaboration Programs and Biogen Conducted
Non-ALS Collaboration Programs, Ionis will supply API (on its own or through a
CMO approved by Biogen) for clinical purposes in accordance with Schedule
1.10.6, and such supply will be at Biogen’s expense using the mechanism set
forth in Section 1.14.1, and Biogen will be responsible for all other aspects of
Clinical Supply for such clinical activities.

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

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

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1.12.
Research and Development Costs Paid by Ionis.

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

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

1.13.
Research and Development Costs Paid by Biogen.

1.13.1.
Before the License Effective Date.

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

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

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(c)
Additional Activities Approved by Biogen. If, with respect to a particular
Collaboration Program, Biogen desires that either Ionis or a Third Party [***]
or conduct other work to support Approval of a Collaboration Product, including
[***], prior to the License Effective Date, and Ionis agrees to perform such
work, Biogen will pay the costs of conducting such work using the payment
mechanisms set forth in Section 1.14.1.

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

1.14.
Payment Mechanisms.

1.14.1.
Payment Mechanics for Additional Activities Approved by Biogen.  Biogen will pay
Ionis (A) costs resulting from requests from Biogen that Ionis perform
additional work under this Agreement, including, the cost of Ionis’ time
incurred in performing such work at the then-applicable Ionis FTE Rate (“FTE
Costs”), the cost of [***], and any [***] incurred by Ionis in performing such
work, or (B) Additional Plan Costs resulting from Biogen-Approved Changes (such
costs, collectively “Biogen-Approved Costs”). For clarity, the Biogen-Approved
Costs shall include Additional Plan Costs for a [***] that result from changes
to such [***] made after the milestone payment with respect to such [***] is
agreed upon in writing by the Parties pursuant to Section 1.10.2(e), if such
cost is increased by [***] as described in Section 1.10.2(e)).  For the
avoidance of doubt, if such cost is increased by more than [***] as described in
Section 1.10.2(e)), such increased costs will constitute an additional milestone
payment to be paid in accordance with the provisions of Section 1.10.2(e), and
will not be handled under this Section 1.14.1.  Ionis will permit Biogen to
review, negotiate (with Ionis) and approve (including through the Neurology JDC)
all Biogen-Approved Costs; provided Biogen will provide a substantive, good
faith response within [***] days of Ionis’ request for approval.  For clarity
(1) this Section 1.14.1 will not be used to establish the initial milestone
payments under Section 1.10.2(e), and (2) expenses paid under Section 1.14.1(a)
and Section 1.14.1(b) are not subject to reconciliation. Once Biogen-Approved
Costs are mutually agreed under this Section 1.14.1, such agreement will be
documented in a written side letter, in the form and format attached hereto as
Appendix 4, which shall be executed by both Parties. Prior to such time as the
Parties mutually agree on such Biogen-Approved Costs and have executed a written
side letter with respect to the foregoing, Ionis may, in its discretion,
commence Development activities for which it is responsible under this
Agreement; provided, however, that Biogen will not be responsible for any costs
of such Development activities if commenced by Ionis prior to the execution of
any such side letter unless and until such a side letter has been executed by
the Parties, and in no event will Biogen be responsible for any amounts incurred
by Ionis for such Development activities in excess of amounts set forth in the
side letter executed by the Parties with respect to such Development activities.

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(a)
For Biogen-Approved Costs resulting from [***], or from [***] that are made
after the milestone payment with respect to such [***] is agreed upon in writing
by the Parties pursuant to Section 1.10.2(e), Biogen will pay Ionis for such
Biogen-Approved Costs [***] within [***] days after receipt of the applicable
invoice by Biogen following [***], or the date that Biogen agrees to such
changes to such [***], as applicable; provided, however, that if such
Biogen-Approved Costs total more than $[***], the Parties will apportion such
total Biogen-Approved Costs into smaller milestone payments in accordance with
Schedule 1.10.2(e) (or, if such Biogen-Approved Costs result from changes to a
[***], then the Neurology JDC shall determine whether and how to apportion such
Biogen-Approved Costs into smaller milestone payments).  Each such smaller
milestone payment shall be payable by Biogen within [***] days after receipt of
the applicable invoice by Biogen following the event that triggered such
milestone payment.  If such Biogen-Approved Costs total $[***] or less, then
such Biogen-Approved Costs shall become due in their entirety upon [***] or the
date that the Parties agree to such Biogen-Approved Costs, if such [***], and
shall be payable by Biogen within [***] days after receipt of the applicable
invoice by Biogen following [***] or the date of such agreement regarding the
Biogen-Approved Costs, as applicable.

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

(c)
For any Biogen-Approved Cost that (i) has an Estimated Biogen-Approved Cost of
less than $[***] and (ii) does not result from [***], from [***] that are made
after the milestone payment with respect to such [***] is agreed upon in writing
by the Parties pursuant to Section 1.10.2(e) or from [***], Ionis will invoice
Biogen directly for such Biogen-Approved Cost in advance, on a [***] basis based
upon the applicable Estimated Biogen-Approved Costs and Biogen will pay the
invoices submitted pursuant to this Section 1.14.1(c) for such Biogen-Approved
Costs within [***] days after receipt of the applicable invoice by Biogen.  For
purposes of this Section 1.14.1(c), “Measurement Period” means each [***].

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(d)
For any Biogen-Approved Costs that (i) has an Estimated Biogen-Approved Cost of
$[***] or more and (ii) does not result from [***], from [***] that are made
after the milestone payment with respect to such [***] is agreed upon in writing
by the Parties pursuant to Section 1.10.2(e) or from [***], Ionis will invoice
Biogen directly for such Biogen-Approved Cost in advance on a [***] basis based
upon the applicable Estimated Biogen-Approved Costs and Biogen will pay the
invoices submitted pursuant to this Section 1.14.1(d) for such Biogen-Approved
Costs within [***] days after receipt of the applicable invoice by Biogen.  For
purposes of this Section 1.14.1(d), “Measurement Period” means each [***].

(e)
Within [***] days after the end of the applicable Measurement Period, Ionis will
provide Biogen with a written statement (i) reconciling the [***] the Estimated
Biogen-Approved Costs and the [***] within the Biogen-Approved Costs (the
“Actual Biogen-Approved Costs”) incurred by Ionis during the just-ended
Measurement Period and (ii) confirming that the FTE Costs portion of the
Estimated Biogen-Approved Costs is a reasonable approximation of the actual FTE
Costs incurred by Ionis during the just-ended Measurement Period. If the
Estimated Biogen-Approved Costs exceed the Actual Biogen-Approved Costs for such
period, Ionis will, offset all such excess payments against any future invoices
under this Agreement until Biogen has recouped all such overpayments.  If the
Estimated Biogen-Approved Costs are less than the Actual Biogen-Approved Costs
for such period, Ionis will invoice Biogen for the remaining amounts owed to
Ionis, and Biogen will pay such invoices within [***] days of receipt of such
invoice. In the case where additional activities under this Section 1.14.1 are
performed by a Third Party, the Parties will arrange for the Third Party to
directly bill Biogen and for Biogen to pay such Third Party directly.

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

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

1.17.
Impact of [***] Development Path. If the Parties mutually agree to amend an
Initial Development Plan for a Collaboration Program that is not an ALS
Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program, where
such amended plan contemplates [***], then the Parties will make appropriate
changes to the operational terms of this Agreement (e.g., [***]) to reflect such
[***] development plan, consistent with the comparable provisions necessary to
support the development plan under the [***]; provided, that if the Initial
Development Plan for a Biogen Conducted Non-ALS Collaboration Program
contemplates such [***] development path, then the Parties will determine by
mutual agreement prior to commencing any [***] under such Initial Development
Plan whether to designate such [***] for such Biogen Conducted Non-ALS
Collaboration Program. Nothing in this Section 1.17 will affect either Party’s
rights or obligations under Section 1.10.2(g).

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1.18.
Research and Development Management.

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

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

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

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

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

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

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

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

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

(viii)
providing input to the JPC as appropriate;

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

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

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

1.18.2.
Neurology JRC. The Parties will establish a joint research committee (the
“Neurology JRC”) reporting to the CSC, to provide advice and make
recommendations on the conduct of activities under the Core Research Program,
Neurological Disease Research Program and each Collaboration Program up to
Development Candidate designation. The Neurology JRC will consist of up to three
representatives appointed by Ionis and up to three representatives appointed by
Biogen. Each Neurology JRC member will have experience and expertise appropriate
for the Core Research Program, Neurological Disease Research Program and/or the
stage of development of the Collaboration Programs. Each Party will designate
one of its representatives who is empowered by such Party to make decisions
related to the performance of such Party’s obligations under this Agreement to
act as the co-chair of the Neurology JRC. The co-chairs will be responsible for
overseeing the activities of the Neurology JRC consistent with the
responsibilities set forth below in this Section 1.18.2. Schedule 1.18.2 sets
forth certain Neurology JRC governance matters agreed to as of the Effective
Date. The Neurology JRC will determine the Neurology JRC operating procedures at
its first meeting, including the Neurology JRC’s policies for replacement of
Neurology JRC members, policies for participation by additional representatives
or consultants invited to attend Neurology JRC meetings, and the location of
meetings, which will be codified in the written minutes of the first Neurology
JRC meeting. Each Party will be responsible for the costs and expenses of its
own employees or consultants attending Neurology JRC meetings. Ionis and Biogen
will use reasonable efforts to schedule meetings of the Neurology JRC to take
place at the same location and on the same dates as meetings of the CSC and the
joint development and steering committees under the Ionis/Biogen Additional
Agreements, to maximize the use of each Party’s time, increase information
sharing efficiencies and reduce the cost of additional travel, lodging and
related expenses.

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

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

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

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

(iv)
allocate resources under Section 1.11;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

1.18.3.
Joint Development Committees. For each Development Candidate, the CSC will
appoint a joint development committee (each, a “Neurology JDC”) approximately
[***] days prior to the date Ionis expects to designate a Development Candidate,
to govern the activities under this Agreement with respect to such Collaboration
Program. Each Neurology JDC will report to the CSC and will consist of an equal
number of representatives appointed by Ionis and Biogen. Each Neurology JDC
member will be a senior clinical development leader or have other experience and
expertise appropriate for the stage of development of the Collaboration Program
in the applicable disease area, and at least one of each Party’s members will
have operational responsibility for the applicable Collaboration Program. Each
Party will designate one of its representatives who is empowered by such Party
to make decisions related to the performance of such Party’s obligations under
this Agreement to act as the co-chair of the Neurology JDC. The co-chairs will
be responsible for overseeing the activities of the Neurology JDC consistent
with the responsibilities set forth below in this Section 1.18.3. Schedule
1.18.3 sets forth certain Neurology JDC governance matters agreed to as of the
Effective Date. Each Neurology JDC will determine its operating procedures at
its first meeting, including the Neurology JDC’s policies for replacement of
Neurology JDC members, policies for participation by additional representatives
or consultants invited to attend Neurology JDC meetings, and the location of
meetings, which will be codified in the written minutes of the first Neurology
JDC meeting. Each Party will be responsible for the costs and expenses of its
own employees or consultants attending Neurology JDC meetings. If practical,
Ionis and Biogen will use reasonable efforts to schedule meetings of each
Neurology JDC to take place at the same location and on the same dates as
meetings of the CSC and the joint development and steering committees under the
Ionis/Biogen Additional Agreements, to maximize the use of each Party’s time,
increase information sharing efficiencies and reduce the cost of additional
travel, lodging and related expenses.

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

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

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

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

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

(v)
if any Biogen-Approved Costs that result from [***] exceed $[***], establishing
whether and how such payments shall be apportioned into smaller milestone
payments as described in Section 1.14.1(a);

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

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

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

1.18.4.
Decision Making.

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

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(b)
Implementation. Each Party will give due consideration to, and consider in good
faith, the recommendations and advice of the CSC, the Neurology JRC and
Neurology JDC (as applicable) regarding the conduct of the Core Research
Program, Neurological Disease Research Program and each Collaboration Program.
Subject to Section 1.10.1 and Section 1.10.2, prior to the License Effective
Date with respect to the applicable Collaboration Program, (i) Ionis will have
the final decision-making authority regarding [***] and (ii) Biogen will have
the final decision-making authority regarding [***]. After the License Effective
Date with respect to a particular Collaboration Program, Biogen will have sole
decision-making authority regarding [***] of Collaboration Products for such
Collaboration Program, provided, however, that [***]. Except as otherwise
expressly stated in this Agreement, the CSC, the Neurology JRC and Neurology JDC
will have no decision making authority and will act as a forum for sharing
information about the activities conducted by the Parties hereunder and as an
advisory body, in each case only on the matters described in, and to the extent
set forth in, this Agreement.

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

1.18.6.
Alliance Managers. Each Party will appoint a representative to act as its
alliance manager under this Agreement (each, an “Alliance Manager”). Each
Alliance Manager will be responsible for supporting the CSC, the Neurology JRC
and Neurology JDC, and performing the activities listed in Schedule 1.18.6.

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ARTICLE 2.
EXCLUSIVITY COVENANTS

2.1.
Exclusivity; Right of First Negotiation.

2.1.1.
Exclusivity Covenants.

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

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

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(c)
Ionis’ Exclusivity Covenants for Biogen Alternate Modality Targets. With respect
to each Biogen Alternate Modality Target, except in the performance of its
obligations or exercise of its rights under this Agreement and except as set
forth in Section 2.1.2, Section 10.4.3 or Section 10.4.4, neither Ionis nor any
of its Affiliates will work independently or for or with any Third Party
(including the grant of any license to any Third Party) with respect to the
discovery, research, development, manufacture or commercialization of an
Oligonucleotide designed to bind to the RNA encoding such Biogen Alternate
Modality Target without Biogen’s prior written consent; provided, however, that
if (A) Biogen, its Affiliates or Sublicensees have not [***] within [***] (or,
if Biogen has used Commercially Reasonable Efforts to [***], within [***]) after
the date the applicable Neurology Target becomes a Biogen Alternate Modality
Target in accordance with this Agreement, or (B) after [***], Biogen, its
Affiliates and Sublicensees thereafter cease to use Commercially Reasonable
Efforts to develop or commercialize such Product (or otherwise stops developing
or commercializing such Product), then (i) the exclusive license granted to
Biogen under Section 4.1.1(b) for such Biogen Alternate Modality Target will
convert to a non-exclusive license, and (ii) Ionis and its Affiliates may
independently or for or with any Third Party (including the grant of any license
to any Third Party) research, develop, and commercialize Oligonucleotides
designed to bind to the RNA encoding such Biogen Alternate Modality Target (each
such Oligonucleotide, an “Ionis Non-Exclusive Product”), but not, for the
avoidance of doubt, any molecule or product designed to [***] that is not [***],
and the license to Biogen under Section 4.1.1(b) will become a non-exclusive
license to the extent necessary to allow Ionis to conduct such activities.

(d)
The Parties’ Exclusivity Covenants during the Option Period for Collaboration
Targets. Each Party agrees that, except in the performance of its obligations or
exercise of its rights under this Agreement and except as set forth in Section
2.1.2, Section 2.2, Section 10.4.3 or Section 10.4.4, neither it nor any of its
Affiliates will work independently or for or with any Third Party (including the
grant of any license to any Third Party) with respect to discovery, research,
development, manufacture or commercialization in the Field of an Oligonucleotide
that is designed to bind to the RNA that encodes a Collaboration Target from the
date such gene target was designated a Collaboration Target under this Agreement
through the expiration or earlier termination of the applicable Option Period.

(e)
The Parties’ Exclusivity Covenants after the License Effective Date. Except in
the performance of its obligations or exercise of its rights under this
Agreement and except as set forth in Section 2.1.2, Section 2.2, Section 10.4.3
or Section 10.4.4, if Biogen timely exercises an Option in accordance with this
Agreement, then neither Ionis nor Biogen nor their respective Affiliates will
work independently or for or with any Third Party (including the grant of any
license to any Third Party) with respect to:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

2.1.4.
Effect of Exclusivity on Indications. The Compounds are designed to bind to the
RNA that encodes a Collaboration Target with the intent of treating a
Neurological Disease in the Field. Ionis and Biogen are subject to exclusivity
obligations under Section 2.1; however, the Parties acknowledge and agree that,
except as otherwise provided herein, each Party and its Affiliates (on its own
or with a Third Party) may continue to discover, research, develop, manufacture
and commercialize products that are designed to bind to the RNA that encodes a
gene that is not (i) a High Interest Target to the extent Section 2.1.1(a) still
applies, (ii) a Biogen Alternate Modality Target to the extent Section 2.1.1(c)
still applies, or (iii) a Collaboration Target, in each case for any indication,
even if such products are designed to treat a Neurological Disease.

2.2.
Right of First Negotiation for Follow-On Compounds. On a Collaboration
Program-by-Collaboration Program basis, during the period commencing on the
Effective Date and ending upon (i) if the applicable Option is not exercised in
accordance with this Agreement, [***], or (ii) if the applicable Option is
exercised in accordance with this Agreement, [***] (such period, the “ROFN
Period”), Ionis hereby grants to Biogen a right of first negotiation to develop
and commercialize any Follow-On Compound developed by or on behalf of Ionis,
which right of first negotiation is granted on the following terms and
conditions:

2.2.1.
Within [***], Biogen may provide Ionis with a non-binding, good faith written
notice expressing Biogen’s desire for Ionis to identify a Follow-On Compound (a
“Follow-On Interest Notice”). If (i) Biogen does not, within such [***] period,
provide Ionis with a Follow-On Interest Notice, or (ii) Biogen does timely
provide Ionis with a Follow-On Interest Notice but the Parties do not agree on a
[***] related to such Follow-On Compound by 5:00 pm (Eastern Time) on the [***]
following the date of the License Effective Date with respect to such
Collaboration Program, then, Ionis may work independently or with any of its
Affiliates or any Third Party with respect to the discovery, research,
development and manufacture of a Follow-On Compound; provided, however, that
during the ROFN Period, Ionis will not grant any license (or an option to obtain
such a license) under any intellectual property owned, controlled or licensed by
Ionis to make, use or sell any Follow-On Compound (a “Follow-On Agreement”)
unless and until Ionis provides a written notice to Biogen (a “Follow-On
Negotiation Notice”), which notice identifies [***].  Ionis will not initiate
negotiations regarding or enter into such a Follow-On Agreement with any Third
Party until [***].

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2.2.2.
If Biogen or one of its Affiliates responds within [***] after its receipt of
the Follow-On Negotiation Notice indicating that Biogen or one of its Affiliates
desires to negotiate with Ionis regarding the proposed Follow-On Agreement,
Ionis and Biogen or one of its Affiliates will negotiate in good faith with each
other until the [***] after the date Ionis provided Biogen the Follow-On
Negotiation Notice (or such other period as mutually agreed by the Parties) (the
“Negotiation Period”) regarding a mutually satisfactory Follow-On Agreement
(which may take the form of an amendment to this Agreement). During the
Negotiation Period, Ionis will make at least [***] to Biogen or its Affiliate
setting forth all material business and legal terms on which Ionis would be
willing to enter into the proposed Follow-On Agreement with Ionis; provided,
that neither Party will have any obligation to enter into a Follow-On Agreement.
If the Negotiation Period expires before Biogen or its Affiliate and Ionis have
entered into such a Follow-On Agreement, Ionis will have no further obligation
to negotiate with Biogen or its Affiliates with respect to such Follow-On
Agreement and Ionis will be free to negotiate and enter an agreement with a
Third Party with respect to a Follow-On Agreement [***]; provided, however, that
Ionis will not enter into any such Follow-On Agreement with any Third Party
unless the terms and pricing of such Follow-On Agreement, [***] during the
Negotiation Period. If, with respect to any Follow-On Compound that was the
subject of the Follow-On Agreement previously discussed by the Parties, after
the end of the Negotiation Period and prior to Ionis entering into a Follow-On
Agreement with a Third Party, [***] regarding the Follow-On Compound, Ionis’
obligations and Biogen’s rights under Section 2.2.1 and this Section 2.2.2 will
reset and Ionis will provide Biogen with a new Follow-On Negotiation Notice.

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

2.2.4.
Notwithstanding anything to the contrary in this Agreement, until [***], Ionis
will provide to Biogen a Follow-On Negotiation Notice for each [***] pursuant to
this Section 2.2, unless Ionis enters into a Follow-On Agreement with a Third
Party pursuant to this Section 2.2 and the terms of such agreement do not permit
Ionis to grant Biogen rights with respect to the applicable Follow-On Compound.

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

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ARTICLE 3.
EXCLUSIVE OPTION

3.1.
Option.

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

3.1.2.
PoC Trial Completion Notice. On a Collaboration Program-by-Collaboration Program
basis where Ionis conducts the first PoC Trial, Ionis will provide to Biogen or
its designated Affiliate (i) a copy of the most recent Investigator’s Brochure
for the applicable Collaboration Product, (ii) written notice from Ionis
regarding completion of the first PoC Trial, and (iii) the PoC Data Package for
such Collaboration Program, to the extent not already provided to Biogen under
Section 3.1.1 above (such notice and package, a “PoC Trial Completion Notice”)
promptly, and in any event within [***] days after database lock for the PoC
Trial for such Collaboration Program.  Within 15 days of receipt of the PoC
Trial Completion Notice, Biogen or an Affiliate will notify Ionis of any
omissions or deficiencies that Biogen or its Affiliate believes in good faith
cause the PoC Trial Completion Notice to be incomplete (“Deficiency Notice”).
Ionis will promptly, and in any event within 15 days of receipt of the
Deficiency Notice, resubmit a complete PoC Trial Completion Notice to Biogen or
its designated Affiliate, including any information required to be included in
the PoC Data Package that Biogen identified in the Deficiency Notice. If the
Parties do not agree as to whether the PoC Trial Completion Notice is complete,
the matter will be referred to the Executives for resolution. The Executives
will meet promptly and negotiate in good faith to resolve the dispute and agree
upon a complete PoC Trial Completion Notice.

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3.1.3.
Option and Option Deadline. On a Collaboration Program-by-Collaboration Program
basis, Ionis hereby grants to Biogen and its Affiliates an exclusive option to
obtain the license set forth in Section 4.1.1(a) with respect to such
Collaboration Program (each an “Option”). Each Option for a Collaboration
Program that is not an ALS Collaboration Program or a Biogen Conducted Non-ALS
Collaboration Program will be available to Biogen and its Affiliates until 5:00
pm (Eastern Time) on the [***] following Biogen’s receipt of a complete PoC
Trial Completion Notice for the applicable Collaboration Program (the
“Standard Option Deadline”). Each Option for an ALS Collaboration Program will
be available to Biogen and its Affiliates until 5:00 pm (Eastern Time) on the
earlier of (A) the [***] following Biogen’s receipt of the data generated under
the statistical analysis plan after initial database lock for the first PoC
Trial for the applicable ALS Collaboration Program, and (B) the [***] of the
date a Development Candidate under such ALS Collaboration Program was designated
(the “ALS Option Deadline”). Each Option for a Biogen Conducted Non-ALS
Collaboration Program will be available to Biogen and its Affiliates until 5:00
pm (Eastern Time) on the earlier of (X) the [***] following Biogen’s receipt of
the data generated under the statistical analysis plan after initial database
lock for the first PoC Trial for the applicable Biogen Conducted Non-ALS
Collaboration Program, and (Y) the [***] of the date a Development Candidate
under such Biogen Conducted Non-ALS Collaboration Program was designated (the
“Biogen Conducted Non-ALS Option Deadline”). Notwithstanding the foregoing, if
Biogen determines that an HSR Filing is required to be made under the HSR Act to
exercise an Option and notifies Ionis of such determination within [***] after
Biogen’s receipt of the complete PoC Trial Completion Notice, the Parties will
promptly file an HSR Filing in accordance with Section 3.1.4 and the Option
Deadline will be extended until 5:00 pm (Eastern Time) on the fifth Business Day
after the HSR Clearance Date. If, by the Option Deadline, Biogen or its
designated Affiliate (i) notifies Ionis in writing that it wishes to exercise
the applicable Option, and (ii) pays to Ionis the license fee set forth in
Section 6.6, Ionis will, and hereby does, grant to Biogen or its designated
Affiliate the license set forth in Section 4.1.1(a). If, by the Option Deadline,
Biogen or its designated Affiliate has not both (y) provided Ionis a written
notice stating that Biogen is exercising its Option, and (z) paid Ionis the
license fee in accordance with Section 6.6, then Biogen’s Option for the
applicable Collaboration Program will expire and Biogen will promptly transfer
to Ionis all data, results and information (including Biogen’s Confidential
Information and any regulatory documentation (including drafts)) related to the
testing and Clinical Studies under such Collaboration Program in the possession
of Biogen and its contractors to the extent such data, results and information
were generated by or on behalf of Biogen under this Agreement (and [***] will
pay all out-of-pocket direct Third Party costs and expenses in transferring such
data, results and information together with Biogen’s FTE Cost in transferring
such data, results and information).

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3.1.4.
HSR Compliance.

(a)
HSR Filing. If Biogen notifies Ionis pursuant to Section 1.7 or Section 3.1.3
that an HSR Filing is required for Biogen to receive the license under Section
4.1.1(b) or exercise an Option under this Agreement, each of Biogen and Ionis
will, within five Business Days after such notice from Biogen (or such later
time as may be agreed to in writing by the Parties), file with the United States
Federal Trade Commission (“FTC”) and the Antitrust Division of the United States
Department of Justice (“DOJ”), any HSR Filing required with respect to the
transactions contemplated hereby. The Parties will cooperate with one another to
the extent necessary in the preparation of any such HSR Filing. Each Party will
be responsible for its own costs and expenses (other than filing fees, which
Biogen will pay) associated with any HSR Filing.

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

3.2.
Changing or Adding Modalities.

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

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

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3.2.3.
Economics for Changing Modalities.

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

(b)
If, pursuant to Section 3.2.2, Biogen elects to designate a Collaboration Target
as a Biogen Alternate Modality Target, the provisions related to Biogen
Alternate Modality Programs under this Agreement, including Sections 6.3 and 6.9
will apply with respect to such Biogen Alternate Modality Target; provided,
however, that (i) if the Collaboration Target Biogen changed to a Biogen
Alternate Modality Target was not an ALS Target, then no payment will be due
under Section 6.2.2 with respect to such Biogen Alternate Modality Target and
(ii) if Ionis elects to continue to develop and commercialize such
Oligonucleotides under clause (ii) of Section 3.2.2 Biogen will not be required
to pay Ionis any un-accrued milestone payments or royalties under Section 6.3
and Section 6.9 solely with respect to the applicable Biogen Alternate Modality
Product Developed and Commercialized by Biogen as a result of its conversion to
a Biogen Alternate Modality Target under Section 3.2.2.

3.2.4.
Adding an Additional Modality.

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

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

3.2.5.
HSR Compliance with Respect to Biogen Alternate Modality Targets.  If Biogen
determines that an HSR Filing is required to be made under the HSR Act for
Biogen to receive the license under Section 4.1.1(b) with respect to any Biogen
Alternate Modality Target that is designated under Section 3.2.2 or Section
3.2.4.2 and notifies Ionis of such determination within 10 days after Biogen’s
notice to Ionis under such section, the Parties will promptly file an HSR Filing
in accordance with Section 3.1.4 and the deadline for Biogen to pay Ionis the
milestone payment (or, if applicable, a portion thereof as provided in Section
3.2.3) under Section 6.2.2 will be extended until 5:00 pm (Eastern Time) on the
fifth Business Day after the HSR Clearance Date.

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

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

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

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

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

ARTICLE 4.
LICENSE GRANTS

4.1.
License Grants to Biogen.

4.1.1.
Development and Commercialization Licenses.

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

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(b)
Biogen Alternate Modality Products. Subject to the terms and conditions of this
Agreement, on a Biogen Alternate Modality Target-by-Biogen Alternate Modality
Target basis, effective upon the date Biogen pays Ionis the milestone payment
under Section 6.2.2 for a particular Biogen Alternate Modality Target, Ionis
grants to Biogen a worldwide, exclusive, royalty-bearing, sublicensable (in
accordance with Section 4.1.2 below) license under the Licensed Technology to
research, Develop, Manufacture, have Manufactured (in accordance with Section
4.1.2 below), register, market and Commercialize Biogen Alternate Modality
Products in the Field.

4.1.2.
Sublicense Rights; CMO Licenses.

(a)
Subject to the terms and conditions of this Agreement, Biogen will have the
right to grant sublicenses under the licenses granted under Section 4.1.1(a) and
Section 4.1.1(b) above and Section 4.3.1(b) below:

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

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

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

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(b)
In connection with Biogen’s selecting and engaging one or more CMOs to supply
Clinical Supplies under Section 4.3.1(b) or after a license is granted under
Section 4.1.1, or supply API and Finished Drug Product for Commercialization,
Ionis will, at Biogen’s option, either (1) grant a license from Ionis to [***]
under the [***] to the extent necessary for [***], which Ionis agrees it will
grant to [***], or (2) permit Biogen to grant a sublicense from Biogen to [***].
For Collaboration Products, each such manufacturing agreement between Biogen and
a CMO will contain [***]. Biogen will provide Ionis with a true and complete
copy of any manufacturing agreement entered into with a CMO within [***] days
after the execution thereof. Notwithstanding the foregoing, if Ionis fails to
comply with the terms of this Section 4.1.2(b) and does not cure such failure
within 90 days after written notice from Biogen specifying the details of any
such failure, Biogen will have the right to [***].

4.1.3.
Effect of Termination on Sublicenses.

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

(b)
If this Agreement terminates for any reason, any Sublicensee of Biogen under
Section 4.3.2 and any Sublicensee of Ionis under Section 4.5.2 will, from the
effective date of such termination, automatically become a direct licensee with
respect to the rights sublicensed to the Sublicensee by the applicable Party
hereunder; so long as (i) such Sublicensee is not in breach of its sublicense
agreement, (ii) such Sublicensee agrees in writing to comply with all of the
terms of this Agreement to the extent applicable to the rights originally
sublicensed to such Sublicensee, and (iii) with respect to Sublicensees of
Ionis, such Sublicensee agrees to pay directly to Biogen such Sublicensee’s
payments under Section 4.4.2 to the extent applicable to the rights sublicensed
to it by Ionis.  Each Party agrees that it will confirm clause (i) of the
foregoing in writing at the request and for the benefit of the other Party and
if requested, the Sublicensee.

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4.1.4.
No Implied Licenses. All rights in and to Licensed Technology not expressly
licensed to Biogen under this Agreement are hereby retained by Ionis or its
Affiliates. All rights in and to Biogen Technology not expressly licensed or
assigned to Ionis under this Agreement, are hereby retained by Biogen or its
Affiliates. Except as expressly provided in this Agreement or to perform Biogen
Activities or Ionis Activities, as applicable, no Party will be deemed by
estoppel or implication to have granted the other Party any license or other
right with respect to any intellectual property.

4.1.5.
License Conditions; Limitations. Subject to Section 6.13, any license granted
under Section 4.1.1, and the sublicense rights under Section 4.1.2 are subject
to and limited by (i) any applicable Third Party Obligations, (ii) the Prior
Agreements, and (iii) the Ionis In-License Agreements, in each case to the
extent the provisions of such obligations or agreements are specifically
disclosed to Biogen in writing (or via electronic data room) prior to the date
the applicable license under Section 4.1.1 is granted hereunder. With respect to
Collaboration Products, Ionis will disclose to Biogen any Third Party
Obligations Ionis believes apply to applicable Collaboration Products each time
Ionis provides (x) the [***]; (y) the [***]; and (z) the [***], and Biogen will
have the right to elect to exclude any Third Party Patent Rights and Know-How to
which such Third Party Obligations apply by providing Ionis written notice prior
to the License Effective Date with respect to a particular Program. If, prior to
the date the applicable license under Section 4.1.1 is granted hereunder, Biogen
provides Ionis with such a written notice to exclude certain Third Party Patent
Rights and Know-How from such license, such Third Party Patent Rights and
Know-How will not be included in the Licensed Technology licensed with respect
to the applicable Products under this Agreement. If Biogen does not provide
Ionis with such a written notice to exclude such Third Party Patent Rights and
Know-How prior to the date the applicable license under Section 4.1.1 is granted
hereunder, such Third Party Patent Rights and Know-How (and any Third Party
Obligations to the extent applicable to Products) will be included in the
Licensed Technology licensed with respect to the applicable Products under this
Agreement.

4.1.6.
Trademarks for Products. If Biogen is granted a license under Section 4.1.1 for
a particular Product, to the extent that (i) Ionis owns any trademark(s)
specific to such Product which Ionis used prior to the date such license was
granted, and (ii) Biogen reasonably believes such trademark(s) would be
necessary or useful for the marketing and sale of the applicable Product, then
upon Biogen’s request and at Biogen’s sole cost and expense relating to such
assignment, Ionis will assign its rights and title to such trademark(s) to
Biogen or one or more designated Affiliates sufficiently in advance of the First
Commercial Sale of the Product to enable Biogen or its Affiliates to offer such
Product for sale under such trademark(s). Other than trademarks owned by Ionis
prior to the date the applicable license under Section 4.1.1 is granted
hereunder, Biogen or its designated Affiliate will be solely responsible for
developing, selecting, searching, registering and maintaining, and, subject to
Section 10.4, will be the exclusive owner of, all trademarks, trade dress,
logos, slogans, designs, copyrights and domain names used on or in connection
with Products.

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

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

4.2.2.
Grant Back to Ionis. Subject to the terms and conditions of this Agreement
(including Ionis’ exclusivity covenants under Section 2.1.1), Biogen grants to
Ionis a worldwide, sublicensable license under any Ionis Product-Specific
Patents and Jointly-Owned Program Patents assigned to Biogen under Section 4.2.1
[***], (b) to conduct its activities with respect to such Program under the
applicable ASO Development Candidate Identification Plans and applicable Initial
Development Plans to the extent permitted by this Agreement, (c) to [***] with
respect to such Program to the extent permitted by this Agreement, (d) to [***]
to the extent permitted under Appendix 3 and (e) to exercise Ionis’ rights under
Section 2.1.1(f) (if applicable) or Section 3.2.2.

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4.3.
Enabling Licenses.

4.3.1.
Licenses During the Option Period.

(a)
Subject to the terms and conditions of this Agreement, Ionis hereby grants
Biogen a worldwide, non-exclusive, sublicensable (but only as permitted in
Section 4.3.2 below), royalty-free license under the Ionis Manufacturing and
Analytical Know-How and Ionis Manufacturing and Analytical Patents solely to
conduct Manufacturing and drug substance process and formulation development
activities with respect to any Compound or Product under any Collaboration
Program during the Option Period for such Collaboration Program (including the
activities set forth on Schedule 4.3.1(a)); provided that the grant of rights
pursuant to this Section 4.3.1(a) shall not include the right to Manufacture any
Compound or Product for Commercialization purposes.

(b)
Subject to the terms and conditions of this Agreement (including Biogen’s
exclusivity covenants under Section 2.1.1), [***] for Biogen to conduct (i)
Manufacturing of Compounds or Products under any Collaboration Program or (ii)
any Biogen Activities that are Development activities with respect to any
Collaboration Program in accordance with this Agreement, in each case ((i) and
(ii) during the Option Period), Ionis hereby grants Biogen a worldwide,
non-exclusive, sublicensable (but only as permitted in Section 4.1.2 above),
royalty-free license under the Licensed Technology. Biogen will [***] arising
under any Third Party agreement as a result of granting Biogen the license under
this Section 4.3.1(b) within [***] days after Biogen’s receipt of the applicable
invoice. For clarity, the grant of rights pursuant to this Section 4.3.1(b)
shall not include the right to Commercialize any such Collaboration Product or
to Manufacture any such Collaboration Product for Commercialization.

4.3.2.
Biogen’s Right to Sublicense.  Biogen will have the right to grant sublicenses
under the license granted under Section 4.3.1(a) above (a) in the case of a
sublicense of Biogen’s right to conduct Manufacturing of Compounds or Products,
other than any sublicense to conduct manufacturing in support of drug substance
process and formulation development activities, solely to (i) [***] or (ii)
[***] and (b) in the case of a sublicense of Biogen’s right to conduct drug
substance process and formulation development activities, including
manufacturing in support thereof, to any [***].  If, within [***] days after
first learning of any breach of such sublicense terms by any such Sublicensee,
Biogen fails to take any action to enforce the sublicense terms of a sublicense
granted pursuant to this Section 4.3.2, which failure would cause an adverse
effect on Ionis, then Biogen hereby grants Ionis the right to enforce such
sublicense terms on Biogen’s behalf and will cooperate with Ionis (which
cooperation will be at Biogen’s sole expense and will include Biogen joining any
action before a court or administrative body filed by Ionis against such
Sublicensee if and to the extent necessary to have legal standing before such
court or administrative body) in connection with enforcing such terms. Biogen
will provide Ionis with a true and complete copy of any sublicense granted to a
Third Party pursuant to this Section 4.3.2 within [***] days after the execution
thereof.  For the avoidance of doubt, Section 4.1.3(b) shall apply to
sublicenses granted under this Section 4.3.2.

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4.3.3.
Enabling Licenses to Biogen.

(a)
Subject to the terms and conditions of this Agreement (including Biogen’s
exclusivity covenants under Section 2.1.1), Ionis hereby grants Biogen an
irrevocable, perpetual, worldwide, non-exclusive, sublicensable (subject to the
restrictions set forth in Section 4.3.3(c)) license under any Ionis Program
Technology Controlled by Ionis or its Affiliates at any time during the
Agreement Term, to research, develop, manufacture, have manufactured and
commercialize (i) a product that is being developed or commercialized by Biogen,
its Affiliates or its Sublicensee under any Ionis/Biogen Additional Agreement or
this Agreement, (ii) products that do not include an Oligonucleotide as an
active pharmaceutical ingredient, and (iii) Gene-Editing Products. The  licenses
in clause (ii) and clause (iii) of this Section 4.3.3(a) and in Section
4.3.3(b) are royalty-free; except that if a product that is not a Product is
being sold by Biogen, its Affiliates or Sublicensees is Covered by a Target
Related Ionis Program Claim in a country, then on a country-by-country basis
Biogen will pay to Ionis a royalty equal to [***]% of Net Sales of such product
sold by Biogen, its Affiliates or Sublicensees so long as such product is
Covered by such Target Related Ionis Program Claim in such country.  A “Target
Related Ionis Program Claim” means a Valid Claim that (A) is within an Ionis
Program Patent that is solely owned by Ionis, (B) Covers a product being sold by
Biogen, its Affiliates or Sublicensee and (C) claims a gene target, or a method
of modulating such gene target to achieve a prophylactic or therapeutic
effect/benefit.

(b)
Subject to the terms and conditions of this Agreement (including Biogen’s
exclusivity covenants under Section 2.1.1), Ionis hereby grants Biogen an
irrevocable, perpetual, worldwide, non-exclusive, sublicensable (subject to the
restrictions set forth in Section 4.3.3(c)) license under any Ionis Program
Know-How and any Enabled Core Program Patents, in each case, Controlled by Ionis
or its Affiliates at any time during the Agreement Term, to research, develop,
manufacture, have manufactured and commercialize any product, including products
that include an Oligonucleotide as an active pharmaceutical ingredient.

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

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4.3.4.
Enabling License to Ionis.

(a)
Subject to the terms and conditions of this Agreement (including Ionis’
exclusivity covenants under Section 2.1.1), Biogen hereby grants Ionis an
irrevocable, perpetual, worldwide, non-exclusive, sublicensable (subject to the
restrictions set forth in Section 4.3.4(c)) license under any Biogen Program
Technology Controlled by Biogen or its Affiliates at any time during the
Agreement Term, other than any Biogen Results licensed to Ionis under Section
4.4.1, to research, develop, manufacture, have manufactured and commercialize
(a) products that include an Oligonucleotide as an active pharmaceutical
ingredient (other than products that include an Oligonucleotide that is designed
to bind to the RNA that encodes the same target as a product that is being
developed or commercialized by Biogen, its Affiliates or Sublicensee under this
Agreement or any Ionis/Biogen Additional Agreement) and (b) Gene-Editing
Products. The licenses set forth in this Section 4.3.4(a) and in Section
4.3.4(b) are royalty-free; except that if a product that is not a Discontinued
Product being sold by Ionis, its Affiliates or Sublicensee is Covered by a
Target Related Biogen Program Claim in a country, then on a country-by-country
basis Ionis will pay to Biogen a royalty equal to [***]% of net sales of such
product sold by Ionis, its Affiliates or Sublicensees, for so long as such
product is Covered by such Target Related Biogen Program Claim in such country. 
For the purpose of the foregoing royalty calculation, “net sales” will be
calculated [***].  The provisions of Sections 6.14.1, 6.14.2, 6.14.3, 6.15,
6.16.1, 6.16.2(a), 6.16.3 and 6.17 shall apply, mutatis mutandis, to any royalty
payments by Ionis to Biogen under this Section 4.3.4. A “Target Related Biogen
Program Claim” means a Valid Claim that (i) is within a Biogen Program Patent
that is solely owned by Biogen, (ii) Covers a product being sold by Ionis, its
Affiliates or Sublicensee and (iii) claims a gene target, or a method of
modulating such gene target to achieve a prophylactic or therapeutic
effect/benefit.

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(b)
Subject to the terms and conditions of this Agreement (including Ionis’
exclusivity covenants under Section 2.1.1), Biogen hereby grants Ionis an
irrevocable, perpetual, worldwide, non-exclusive, sublicensable (subject to the
restrictions set forth in Section 4.3.4(c)) license under any Biogen Program
Know-How and any Enabled Core Program Patents, in each case, Controlled by
Biogen or its Affiliates at any time during the Agreement Term, to research,
develop, manufacture, have manufactured and commercialize any product, including
products that do not include an Oligonucleotide as an active pharmaceutical
ingredient.

(c)
Ionis may share any raw data included in the Biogen Program Know-How licensed to
Ionis under Sections 4.3.4(a) and 4.3.4(b) for use in the performance of its
obligations or exercise of its rights under this Agreement or any Ionis/Biogen
Additional Agreement, and Ionis may share the conclusions drawn from or based on
the review of such raw data with any Third Party. Other than in accordance with
the foregoing sentence, Ionis shall not share with any Third Party that is not
an academic or non-profit institution or a contractor acting on Biogen’s behalf
any raw data included in such Biogen Program Know-How or any tangible
embodiments thereof to the extent such raw data and tangible embodiments
constitute Confidential Information of Biogen.

4.4.
Licenses to Ionis for Biogen Results.

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

4.4.2.
The license granted in Section 4.4.1 shall be [***] with respect to any [***]. 
Such license will be [***] with respect to any [***] as follows: on a
country-by-country, product-by-product and Biogen Manufacturing Program
Patent-by-Biogen Manufacturing Program Patent basis, Ionis will pay to Biogen
[***].  If one or more Biogen Manufacturing Program Patents expires, is
invalidated or otherwise ceases to Cover a product bearing royalties as set
forth above, the applicable royalty rate under this Section 4.4.2 shall be
recalculated to reflect the number of Biogen Manufacturing Program Patents
then-Covering such product.  For the purpose of the foregoing royalty
calculation, [***] will be calculated as follows: [***].  If Ionis grants a
sublicense under this Section 4.4 to an entity that is an Ionis Affiliate at the
time Ionis grants such sublicense, such applicable sublicense will [***].  The
provisions of Section 6.14 (other than Section 6.14.4), Section 6.15, Section
6.16 (other than Section 6.16.2(b)) and Section 6.17 shall apply, mutatis
mutandis, to any royalty payments by Ionis to Biogen under this Section 4.4.2.

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

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

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

4.6.
Ownership of and Assistance with Regulatory Filings. If requested by Biogen,
Ionis’ and Biogen’s regulatory teams will meet and begin to prepare a plan,
which plan will be completed no later than [***] prior to such anticipated
filing date, for drafting and reviewing the sections of the NDA and MAA for the
applicable Collaboration Product (including establishing responsibilities for
drafting and reviewing common technical document (“CTD”) modules, authorship,
plan activity timelines and associated costs and expenses) and assigning  all
necessary filings with any Regulatory Authority related to the applicable
Collaboration Product to Biogen to ensure a smooth transition to Biogen,
accelerate CTD completion and facilitate rapid NDA and MAA filing. Each CTD will
be consistent with the Specific Performance Milestone Events for the applicable
Collaboration Program.  The Parties regulatory teams will submit such plan to
the CSC, if still active.  The Parties will act in good faith and mutually agree
upon each such plan, provided, however, that, after exercising an Option for the
applicable Collaboration Program, Biogen will have final decision-making
authority with respect to the [***]. Once such plan is complete, each Party will
use Commercially Reasonable Efforts to execute their respective tasks and
responsibilities under such plan in the time frames set forth in such plan.
After exercising an Option for a particular Collaboration Program, if Biogen
requests, Ionis will assist Biogen in preparing regulatory filings for the
Collaboration Product, under terms negotiated in good faith between Ionis and
Biogen, including payment for Ionis’ time at Ionis’ then applicable FTE Rate
plus any reasonable out of pocket expenses incurred by Ionis in providing such
assistance, utilizing the payment mechanism set forth in Section 1.14.1.

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4.7.
Subcontracting.

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

4.7.2.
Ionis agrees that, where Biogen wishes to (sub)contract with a Third Party with
respect to any of the rights granted under Section 4.3.1(a), Ionis shall, within
[***] days of any request by Biogen, provide Biogen with a letter of
authorization as necessary for Biogen to be able to contract with such Third
Party in accordance with the terms of this Agreement.  Biogen will ensure that
any Third Party (sub)contractors Biogen uses to conduct the process development
or manufacturing activities contemplated by Section 4.3.1(a) will be obligated
to assign to Biogen all right, title and interest in and to any inventions
developed by such (sub)contractors in the performance of such activities.  For
clarity, solely with respect to the Biogen Results, this Section 4.7.2 shall
supersede and replace Section 7.1.3 of this Agreement to the extent of any
conflict.  Biogen will not enter into any new agreement or other obligation with
any Third Party, or amend an existing agreement with a Third Party, in each case
that restricts, limits, diminishes or encumbers the rights granted to Ionis
under the Manufacturing Process Development Terms. In addition, after the First
Amendment Date, Biogen will use reasonable efforts to include, in any agreement
with a (sub)contractor that has substantial material obligations related to the
Development, Manufacture or Commercialization of a Product, provisions requiring
that, in the event the applicable Option is terminated, expires unexercised or
this Agreement is terminated, such (sub)contractor would enter into an agreement
with Ionis with respect to such Product that is substantially similar to such
(sub)contractor’s agreement with Biogen and would reasonably cooperate with
Ionis to facilitate the transition of such Product to Ionis following such
termination or Option expiration, including the transfer to Ionis of data and
information in such (sub)contractor’s possession related to the Product.

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4.8.
Technology Transfer.

4.8.1.
Technology Transfer to Biogen during the Option Period. Within [***] days after
the First Amendment Date, Ionis will deliver to Biogen or one or more designated
Affiliates, solely for use by Biogen, [***] to conduct any Biogen Activities
that are Development activities with respect to any High Interest Target or
Collaboration Target in accordance with this Agreement, all Ionis Manufacturing
and Analytical Know-How in Ionis’ Control [***] to conduct such Biogen
Activities. If requested by Biogen, Ionis will provide Biogen with a reasonable
level of assistance in connection with such transfer, which Biogen will
reimburse Ionis for its time incurred in providing such assistance at the
then-applicable Ionis FTE Rate, plus any reasonable out-of-pocket expenses
incurred by Ionis in providing such assistance, using the payment mechanism set
forth in Section 1.14.1.

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

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(a)
Ionis Know-How. All Ionis Know-How in Ionis’ possession that has not previously
been provided hereunder, for use solely in accordance with the licenses granted
under Section 4.1.1 and Section 10.4.2, and Ionis will and does hereby assign to
Biogen all of Ionis’ right, title and interest in and to the IND for the
applicable Development Candidate, together with all Regulatory Materials
(including drafts) that relate to the applicable Development Candidate; provided
that, (i) notwithstanding the foregoing, and subject to the provisions of
Section 2.1, the Parties acknowledge that Ionis shall be permitted to use
excerpts or portions of any such assigned Regulatory Materials in any other
regulatory submissions, notifications, registrations, approvals and/or other
filings and correspondence made to or with a Regulatory Authority in any country
or jurisdiction related to products other than the Development Candidate,
provided, further that such excerpts or portions shall not include (A) any
non-public data or information, in each case, related solely to the applicable
Development Candidate, or (B) any Confidential Information of Biogen, and (ii)
for clarity, such assignment of Ionis’ right, title and interest in and to such
Regulatory Materials shall not include the assignment of any Know-How (including
any data) contained therein. If Ionis intends to use any excerpt or portion of
any such assigned Regulatory Materials in accordance with clause (i) of the
preceding sentence that are not in the public domain and do not relate to Ionis’
antisense oligonucleotide chemistry platform, Ionis shall, at least [***] days
in advance of the anticipated submission of such excerpt or portion to a
Regulatory Authority, notify Biogen of such intent and provide to Biogen a copy
of such proposed excerpt or portion for review and comment. The Parties shall
discuss in good faith any comments of Biogen with respect to such proposed
excerpt or portion prior to submission thereof. To assist with the transfer and
assignment of such Ionis Know-How, Ionis will make its personnel reasonably
available to Biogen during normal business hours for up to [***] ([***]) of
Ionis’ time for each Collaboration Program to transfer such Ionis Know-How under
this Section 4.8.2(a). Thereafter, if requested by Biogen, Ionis will provide
Biogen with a reasonable level of assistance in connection with such transfer,
which Biogen will reimburse Ionis for its time incurred in providing such
assistance at the then-applicable Ionis FTE Rate, plus any reasonable
out-of-pocket expenses incurred by Ionis in providing such assistance, using the
payment mechanism set forth in Section 1.14.1.

(b)
Ionis Manufacturing and Analytical Know-How. Solely for use by Biogen, its
Affiliates or a Third Party acting on Biogen’s behalf to Manufacture API in
Biogen’s own or an Affiliate’s manufacturing facility, all Ionis Manufacturing
and Analytical Know-How in Ionis’ Control relating to applicable Products, which
is necessary for the exercise by Biogen, its Affiliates or a Third Party of the
Manufacturing rights granted under Section 4.1.1(a). Upon Biogen’s request,
subject to Section 4.1.2, Ionis will provide up to [***] for [***] ([***]) of
its time for each Collaboration Program to transfer such Ionis Manufacturing and
Analytical Know-How under this Section 4.8.2(b) to any Third Party Manufacturing
API, Clinical Supplies or Finished Drug Product on Biogen’s behalf solely to
Manufacture API, Clinical Supplies or Finished Drug Product in accordance with
the terms of this Agreement. Thereafter, if requested by Biogen, Ionis will
provide Biogen with a reasonable level of assistance in connection with such
transfer, which Biogen will reimburse Ionis for its time incurred in providing
such assistance at the then-applicable Ionis FTE Rate, plus any reasonable
out-of-pocket expenses incurred by Ionis in providing such assistance, using the
payment mechanism set forth in Section 1.14.1.

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

(d)
Trial Master File.  Upon Biogen’s written request, Ionis will provide to Biogen
or its designated Affiliate a copy of Ionis’ trial master file for such
Collaboration Program (such trial master file, the “Trial Master File”)
promptly, and in any event within [***] days after Ionis’ receipt of such
written request. Within [***] days after receipt of the Trial Master File,
Biogen or an Affiliate may notify Ionis of any omissions or deficiencies that
Biogen or its Affiliate believes in good faith cause the Trial Master File to be
incomplete (such notice, a “Trial Master File Deficiency Notice”). Ionis will
promptly, and in any event within [***] days after receipt of the Trial Master
File Deficiency Notice, resubmit a complete Trial Master File to Biogen or its
designated Affiliate, including any information required to be included in a
Trial Master File that Biogen requests be included in the Trial Master File. If
the Parties do not agree as to whether the Trial Master File is complete, the
matter will be referred to the Executives for resolution. The Executives will
meet promptly and negotiate in good faith to resolve the dispute and agree upon
a complete Trial Master File. If Ionis is the Commercializing Party of a
Discontinued Collaboration Product, this Section 4.8.2(d) will apply to such
Discontinued Collaboration Product mutatis mutandis such that Biogen will
transfer to Ionis Biogen’s trial master file for such Discontinued Collaboration
Product.

4.8.3.
Results.

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

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(b)
For clarity, the Manufacturing Process Development Terms, and not the enabling
licenses set forth in Section 4.3.3 and Section 4.3.4, shall govern with respect
to all Results.

ARTICLE 5.
DEVELOPMENT, MANUFACTURING AND COMMERCIALIZATION

5.1.
Biogen Diligence.

5.1.1.
Collaboration Products.

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

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(b)
Following the License Effective Date with respect to a Collaboration Program,
Biogen will be solely responsible for all Development, Manufacturing and
Commercialization activities, and for all costs and expenses associated
therewith, with respect to the Development, Manufacture and Commercialization of
applicable Products; and Biogen will use Commercially Reasonable Efforts to
Develop, Manufacture and Commercialize at least one Product from each
Collaboration Program for which an Option has been exercised.

5.1.2.
Biogen Alternate Modality Products. Following the date a license is granted to
Biogen under Section 4.1.1(b) for a particular Biogen Alternate Modality
Product, Biogen will be solely responsible for all Development, Manufacturing
and Commercialization activities, and for all costs and expenses associated
therewith, with respect to the development, manufacture and commercialization of
applicable Biogen Alternate Modality Products; and Biogen will use Commercially
Reasonable Efforts to develop, manufacture and commercialize at least one Biogen
Alternate Modality Product for each Biogen Alternate Modality Target.

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

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

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

5.1.6.
Integrated Development Plan for Products. On a Product-by-Product basis, Biogen
will prepare a Development and global integrated Product plan outlining key
aspects of the Development of each Product through Approval as well as key
aspects of worldwide regulatory strategy, market launch, and Commercialization,
including Product sales forecasts (each, an “Integrated Development Plan” or
“IDP”). Biogen will prepare the IDP no later than (i) [***] after the License
Effective Date with respect to a Collaboration Program or (ii) after the First
Commercial Sale of a Biogen Alternate Modality Product, and the IDP will include
information consistent in scope and content with the information Biogen’s senior
management uses for internal decision-making for such Product. Schedule 5.1.6
sets forth examples of the types of information Biogen expects will be available
to include in the IDP at different stages of development and commercialization.
Once Biogen has prepared such plans, Biogen will update the IDP consistent with
Biogen’s standard practice and provide such updates to the CSC [***] (or Ionis
after the CSC terminates under Section 1.18.5). Biogen and Ionis will meet [***]
basis to discuss the draft of the IDP and Biogen will consider, in good faith,
any proposals and comments made by the CSC (or Ionis after the CSC terminates
under Section 1.18.5) for incorporation in the final IDP. Notwithstanding the
foregoing, Biogen’s obligations to provide Ionis with information or reports
with respect to a Product under this Section 5.1.6 will terminate if [***].

5.1.7.
Investigator’s Brochure for Collaboration Products. After the License Effective
Date with respect to a Collaboration Program, Ionis will provide to Biogen an
up-to-date version of the Investigator’s Brochure for the applicable
Collaboration Product. Biogen will keep Ionis reasonably informed with respect
to the status, activities and progress of Development of Collaboration Products
by providing updated versions of the Investigator’s Brochure for each
Collaboration Product to Ionis [***] and when Development of such Collaboration
Product results in any substantive change to the safety or risk to the
Collaboration Product. Biogen’s obligations under this Section 5.1.7 will
terminate with respect to a Collaboration Product if [***].

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5.1.8.
Applicable Laws. Biogen will perform its activities pursuant to this Agreement
in compliance with good laboratory and clinical practices and cGMP, in each case
as applicable under the laws and regulations of the country and the state and
local government wherein such activities are conducted.

5.2.
Regulatory Matters; Global Safety Database; Pharmacovigilance Agreement.

5.2.1.
IND-Holder. Subject to this Section 5.2, for Collaboration Programs that are not
ALS Collaboration Programs or Biogen Conducted Non-ALS Collaboration Programs,
Ionis will be the IND-holder and will be responsible for all communications with
Regulatory Authorities regarding such Collaboration Programs prior to the
applicable License Effective Date.  Subject to this Section 5.2, for ALS
Collaboration Programs and Biogen Conducted Non-ALS Collaboration Programs,
Biogen will be the IND-holder and will be responsible for all communications
with Regulatory Authorities regarding such ALS Collaboration Programs and Biogen
Conducted Non-ALS Collaboration Programs.  Biogen will be the IND-holder after
the applicable License Effective Date for each Collaboration Program in
accordance with Section 3.1.3, and, except as otherwise provided in this Section
5.2, shall thereafter have sole decision-making authority with respect to the
matters set forth in this Section 5.2.

5.2.2.
Pharmacovigilance Agreement. As soon as reasonably practicable following
designation of a particular Development Candidate, and in any event no later
than [***] prior to the date on which Ionis or Biogen anticipates filing an IND
for the associated Collaboration Product with a Regulatory Authority, the
Parties will enter into a Safety Drug Exchange Agreement relating to the
collection, review, assessment, tracking, exchange and filing of information
related to adverse events associated with such Collaboration Product occurring
prior to the First Commercial Sale in any country on terms substantially the
same as the terms of the Safety Drug Exchange Agreement to be entered into by
the Parties with respect to adverse events associated with products developed
under the Ionis/Biogen Additional Agreements. In addition, following the First
Amendment Date the Parties will discuss in good faith the possibility of
entering into a single Safety Drug Exchange Agreement with respect to all
activities under this Agreement and the Ionis/Biogen Additional Agreements. No
later than [***] days prior the date on which Biogen reasonably anticipates that
it will exercise an Option, Biogen will so notify Ionis and the
pharmacovigilance departments of each of Ionis and Biogen will meet and
determine the approach to be taken for the collection, review, assessment,
tracking, exchange and filing of information related to adverse events
associated with the applicable Collaboration Product occurring after such First
Commercial Sale, consistent with the provisions of this Section 5.2. Such
approach will be documented in a separate and appropriate written
pharmacovigilance agreement between the Parties which will control with respect
to the subject matter covered therein (the “Pharmacovigilance Agreement”). Such
agreement will specify that the owner of the IND for a Collaboration Product
will be the global commercial safety database owner for such Collaboration
Product with primary responsibility for maintaining such database, and that
Ionis will be and remain the owner of the Ionis Internal ASO Safety Database
with primary responsibility for maintaining such database. Such agreement will
also specify that, prior to the License Effective Date for a particular
Collaboration Program, the Parties will communicate updates on safety data
regarding a Collaboration Product to Biogen through monthly telephone calls
between the drug safety representatives of Biogen and Ionis.  Biogen and Ionis
will jointly review and discuss safety issues arising under any Collaboration
Program that may have implications on any Initial Development Plan for such
Collaboration Program. Biogen may suggest actions to address Collaboration
Product safety data or audit findings, and Ionis will consider all such
suggestions in good faith. The Pharmacovigilance Agreement will be in accordance
with, and will enable the Parties and their Affiliates or licensees or
Sublicensees, as applicable, to fulfill, local and international regulatory
reporting obligations to Regulatory Authorities and other Applicable Law.

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5.2.3.
Regulatory Communications Regarding Clinical Study Trial Designs.

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

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

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

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

5.2.4.
Participation in Regulatory Meetings for Collaboration Products. With respect to
a Collaboration Program, each Party will provide the other Party with as much
advance written notice as practicable of any meetings that such first Party has
or plans to have with a Regulatory Authority regarding pre-approval or Approval
matters for a Collaboration Product under such Collaboration Program or that
directly relate to Ionis’ antisense oligonucleotide chemistry platform, and will
allow two representatives of the other Party to participate in any such meetings
under the direction of such first Party; provided, however, that, if such first
Party is Ionis, Ionis may exclude Biogen from any portion of such meeting that
does not pertain to such Collaboration Product; and provided, further, that, if
such first Party is Biogen, Biogen may exclude Ionis from any portion of such
meeting that does not pertain to such Collaboration Product or to Ionis’
antisense oligonucleotide chemistry platform.

5.2.5.
Regulatory Communications for Collaboration Products. With respect to a
Collaboration Program, each Party will promptly provide the other Party with
copies of documents and communications submitted to (including drafts thereof)
and received from Regulatory Authorities [***] that materially impact the
Development or Commercialization of Collaboration Products under such
Collaboration Program for such other Party’s review and comment, and such first
Party will consider in good faith including any comments provided by such other
Party to such documents and communications.  Each Party will promptly notify the
other Party upon receipt of any such documents or communications from any
Regulatory Authority [***].

5.2.6.
Class Generic Claims for Collaboration Products. To the extent Biogen intends to
make any claims in a Collaboration Product label or regulatory filing that are
class generic to ASOs, Biogen will provide such claims and regulatory filings to
Ionis in advance and will consider in good faith any proposals and comments made
by Ionis, provided, however, that Biogen is not obligated to incorporate such
proposals and comments in any such claims and regulatory filings.

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5.2.7.
Ionis’ Antisense Safety Database.

(a)
Ionis maintains an internal database that includes information regarding the
tolerability of its drug compounds, individually and as a class, including
information discovered during pre-clinical and clinical development (the “Ionis
Internal ASO Safety Database”). In an effort to maximize understanding of the
safety profile and pharmacokinetics of Ionis compounds, Biogen will cooperate in
connection with populating the Ionis Internal ASO Safety Database. To the extent
collected by Biogen and in the form in which Biogen uses/stores such information
for its own purposes, Biogen will provide Ionis with information concerning
toxicology, pharmacokinetics, safety pharmacology study(ies), serious adverse
events and other safety information related to Collaboration Product as soon as
practicable following the date such information is available to Biogen (but not
later than [***] days after Biogen’s receipt of such information). In connection
with any reported serious adverse event, Biogen will provide Ionis all serious
adverse event reports, including initial, interim, follow-up, amended, and final
reports. In addition, with respect to Collaboration Product, Biogen will provide
Ionis with copies of Annual safety updates filed with each IND and the safety
sections of any final Clinical Study reports within [***] days following the
date such information is filed or is available to Biogen, as applicable.
Furthermore, Biogen will promptly provide Ionis with any supporting data and
answer any follow-up questions reasonably requested by Ionis. All such
information disclosed by Biogen to Ionis will be Biogen Confidential
Information; provided, however, that Ionis may disclose any such Biogen
Confidential Information to (i) Ionis’ other partners pursuant to Section
5.2.7(b) below if such information is regarding class generic properties of
ASOs, or (ii) any Third Party, in each case, so long as Ionis does not disclose
the identity of a Collaboration Product or Biogen. Biogen will deliver all such
information to Ionis for the Ionis Internal ASO Safety Database to Ionis
Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, California 92010,
Attention: Chief Medical Officer (or to such other address/contact designated in
writing by Ionis). Biogen will also cause its Affiliates and Sublicensees to
comply with this Section 5.2.7(a).

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

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

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

ARTICLE 6.
FINANCIAL PROVISIONS

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

6.2.
Drug Discovery Milestone Payments.

6.2.1.
Collaboration Targets. For each Collaboration Program, after (a) a Collaboration
Target is designated under this Agreement, and (b) Ionis begins designing human
development candidates under such Collaboration Program for human candidate
screening under the applicable ASO Development Candidate Identification Plan
([***]), Ionis will so notify Biogen (such notice, the “Design Notice”) and
Biogen will pay Ionis a milestone payment equal to (i) $[***] for Collaboration
Programs that are not ALS Collaboration Programs [***], subject to any
applicable credits permitted by Section 1.8.3 or Section 1.8.4, (ii) $[***] for
ALS Collaboration Programs [***], or (iii) $[***].

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

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

Table X
Biogen Alternate Modality Milestone
Event
Milestone Event Payment per Biogen
Alternate Modality Target
[***] $[***]
[***]
$[***] [***] $[***]
[***]
$[***]
[***] $[***] [***]
$[***]

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

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Table 1
Standard Pre-Licensing
Milestone Event
Milestone Event Payment per
Collaboration Program that is not
an ALS Collaboration Program
or Biogen Conducted Non-ALS
Collaboration Program
Milestone Event Payment per
Biogen Conducted Non-ALS
Collaboration Program
[***] $[***] $[***]
[***]
[***]
$[***]
[***] [***] $[***]

On a Collaboration Program-by-Collaboration Program basis, where such a
Collaboration Program is not an ALS Collaboration Program, Biogen will pay to
Ionis the Milestone Event payments as set forth in Table 1 after the applicable
Milestone Event is first achieved by a Collaboration Product under such
Collaboration Program, even if Biogen has exercised the applicable Option prior
to achievement of the Milestone Event; provided, however, that if Biogen
exercises the Option prior to achievement of the [***] Milestone Event, then the
milestone payment for achievement of the [***] Milestone Event will be reduced
to $[***].

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

Table 2
 
 
ALS Pre-Licensing
Milestone Event
Column 1
Milestone Event
Payment per ALS
Collaboration Program
that is not a [***]
Collaboration Program
[***]
Column 2
Milestone Event
Payment per [***]
Collaboration Program
Column 3
Milestone Event
Payment for the [***]
[***] $[***] $[***] [***] [***] $[***] $[***] [***] [***] $[***] $[***] [***]
[***] [***] [***] $[***] [***] $[***] $[***] $[***]

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

6.6.
License Fee. On an Option-by-Option basis, together with Biogen’s written notice
to Ionis stating that Biogen is exercising such Option in accordance with this
Agreement, Biogen will pay to Ionis a license fee of (A) $[***] for any
Collaboration Program [***]; provided, however, that if (i) Biogen exercises the
Option prior to the [***], the license fee for such Option will be [***] or (ii)
Biogen exercises the Option to a [***] Collaboration Program, subject to the
last paragraph of Section 6.7, the license fee for such Option will be [***], or
(B) $[***]; provided, however, that if Biogen exercises the Option prior to the
[***], the license fee for such Option will be [***]. If Biogen notifies Ionis
that it desires to exercise an Option prior to the [***], then the Parties will
discuss and negotiate in good faith.

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

Table 3
 
Post-Licensing Milestone
Event
Column 1
Milestone Event Payment per
Collaboration Program that is
not a [***] Collaboration
Program
Column 2

Milestone Event Payment
per [***] Collaboration
Program
[***] $[***] $[***] [***] $[***] $[***] [***] $[***] $[***] [***] $[***] $[***]

On a Collaboration Program-by-Collaboration Program basis, if Biogen exercises
an Option for a Collaboration Program that is not a [***] Collaboration Program,
prior to the [***], Biogen will pay to Ionis [***] upon the earlier of (a) [***]
or (b) [***]. For the avoidance of doubt, if such $[***] payment is paid
pursuant to clause (b) of the preceding sentence, such payment will be in
addition to the amount due upon the occurrence of the corresponding
Post-Licensing Milestone Event under Table 3 above.

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

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

6.8.
Limitations on Milestone Payments; Exceptions; Notice.

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

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

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

6.8.4.
If a particular Milestone Event is not achieved because Development activities
transpired such that achievement of such earlier Milestone Event was unnecessary
or did not otherwise occur, then upon achievement of a later Milestone Event the
Milestone Event payment applicable to such earlier Milestone Event will also be
due. For example, if a Party proceeds directly to [***] without achieving the
[***] then upon achieving the [***] Milestone Event, both the [***] and [***]
Milestone Event payments are due. Similarly, if a Party proceeds directly to
[***] without achieving the [***] then upon achieving the [***] Milestone Event,
both the [***] and [***] Milestone Event payments are due. If Biogen [***] for a
Biogen Alternate Modality Product, then both the [***] milestone payment and the
[***] milestone payment will be due upon [***].

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6.8.5.
Each time a Milestone Event is achieved under this ARTICLE 6, Biogen will send
Ionis, or Ionis will send Biogen, as the case may be, a written notice thereof
promptly (but no later than five Business Days) following the date of
achievement of such Milestone Event and such payment will be due within [***]
days of the date such notice was delivered.

6.8.6.
With respect to the [***] Collaboration Program for [***], except as expressly
set forth in Section 6.5, the milestone payments and license fees set forth in
Section 6.5, Section 6.6 and Section 6.7 for [***] Collaboration Programs that
are not [***] Collaboration Programs shall apply with respect to such [***]
Collaboration Program.  For clarity, the provisions of the Neurology Drug
Discovery and Development Collaboration, Option and License Agreement between
Ionis and Biogen, dated as of December 10, 2012, as such agreement may be
amended from time to time, shall not apply with respect to the [***]
Collaboration Program for [***].

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

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

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

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

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

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

6.10.
Royalty Payments to Ionis for Collaboration Products.

6.10.1.
Biogen Full Royalty for Collaboration Products. As partial consideration for the
rights granted to Biogen hereunder, subject to the provisions of this Section
6.10.1 and Section 6.10.2, Biogen will pay to Ionis royalties on a Collaboration
Program-by-Collaboration Program basis, on Annual worldwide Net Sales of
Collaboration Products included in the applicable Collaboration Program sold by
Biogen, its Affiliates or Sublicensees, on a country-by-country basis, in each
case in the amounts as follows in Table 4 below (the “Biogen Full Royalty”):

Table 4
Royalty
Tier
Annual Worldwide Net Sales of Collaboration
Products for the applicable Collaboration
Program
Royalty
Rate
1 For the portion of Annual Worldwide Net Sales  < $[***] [***]% 2 For the
portion of Annual Worldwide Net Sales  > $[***] but < $[***] [***]% 3 For the
portion of Annual Worldwide Net Sales  > $[***] but < $[***] [***]% 4 For the
portion of Annual Worldwide Net Sales  > $[***] [***]%

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

(a)
Biogen will pay Ionis royalties on Net Sales of Collaboration Products arising
from named patient and other similar programs under Applicable Laws, and Biogen
will provide reports and payments to Ionis consistent with Section 6.14. No
royalties are due on Net Sales of Collaboration Products arising from
compassionate use and other programs providing for the delivery of Collaboration
Product at no cost. The sales of Collaboration Products arising from named
patient, compassionate use, or other similar programs will not be considered a
First Commercial Sale for purposes of calculating the Full Royalty Period.

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

(c)
For clarity, the provisions of this Section 6.10 shall apply to Net Sales of
Collaboration Products under the [***] Collaboration Program for [***], and the
provisions of the Neurology Drug Discovery and Development Collaboration, Option
and License Agreement between Ionis and Biogen, dated as of December 10, 2012,
as such agreement may be amended from time to time, shall not apply.

6.10.2.
Application of Royalty Rates for Collaboration Products. All royalties set forth
under Section 6.10.1 are subject to the provisions of this Section 6.10.2, and
are payable as follows:

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

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(b)
Competition from Generic Products for Collaboration Products. Subject to Section
6.11, on a country-by-country and Collaboration Product-by-Collaboration Product
basis, if, within the [***], a Generic Product is sold in a country, then the
Biogen Full Royalty rate used to pay Ionis royalties on such Collaboration
Product in such country will be reduced to [***]% of the otherwise applicable
Biogen Full Royalty rate. For the purpose of determining the [***] for a
particular Collaboration Product under this Section 6.10.2(b), if requested by
Biogen, Ionis and Biogen will meet and confer and mutually agree upon the
Parties’ best estimate of when the Full Royalty Period [***] in each country
where Collaboration Products are being sold.

(c)
Reduced Royalty Period for Collaboration Products. Subject to Section 6.11, on a
country-by-country and Collaboration Product-by-Collaboration Product basis,
after the expiration of the Full Royalty Period and until the end of the Reduced
Royalty Period, in lieu of the royalty rates set forth in Table 4 of Section
6.10.1, Biogen will pay Ionis royalty rates (the “Biogen Reduced Royalty”) on
Net Sales of Collaboration Products calculated on a Calendar Year-by-Calendar
Year basis by [***]; provided, however, that the Biogen Reduced Royalty rate in
each country will in no event exceed the [***].

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

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

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

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

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

6.11.2.
In no event will the aggregate royalty offsets under Section 6.13.3(b), Section
6.13.3(d) and Section 7.1.3(c) reduce the royalties payable to Ionis on Net
Sales of a Collaboration Product in any given period to an amount that is less
than the greater of [***].

For example, if the Royalty Quotient during a given Calendar Year in the Reduced
Royalty Period is less than [***]%, then the offsets under Section 6.13.3(b),
Section 6.13.3(d) and Section 7.1.3(c) will not apply during such Calendar Year
but the full Royalty Quotient reduction pursuant to Section 6.10.2(c) will
apply.

As an additional example, if the Royalty Quotient during a given Calendar Year
in the Reduced Royalty Period is [***]%, and the [***] in such Calendar Year are
[***]% of the applicable royalty rates in Table 4 of Section 6.10.1, then Biogen
may apply the offsets under Section 6.13.3(b), Section 6.13.3(d) and Section
7.1.3(c) until the actual royalty payment made to Ionis in such Calendar Year is
equal to [***]% of the applicable royalty rates in Table 4 of Section 6.10.1.

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

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

6.12.2.
Applicable Royalty Provisions. In addition to this Section 6.12, the definition
of Net Sales in Appendix 1 and the other provisions contained in this ARTICLE 6
governing payment of royalties from Biogen to Ionis will govern the payment of
Reverse Royalties from Ionis to Biogen under this Section 6.12, mutatis
mutandis, including the provisions of Sections 6.10.2, 6.13, 6.14, 6.15, 6.16,
and 6.17.

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6.13.
Third Party Payment Obligations.

6.13.1.
Existing Ionis In-License Agreements.

(a)
Certain of the Licensed Technology Controlled by Ionis as of the Effective Date
licensed to Biogen under Section 4.1.1(a) or Section 4.1.1(b) were in-licensed
or were acquired by Ionis under the agreements with Third Party licensors or
sellers listed on Schedule 6.13.1 or in a separate written agreement between the
Parties (all such license or purchase agreements being the “Ionis In-License
Agreements”), and certain milestone or royalty payments and license maintenance
fees may become payable by Ionis to such Third Parties under the Ionis
In-License Agreements based on the Development and Commercialization of a
Product by Biogen under this Agreement.

(b)
Any payment obligations arising under the Ionis In-License Agreements as
existing on the Effective Date as they apply to Collaboration Products for High
Interest Targets designated as of the Effective Date, will be paid by [***] as
[***]. 

6.13.2.
New In-Licensed Ionis Product-Specific Patents; Ionis Manufacturing and
Analytical Patents. If after the Effective Date, Ionis obtains Third Party
Patent Rights necessary or useful to Develop, Manufacture or Commercialize a
Product that would have been considered an Ionis Product-Specific Patent had
Ionis Controlled such Patent Rights on the Effective Date, to the extent
Controlled by Ionis, Ionis will include such Third Party Patent Rights in the
license granted to Biogen under Section 4.1.1(a) or Section 4.1.1(b) (as
applicable) if Biogen agrees in writing to pay Ionis as [***].

6.13.3.
Additional Core IP In-License Agreements.

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

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(b)
If, however, Ionis elects not to obtain such a license to such Third Party
intellectual property, Ionis will so notify Biogen, and Biogen may obtain such a
Third Party license and, subject to Section 6.11.2, Biogen may offset an amount
equal to [***]% of any [***] paid by Biogen under such Third Party license
against any [***] of this Agreement in such country for [***].

(c)
If it is unclear whether certain intellectual property identified by Biogen
pursuant to Section 6.13.3(a) is Additional Core IP under Section 6.13.3(b),
Ionis will send written notice to such effect to Biogen, and the Parties will
engage a mutually agreed upon independent Third Party intellectual property
lawyer with expertise in the patenting of Oligonucleotides, and appropriate
professional credentials in the relevant jurisdiction, to determine the question
of whether or not such Third Party intellectual property is Additional Core IP.
The determination of the Third Party expert engaged under the preceding sentence
will be binding on the Parties solely for purposes of determining whether Biogen
is permitted to [***]. The costs of any Third Party expert engaged under this
Section 6.13.3(c) will be paid by the Party against whose position the Third
Party lawyer’s determination is made.

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

6.13.4.
Other Third Party Payments.

(a)
Ionis’ Third Party Agreements. Except as otherwise expressly agreed to by Biogen
under Section 6.13.2, after Biogen is granted the license under Section 4.1.1(a)
or Section 4.1.1(b) for a particular Product, Biogen will be responsible for
paying [***]% of the [***] arising under any Third Party agreements entered into
by Ionis where either [***].

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

6.14.
Payments.

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6.14.1.
Commencement. Beginning with the Calendar Quarter in which the First Commercial
Sale for a Product is made and for each Calendar Quarter thereafter, Biogen will
make royalty payments to Ionis under this Agreement within [***] following the
end of each such Calendar Quarter. Each royalty payment will be accompanied by a
report, summarizing Net Sales for Products during the relevant Calendar Quarter
and the calculation of royalties due thereon, including country, units, sales
price, the exchange rate used and the type of Product (i.e., whether it is a
Collaboration Product or Biogen Alternate Modality Product) and the aggregate
reduction to gross sales to arrive at Net Sales. Following the end of the first
full Calendar Quarter subsequent to First Commercial Sale in a Major Market of
any Product (but not in any subsequent Calendar Quarter unless there is a
material change in the amount of any reduction to gross sales or the methodology
used by Biogen to calculate any such reduction), Biogen will also include in
such report a description of the reductions to gross sales to arrive at Net
Sales, broken down by each category of reduction listed in clauses (a) through
(d) of the definition of “Net Sales” and a non-binding qualitative analysis
describing how Biogen anticipates such reductions may fluctuate over time. If no
royalties are payable in respect of a given Calendar Quarter, Biogen will submit
a written royalty report to Ionis so indicating together with an explanation as
to why no such royalties are payable. In addition, beginning with the Calendar
Quarter in which the First Commercial Sale for a Product is made and for each
Calendar Quarter thereafter, within [***] following the end of each such
Calendar Quarter, Biogen will provide Ionis a [***] report estimating the total
Net Sales of, and royalties payable to Ionis for Products projected for such
Calendar Quarter.

6.14.2.
Mode of Payment. All payments under this Agreement will be (i) payable in full
in U.S. dollars, regardless of the country(ies) in which sales are made, (ii)
made by wire transfer of immediately available funds to an account designated by
Ionis in writing, and (iii) non-creditable [***], irrevocable and
non-refundable. Whenever for the purposes of calculating the royalties payable
under this Agreement conversion from any foreign currency will be required, all
amounts will first be calculated in the currency of sale and then converted into
United States dollars by applying the monthly average rate of exchange
calculated by using the foreign exchange rates published in Bloomberg during the
applicable month starting two Business Days before the beginning of such month
and ending two Business Days before the end of such month as utilized by Biogen,
in accordance with generally accepted accounting principles, fairly applied and
as employed on a consistent basis throughout Biogen’s operations.

6.14.3.
Records Retention. Commencing with the First Commercial Sale of a Product,
Biogen will keep complete and accurate records pertaining to the sale of
Products for a period of [***] after the year in which such sales occurred, and
in sufficient detail to permit Ionis to confirm the accuracy of the Net Sales or
royalties paid by Biogen hereunder.

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

6.15.
Audits. After Biogen is granted the license under Section 4.1.1(a) or Section
4.1.1(b) for a particular Product, during the Agreement Term and for a period of
[***] thereafter, at the request and expense of Ionis, Biogen will permit an
independent certified public accountant of nationally recognized standing
appointed by Ionis, at reasonable times and upon reasonable notice, but in no
case more than [***], to examine such records as may be necessary for the
purpose of verifying the calculation and reporting of Net Sales and the
correctness of any royalty payment made under this Agreement for any period
within the preceding [***]. As a condition to examining any records of Biogen,
such auditor will sign a nondisclosure agreement reasonably acceptable to Biogen
in form and substance. Any and all records of Biogen examined by such
independent certified public accountant will be deemed Biogen’s Confidential
Information. Upon completion of the audit, the accounting firm will provide both
Biogen and Ionis with a written report disclosing whether the royalty payments
made by Biogen are correct or incorrect and the specific details concerning any
discrepancies (“Audit Report”). If, as a result of any inspection of the books
and records of Biogen, it is shown that Biogen’s payments under this Agreement
were less than the royalty amount which should have been paid, then Biogen will
make all payments required to be made by paying Ionis the difference between
such amounts to eliminate any discrepancy revealed by said inspection within
[***] days of receiving the Audit Report, with interest calculated in accordance
with Section 6.17. If, as a result of any inspection of the books and records of
Biogen, it is shown that Biogen’s payments under this Agreement were greater
than the royalty amount which should have been paid, then [***]; provided,
however, that if [***]. Ionis will pay for such audit, except that if Biogen is
found to have underpaid Ionis by more than [***]% of the amount that should have
been paid, Biogen will reimburse Ionis’ reasonable costs of the audit.

6.16.
Taxes.

6.16.1.
Taxes on Income. Each Party will be solely responsible for the payment of all
taxes imposed on its share of income arising directly or indirectly from the
activities of the Parties under this Agreement.

6.16.2.
Withholding Tax.

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

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

6.16.3.
Tax Cooperation. Ionis will provide Biogen with any and all tax forms that may
be reasonably necessary in order for Biogen to lawfully not withhold tax or to
withhold tax at a reduced rate under an applicable bilateral income tax treaty.
Following Biogen’s timely receipt of such tax forms from Ionis, Biogen will not
withhold tax or will withhold tax at a reduced rate under an applicable
bilateral income tax treaty, if appropriate under the Applicable Laws.  Ionis
will provide any such tax forms to Biogen upon request and in advance of the due
date. Each Party will provide the other with reasonable assistance to determine
if any taxes are applicable to payments under this Agreement and to enable the
recovery, as permitted by Applicable Law, of withholding taxes resulting from
payments made under this Agreement, such recovery to be for the benefit of the
Party who would have been entitled to receive the money but for the application
of withholding tax under this Section 6.16.

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

6.17.
Interest. Any undisputed payments to be made hereunder that are not paid on or
before the date such payments are due under this Agreement will bear interest at
a rate per annum equal to the lesser of (i) the rate announced by Bank of
America (or its successor) as its prime rate in effect on the date that such
payment would have been first due plus 1% or (ii) the maximum rate permissible
under Applicable Law.

ARTICLE 7.
INTELLECTUAL PROPERTY

7.1.
Ownership.

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

7.1.2.
Agreement Technology. As between the Parties, Biogen is and will be the sole
owner of any Know-How discovered, developed, invented or created solely by or on
behalf of Biogen or its Affiliates under this Agreement (“Biogen Program
Know-How”) and any Patent Rights that claim or cover Biogen Program Know-How
(“Biogen Program Patents” and together with the Biogen Program Know-How, the
“Biogen Program Technology”), and will retain all of its rights, title and
interests thereto, subject to any rights or licenses expressly granted by Biogen
to Ionis under this Agreement. As between the Parties, Ionis is and will be the
sole owner of any Know-How discovered, developed, invented or created solely by
or on behalf of Ionis or its Affiliates under this Agreement (“Ionis Program
Know-How”) and any Patent Rights that claim or cover such Know-How (“Ionis
Program Patents” and together with the Ionis Program Know-How, the “Ionis
Program Technology”), and will retain all of its rights, title and interests
thereto, subject to any assignment, rights or licenses expressly granted by
Ionis to Biogen under this Agreement. Any Know-How discovered, developed,
invented or created jointly under this Agreement by or on behalf of both Parties
or their respective Affiliates or Third Parties acting on their behalf
(“Jointly-Owned Program Know-How”) and any Patent Rights that claim or cover
such Jointly-Owned Program Know-How (“Jointly-Owned Program Patents” and
together with the Jointly-Owned Program Know-How, the “Jointly-Owned Program
Technology”), are and will be owned jointly by Biogen and Ionis on an equal and
undivided basis, including all rights, title and interests thereto, subject to
any rights or licenses expressly granted by one Party to the other Party under
this Agreement. Except as expressly provided in this Agreement, neither Party
will have any obligation to account to the other for profits with respect to, or
to obtain any consent of the other Party to license or exploit, Jointly-Owned
Program Technology by reason of joint ownership thereof, and each Party hereby
waives any right it may have under the Laws of any jurisdiction to require any
such consent or accounting. Each Party will promptly disclose to the other Party
in writing, and will cause its Affiliates to so disclose, the discovery,
development, invention or creation of any Jointly-Owned Program Technology. The
Biogen Program Patents, Ionis Program Patents and Jointly-Owned Program Patents
are collectively referred to herein as the “Program Patents.”

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7.1.3.
Joint Patent Committee.

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

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

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

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(d)
Notwithstanding any provision to the contrary in this Agreement, including under
Section 6.11, if Collaborator IP (other than Additional Core IP arises from
activities performed by a Third Party under the applicable Neurology Plan, then
any payment obligations arising under the applicable Collaborator License based
on the Development or Commercialization of a Product will be [***] as follows:
(i) in the case where [***] enters into such Collaborator License, [***] will be
solely responsible for paying any payment obligations that [***], except that
[***] will be solely responsible for paying any payment obligations that [***]
under any such Collaborator Licenses that [***] approved prior to execution
thereof, and (ii) in the case where [***] enters into such Collaborator License,
[***] will be [***] responsible for paying any payment obligations that [***].

(e)
With respect to any such Collaborator IP licensed by Ionis under a Collaborator
License with such Third Party, Biogen will have the right in accordance with
Section 4.1.5 to elect to exclude any such Collaborator IP from the applicable
license granted to Biogen under Section 4.1.1 by providing Ionis written notice
prior to the License Effective Date for the applicable Collaboration Program.
If, Biogen timely provides Ionis with such a written notice to exclude certain
of such Collaborator IP from such license, then such Collaborator IP will not be
included in the Licensed Technology licensed with respect to such Collaboration
Program under this Agreement. If Biogen does not provide Ionis with such a
written notice to exclude such Collaborator IP prior to the License Effective
Date for the applicable Collaboration Program hereunder, then such Collaborator
IP (and any Third Party Obligations to the extent applicable to Products) will
be included in the Licensed Technology licensed with respect to the applicable
Collaboration Program under this Agreement.

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

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

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

7.2.
Prosecution and Maintenance of Patents.

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7.2.1.
Patent Filings. Subject to Biogen’s right to provide reasonable input and
comment as set forth in Section 7.2.5(a), the Party responsible for Prosecution
and Maintenance of any Patent Rights as set forth in Section 7.2.2 and Section
7.2.3 will endeavor to obtain patent protection for the applicable Product as it
Prosecutes and Maintains its other patents Covering products in development,
using counsel of its own choice but reasonably acceptable to the other Party, in
such countries as the responsible Party sees fit.

7.2.2.
Licensed Patents and Biogen Patents.

(a)
Licensed Patents In General. Prior to the License Effective Date for a
Collaboration Program or Biogen Alternate Modality Program (as applicable) (a
“Program”), and subject to Biogen’s right to provide reasonable input and
comment as set forth in Section 7.2.5(a), Ionis will control and be responsible
for all aspects of the Prosecution and Maintenance of all Licensed Patents that
are the subject of such license grant for such Program, subject to this Section
7.2.2(a) and Section 7.2.3. During the Agreement Term, Ionis will control and be
responsible for all aspects of the Ionis Core Technology Patents and Ionis
Manufacturing and Analytical Patents. Ionis will use commercially reasonable
efforts to diligently Prosecute and Maintain all Jointly-Owned Program Patents
for which Ionis has the right to Prosecute and Maintain. On a
Program-by-Program, until the earlier of the License Effective Date with respect
to such Program and the expiration or termination of Biogen’s right to be
granted such license, Ionis will use commercially reasonable efforts to
diligently Prosecute and Maintain all Ionis Product-Specific Patents that are
the subject of such Program to the extent that Ionis has the right to Prosecute
and Maintain such Patent Rights.

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

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

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7.2.3.
Jointly-Owned Program Patents. Subject to Biogen’s right to provide reasonable
input and comment as set forth in Section 7.2.5(a), Ionis will control and be
responsible for all aspects of the Prosecution and Maintenance of Jointly-Owned
Program Patents that do not Cover Products. Prior to the License Effective Date
for a Program and subject to Biogen’s right to provide reasonable input and
comment as set forth in Section 7.2.5(a), Ionis will control and be responsible
for all aspects of the Prosecution and Maintenance of Jointly-Owned Program
Patents Covering Products that are the subject of such Program. After the
License Effective Date for a Collaboration Program, Biogen will control and be
responsible for all aspects of the Prosecution and Maintenance of Jointly-Owned
Program Patents Covering Products that are the subject of such Program.

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

7.2.5.
Other Matters Pertaining to Prosecution and Maintenance of Patents.

(a)
Ionis will keep Biogen reasonably informed through the Joint Patent Committee
(or directly, if the Joint Patent Committee has been disbanded) as to material
developments with respect to the Prosecution and Maintenance of (i) those Ionis
Core Technology Patents and Ionis Manufacturing and Analytical Patents that
Cover any Development Candidate or Product and (ii) the Ionis Product-Specific
Patents and Jointly-Owned Program Patents, in each case ((i) and (ii)), for
which Ionis has the responsibility to Prosecute and Maintain pursuant to Section
7.2.2, Section 7.2.3 or this Section 7.2.5, including by providing copies of
material data as it arises. Ionis will timely provide Biogen the timely
opportunity to have reasonable input into the strategic aspects of such
Prosecution and Maintenance, including the countries in which such Patent Rights
are filed, and will consider Biogen’s input with respect to such strategic
aspects in good faith but which will not be binding on Ionis. Additionally,
Ionis will promptly provide to Biogen drafts of all patent-related filings and
communications related to the such Patent Rights, including copies of office
actions or other correspondence that Ionis receives from any patent office,
drafts of office action responses or other correspondence that Ionis provides to
any patent office, and copies and drafts of all interferences, reissues,
re-examinations, oppositions or requests for patent term extensions, in each
case, for Biogen’s review and comment, and Ionis will consider in good faith any
reasonable comments timely provided by Biogen with respect to such draft filings
and communications.

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(b)
Following the License Effective Date with respect to a particular Program,
Biogen will keep Ionis reasonably informed through the Joint Patent Committee
(or directly, if the Joint Patent Committee has been disbanded) as to material
developments with respect to the Prosecution and Maintenance of Product-Specific
Patents or Jointly-Owned Program Patents for which Biogen has the responsibility
to Prosecute and Maintain pursuant to Section 7.2.2, Section 7.2.3 or this
Section 7.2.5, including by providing copies of material data as it arises and
will provide Ionis the timely opportunity to have reasonable input into the
strategic aspects of such Prosecution and Maintenance, which input Biogen will
consider in good faith but which will not be required to implement. Following
the License Effective Date with respect to a particular Program, Biogen will
have final decision-making authority with respect to the Prosecution and
Maintenance, enforcement and defense of such Product-Specific Patents or
Jointly-Owned Program Patents related to such Program, including any Proceeding
related to the infringement of such Patent Rights and any patent term extensions
related to such Patent Rights.

(c)
If Biogen elects (i) not to file and prosecute patent applications for the
Jointly-Owned Program Patents or Ionis Product-Specific Patents that have been
licensed or assigned to Biogen under this Agreement or the Biogen
Product-Specific Patents (“Biogen-Prosecuted Patents”) in a particular country,
(ii) not to continue the Prosecution and Maintenance (including any
interferences, oppositions, reissue proceedings, re-examinations, and patent
term extensions, adjustments, and restorations) of any Biogen-Prosecuted Patent
in a particular country or (iii) not to file and prosecute patent applications
for the Biogen-Prosecuted Patent in a particular country following a written
request from Ionis to file and prosecute in such country, then in each case ((i)
– (iii)), Biogen will so notify Ionis promptly in writing of its intention
(including a reasonably detailed rationale for doing so) with sufficient time to
enable Ionis to meet any deadlines by which an action must be taken to establish
or preserve any such Patent Right in such country; and except as set forth in
Section 7.2.5(d) Ionis will have the right, but not the obligation, to file,
prosecute, maintain, enforce or otherwise pursue such Biogen-Prosecuted Patent
in the applicable country at its own expense with counsel of its own choice. In
such case, Biogen will cooperate with Ionis to file for, or continue to
Prosecute and Maintain, enforce or otherwise pursue such Biogen-Prosecuted
Patent in such country in Ionis’ own name, but only to the extent that Biogen is
not required to take any position with respect to such abandoned
Biogen-Prosecuted Patent that would be reasonably likely to adversely affect the
scope, validity or enforceability of any of the other Patent Rights being
prosecuted and maintained by Biogen under this Agreement. Notwithstanding
anything to the contrary in this Agreement, if Ionis assumes responsibility for
the Prosecution and Maintenance of any such Biogen-Prosecuted Patent under this
Section 7.2.5(c), then Ionis will have no obligation to notify Biogen if Ionis
intends to abandon such Biogen-Prosecuted Patent.

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(d)
Notwithstanding Section 7.2.5(c) above, if, after having consulted with outside
counsel, Biogen reasonably determines that filing or continuing to prosecute a
patent application in a particular country for a Biogen-Prosecuted Patent (the
“Conflicting Patent Right”) is reasonably likely to adversely affect the scope,
validity or enforceability of a patent application or issued patent in a
particular country for another Biogen-Prosecuted Patent (the “Superior Patent
Right”), in each case where both the Conflicting Patent Right and the Superior
Patent Right if issued would meet the criteria set forth in clause (i) of
Section 6.10.2(a), then so long as Biogen continues to Prosecute and Maintain
the Superior Patent Right in accordance with this Agreement, Ionis will not have
the right under Section 7.2.5(c) above to file or prosecute the Conflicting
Patent Right.

(e)
If, during the Agreement Term, Ionis intends not to file or to abandon in any
jurisdiction any Ionis Product-Specific Patent for which Ionis is responsible
for Prosecution and Maintenance without first filing a continuation or
substitution, then, if Biogen’s right to obtain a license under Section 4.1.1 to
such Ionis Product-Specific Patent has not expired or terminated, Ionis will
notify Biogen of such intention at least [***] days before such Patent Right
will become abandoned, and Biogen will have the right, but not the obligation,
to assume responsibility and final decision-making authority for the Prosecution
and Maintenance thereof at its own expense (subject to Section 7.3.1) with
counsel of its own choice.  Notwithstanding anything to the contrary in this
Agreement, if Biogen assumes responsibility for the Prosecution and Maintenance
of any such Ionis Product-Specific Patent under this Section 7.2.5(e), then
Biogen will have no obligation to notify Ionis if Biogen intends to abandon such
Ionis Product-Specific Patent.

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

(g)
If the Party responsible for Prosecution and Maintenance of a Jointly-Owned
Program Patent pursuant to Section 7.2.3 intends to abandon such Jointly-Owned
Program Patent without first filing a continuation or substitution, then such
Party will notify the other Party of such intention at least [***] days before
such Jointly-Owned Program Patent will become abandoned, and such other Party
will have the right, but not the obligation, to assume responsibility and final
decision-making authority for the Prosecution and Maintenance thereof at its own
expense (subject to Section 7.3.1) with counsel of its own choice, in which case
the abandoning Party will, and will cause its Affiliates to, assign to the other
Party (or, if such assignment is not possible, grant a fully-paid exclusive
license in) all of their rights, title and interests in and to such
Jointly-Owned Program Patents. If a Party assumes responsibility for the
Prosecution and Maintenance of any such Jointly-Owned Program Patents under this
Section 7.2.5(g), such Party will have no obligation to notify the other Party
of any intention of such Party to abandon such Jointly-Owned Program Patents.

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

7.3.
Patent Costs.

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

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

7.4.
Defense of Claims Brought by Third Parties.

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

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

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

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7.5.
Enforcement of Patents Against Competitive Infringement.

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

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

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

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

7.5.5.
Joinder.

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

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

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

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

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

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

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

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

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

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7.6.
Other Infringement.

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

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

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

7.7.
Patent Listing.

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

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

7.8.
Joint Research Agreement under the Leahy-Smith America Invents Act.
Notwithstanding anything to the contrary in this ARTICLE 7, neither Party will
have the right to make an election under 35 U.S.C. § 102(c) of the Leahy-Smith
America Invents Act when exercising its rights under this ARTICLE 7 without the
prior written consent of the other Party, which will not be unreasonably
withheld, conditioned or delayed.  With respect to any such permitted election,
each Party will use reasonable efforts to cooperate and coordinate their
activities with the other Party with respect to any submissions, filings or
other activities in support thereof. The Parties acknowledge and agree that this
Agreement is a “joint research agreement” as defined in 35 U.S.C. § 100(h).

7.9.
Obligations to Third Parties. Notwithstanding any of the foregoing, each Party’s
rights and obligations with respect to Licensed Technology under this ARTICLE 7
will be subject to the Third Party rights and obligations under any (a) New
Third Party License the restrictions and obligations of which Biogen has agreed
to under Section 6.13.2, (b) Prior Agreements, and (c) Ionis In-License
Agreements; provided, however, that, to the extent that Ionis has a
non-transferable right to prosecute, maintain or enforce any Patent Rights
licensed to Biogen hereunder and, this Agreement purports to grant any such
rights to Biogen, Ionis will act in such regard with respect to such Patent
Rights at Biogen’s direction.

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

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

ARTICLE 8.
REPRESENTATIONS AND WARRANTIES

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

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

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

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

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

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

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

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

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

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

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

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

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

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

8.2.7.
Ionis has set forth on Schedule 6.13.1 or in a separate written agreement with
Biogen true, correct and complete lists of the agreements with Third Party
licensors or sellers pursuant to which Ionis has licensed or acquired the
Licensed Technology Controlled by Ionis as of the Effective Date licensed to
Biogen under Section 4.1.1(a) that is necessary or useful to conduct the
research, Development, Manufacture or Commercialization of any High Interest
Target listed on the High Interest Target List as of the Effective Date.  All
Ionis In-License Agreements are in full force and effect and have not been
modified or amended. Neither Ionis nor, to the best knowledge of Ionis, the
Third Party licensor in an Ionis In-License Agreement is in default with respect
to a material obligation under such Ionis In-License Agreement, and neither such
party has claimed or has grounds upon which to claim that the other party is in
default with respect to a material obligation under, any Ionis In-License
Agreement.

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

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

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

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

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

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

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

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

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

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

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

ARTICLE 9.
INDEMNIFICATION; INSURANCE

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

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

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

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

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

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

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

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

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

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

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

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

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

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9.4.
Insurance.

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

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

9.5.
LIMITATION OF CONSEQUENTIAL DAMAGES. EXCEPT FOR (a) CLAIMS OF A THIRD PARTY THAT
ARE SUBJECT TO INDEMNIFICATION UNDER THIS ARTICLE 9, (b) CLAIMS ARISING OUT OF A
PARTY’S WILLFUL MISCONDUCT OF THIS AGREEMENT, (c) A PARTY’S BREACH OF ARTICLE 2,
OR A BREACH OF SECTION 10.4.4(a) BY BIOGEN OR ITS AFFILIATES OR (d) CLAIMS
ARISING OUT OF A PARTY’S BREACH OF ITS CONFIDENTIALITY OBLIGATIONS UNDER THIS
AGREEMENT, NEITHER PARTY NOR ANY OF ITS AFFILIATES WILL BE LIABLE TO THE OTHER
PARTY TO THIS AGREEMENT OR ITS AFFILIATES FOR ANY INCIDENTAL, CONSEQUENTIAL,
SPECIAL, PUNITIVE OR OTHER INDIRECT DAMAGES OR LOST OR IMPUTED PROFITS OR
ROYALTIES, LOST DATA OR COST OF PROCUREMENT OF SUBSTITUTE GOODS OR SERVICES,
WHETHER LIABILITY IS ASSERTED IN CONTRACT, TORT (INCLUDING NEGLIGENCE AND STRICT
PRODUCT LIABILITY), INDEMNITY OR CONTRIBUTION, AND IRRESPECTIVE OF WHETHER THAT
PARTY OR ANY REPRESENTATIVE OF THAT PARTY HAS BEEN ADVISED OF, OR OTHERWISE
MIGHT HAVE ANTICIPATED THE POSSIBILITY OF, ANY SUCH LOSS OR DAMAGE.

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ARTICLE 10.
TERM; TERMINATION

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

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

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

10.1.3.
where there are no Collaboration Targets and no Biogen Alternate Modality
Targets designated by the expiration of the Research Term as described in
Section 1.9;

10.1.4.
where there are no Biogen Alternate Modality Targets designated by the
expiration of the Research Term as described in Section 1.9, and no Development
Candidates designated by the expiration of the ASO Development Candidate
Identification Term as described in Section 1.10.1(d); and

10.1.5.
where there are no Biogen Alternate Modality Targets designated by the
expiration of the Research Term as described in Section 1.9, and every Option
has expired as a result of Biogen not providing Ionis a written notice stating
Biogen is exercising such Options and paying Ionis the applicable license fees
under Section 6.6 by the Option Deadline, or as a result of Section 1.10.2(g) or
Section 10.4.3.

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

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10.2.
Termination of the Agreement.

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

10.2.2.
Termination for Failure to Divest Competitive Product. If, after the acquisition
by a Party of a Third Party that is developing or commercializing an Acquired
Competitive Product or an Acquired Competitive Program, such Party does not, by
the end of the Collaboration Divestiture Period, divest itself of a Competitive
Collaboration Product or Competitive Collaboration Program, as applicable, or
terminate the development and commercialization of such Acquired Competitive
Product or activities under such Acquired Competitive Program or assign this
Agreement to a Third Party that is not itself developing or commercializing a
Competitive Collaboration Product or engaged in a Competitive Collaboration
Program, as set forth in Section 12.5.3, then the non-acquiring Party may
terminate this Agreement solely with respect to the Collaboration Program(s)
affected thereby immediately upon providing written notice to the acquiring
Party.

10.2.3.
Termination Due to Failure to Obtain HSR Clearance.

(a)
If the Parties make an HSR Filing with respect to a proposed Program under
Section 1.7, Section 3.1.3 or Section 3.2.5 of this Agreement and the HSR
Clearance Date has not occurred on or prior to 90 days after the effective date
of the latest HSR Filing made by the Parties, this Agreement will terminate
solely with respect to the applicable proposed Program (i) at the election of
either Party immediately upon notice to the other Party, if the FTC or the DOJ
has instituted (or threatened to institute) any action, suit or proceeding
including seeking, threatening to seek or obtaining a preliminary injunction
under the HSR Act against Biogen and Ionis to enjoin or otherwise prohibit the
transactions contemplated by this Agreement related to such proposed Program, or
(ii) at the election of either Party, immediately upon notice to the other
Party, if the Parties have not resolved any and all objections of the FTC and
DOJ as contemplated by Section 3.1.4(b). Notwithstanding the foregoing, this
Section 10.2.3 will not apply if an HSR Filing is not required to fully perform
this Agreement with respect to a proposed Program, as applicable.

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

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

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

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

10.2.4.
Termination for Material Breach.

(a)
Biogen’s Right to Terminate. If Biogen believes that Ionis is in material breach
of this Agreement (other than with respect to a failure to use Commercially
Reasonable Efforts under ARTICLE 1, which is governed by Section 10.2.5 below),
then Biogen may deliver notice of such material breach to Ionis. If the breach
is curable, Ionis will have [***] days to cure such breach. If Ionis fails to
cure such breach within the [***] day period, or if the breach is not subject to
cure, Biogen may terminate this Agreement with respect to the Neurology Target
or Collaboration Program affected by such breach by providing written notice to
Ionis. Without limiting the foregoing, breach by a Party of ARTICLE 2 of this
Agreement constitutes a material breach of this Agreement with respect to the
Neurology Target or Collaboration Program affected by such breach.

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

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10.2.5.
Remedies for Failure to Use Commercially Reasonable Efforts.

(a)
If Ionis, in Biogen’s reasonable determination, fails to use Commercially
Reasonable Efforts in the activities contemplated in ARTICLE 1 prior to the date
Biogen is granted a license under Section 4.1.1(a) or Section 4.1.1(b) (as
applicable) with respect to a particular High Interest Target or Collaboration
Program, Biogen will notify Ionis and, within [***] days thereafter, Ionis and
Biogen will meet and confer to discuss and resolve the matter in good faith, and
attempt to devise a mutually agreeable plan to address any outstanding issues
related to Ionis’ use of Commercially Reasonable Efforts in ARTICLE 1. Following
such a meeting, if Ionis fails to use Commercially Reasonable Efforts as
contemplated by ARTICLE 1 with respect to such High Interest Target or
Collaboration Program, then subject to Section 10.2.6 below, Biogen will have
the right, at its sole discretion, to (i) terminate this Agreement as it relates
to the applicable High Interest Target or Collaboration Program or, (ii) if the
breach involves a Collaboration Program prior to the applicable License
Effective Date, Biogen may elect to trigger the alternative remedy provisions of
Section 10.3 below as it relates to the applicable Collaboration Program in lieu
of terminating this Agreement for such Collaboration Program by providing
written notice to Ionis. This Section 10.2.5(a) sets forth Biogen’s sole and
exclusive remedies if Ionis fails to use Commercially Reasonable Efforts in the
activities contemplated in ARTICLE 1 prior to the date Biogen is granted a
license under Section 4.1.1(a) or Section 4.1.1(b) (as applicable).

(b)
If Biogen, in Ionis’ reasonable determination, fails to use Commercially
Reasonable Efforts under Section 5.1 with respect to a Collaboration Program,
Ionis will notify Biogen and, within [***] days thereafter, Ionis and Biogen
will meet and confer to discuss and resolve the matter in good faith, and
attempt to devise a mutually agreeable plan to address any outstanding issues
related to Biogen’s use of Commercially Reasonable Efforts in Section 5.1.
Following such a meeting, if Biogen fails to use Commercially Reasonable Efforts
with respect to the applicable Collaboration Program as contemplated by Section
5.1, then subject to Section 10.2.6 below, Ionis will have the right, at its
sole discretion, to terminate this Agreement as it relates to such Collaboration
Program.

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

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10.2.7.
Termination for Insolvency.

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

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

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

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

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

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

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

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

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

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

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

(e)
Biogen’s obligation to make further disclosures of Know-How or other information
to Ionis regarding the applicable Collaboration Products pursuant to this
Agreement (including pursuant to Section 4.8 and Section 5.2.7) will terminate,
other than reports required by Section 6.14.1, Section 10.4.4 (if applicable),
and as reasonably required to permit Ionis to perform its obligations under this
Agreement; provided such remedy will not limit or diminish the scope of any
licenses granted by Biogen to Ionis under this Agreement;

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

(g)
If such Collaboration Program is not an ALS Collaboration Program the financial
provisions of ARTICLE 6 as they apply to such Collaboration Program will be
modified as follows:

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

(ii)
License Fee. The license fee set forth in Section 6.6 for the applicable
Collaboration Product will be [***]. Such [***] will be due within 90 days after
[***] and Biogen’s [***].

The milestone provisions of Section 6.7 and the royalty provisions of Section
6.10 will [***].

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10.4.
Consequences of Expiration or Termination of the Agreement.

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

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

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

(c)
Survival. The following provisions of this Agreement will survive the expiration
or termination of this Agreement: Section 1.9 (End of Research Term), Section
1.10.1(d) (End of ASO Development Candidate Identification Term), Section
2.1.1(f) (Failure to Defer or Designate a High Interest Target a Collaboration
Target or Biogen Alternate Modality Target), Section 3.1.3 (Option and Option
Deadline) (but only with respect to Biogen’s transfer obligations thereunder),
Section 4.1.3 (Effect of Termination on Sublicenses), Section 4.2.2 (Grant Back
to Ionis), Section 4.3.3 (Enabling License to Biogen), Section 4.3.4 (Enabling
License to Ionis), Section 4.4 (Licenses to Ionis for Biogen Results), Section
4.5 (Right to Obtain Direct License from Biogen to Ionis Partner; Sublicensees
of Ionis), Section 4.8.2 (Technology Transfer after License Effective Date) (but
only to the extent necessary to satisfy the requirements of Section 10.4.4),
Section 6.12 (Reverse Royalty Payments to Biogen for a Discontinued
Collaboration Product), Section 6.14.3 (Records Retention), Section 6.15
(Audits), Section 7.1.1 (Ionis Technology and Biogen Technology), Section 7.1.2
(Agreement Technology), Section 8.4 (Disclaimer), ARTICLE 9 (Indemnification;
Insurance), Section 10.2.3(b), Section 10.2.7 (Termination for Insolvency),
Section 10.4 (Consequences of Expiration or Termination of the Agreement)
(except Section 10.4.5 (Remedies Available to Biogen for Ionis’ Material Breach
After License Effective Date)), ARTICLE 11 (Confidentiality), ARTICLE 12
(Miscellaneous) and Appendix 1 (Definitions) (to the extent definitions are
embodied in the foregoing listed Articles and Sections).

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10.4.2.
Natural Expiration. If this Agreement expires in accordance with Section 10.1.1
or Section 10.1.2, the following terms will apply to any Biogen Alternate
Modality Product or Collaboration Product (as applicable) that is the subject of
such expiration:

(a)
Perpetual, Royalty-Free Non-Exclusive License. If Biogen has been granted a
license under Section 4.1.1(a) or Section 4.1.1(b) (as applicable) for a
particular Product, then upon expiration of the Biogen Alternate Modality
Royalty Period or Reduced Royalty Period, as the case may be, in all countries
in which the applicable Products are being or have been sold, Ionis will and
hereby does grant to Biogen a perpetual, non-exclusive, worldwide, royalty-free,
fully paid-up, sublicensable license under the Ionis Know-How to Manufacture,
Develop and Commercialize the applicable Product.

10.4.3.
Termination Prior to License Effective Date. If this Agreement expires or is
terminated by a Party in accordance with this ARTICLE 10 before the License
Effective Date for a particular Program, then, in addition to the terms set
forth in Section 10.4.1, the following terms will apply to each Product,
Neurology Target, High Interest Target or Collaboration Program that is the
subject of such expiration or termination:

(a)
Biogen’s right to designate High Interest Targets as Collaboration Targets or
Biogen Alternate Modality Targets under this Agreement will expire and Ionis
will be free to Develop and Commercialize the applicable Product (and any other
applicable Compounds) on its own or with a Third Party.

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

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

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

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

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

(g)
If Biogen terminates this Agreement for convenience with respect to a
Collaboration Program that is not an ALS Collaboration Program or a Biogen
Conducted Non-ALS Collaboration Program, then solely with respect to such
Collaboration Program:

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

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

(h)
If Biogen terminates this Agreement for convenience with respect to an ALS
Collaboration Program or a Biogen Conducted Non-ALS Collaboration Program, then
solely with respect to such Collaboration Program:

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

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

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

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

10.4.4.
Termination After License Effective Date. If this Agreement is terminated by a
Party in accordance with this ARTICLE 10 after the License Effective Date for a
particular Product, then, in addition to the terms set forth in Section 10.4.1,
the following terms will apply to any Product or Collaboration Program that is
the subject of such termination:

(a)
The applicable licenses granted by Ionis to Biogen under this Agreement will
terminate. Biogen, its Affiliates and Sublicensees will cease selling the
applicable Products, unless Ionis elects to have Biogen continue to sell the
applicable Products as part of the Transition Services to the extent provided in
Section 10.4.6.

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

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

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

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

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

(iii)
Within [***] days following the date of the termination, Biogen will transfer to
Ionis solely for use with respect to the Development and Commercialization of
the applicable Discontinued Collaboration Product(s), any Know-How, data,
results and copies of Regulatory Materials in the possession of Biogen as of the
date of such reversion to the extent related to such Discontinued Collaboration
Product(s), and any other information or material specified in Section 4.8,
provided that, for the avoidance of doubt, as between the Parties, title to any
intellectual property that is Biogen Technology within any of the foregoing will
remain with Biogen subject to the license granted to Ionis under Section
10.4.4(d)(i), except as otherwise provided in Section 10.4.4(d)(iv) below;

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

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(v)
Biogen will, and does hereby, exclusively license to Ionis any trademarks that
are specific to a Discontinued Collaboration Product(s) solely for use with such
Discontinued Collaboration Product(s), in accordance with Section 4.1.6, mutatis
mutandis; provided, however, in no event will Biogen have any obligation to
license to Ionis any trademarks used by Biogen both in connection with the
Product and in connection with the sale of any other product or service,
including any BIOGEN- or BIOGEN-formative marks;

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

(vii)
Ionis will have the obligation to pay royalties to Biogen under Section 6.12
with respect to the applicable Discontinued Collaboration Product(s).  Such
payments will be governed by the financial provisions in Section 6.14, and the
definition of Net Sales will apply to sales of Discontinued Collaboration
Product(s) by Ionis, in each case mutatis mutandis.

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

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

(g)
If Biogen under Section 10.2.1 or Section 10.2.2 voluntarily terminates its
license under Section 4.1.1(b) with respect to a High Interest Target Biogen
designated as a Biogen Alternate Modality Target then Section 2.1.1(f) will
apply.

10.4.5.
Remedies Available to Biogen for Ionis’ Material Breach After License Effective
Date.

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

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

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

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

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

(v)
Terminate Biogen’s obligation to make further disclosures of Know-How or other
information to Ionis pursuant to this Agreement related to the applicable
Collaboration Products, including pursuant to Section 4.8 and Section 5.2.7,
other than reports required by Section 6.14.1, Section 10.4.4 (if applicable),
and as reasonably required to permit Ionis to perform its obligations under this
Agreement; provided such remedy will not limit or diminish the scope of any
licenses granted by Biogen to Ionis under this Agreement; and

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

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

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(b)
Biogen’s Right of Setoff. If there is [***] and Biogen does not wish to [***],
then, in addition to any other remedies Biogen may have under this Agreement or
otherwise, Biogen may setoff against any amounts owed to Ionis pursuant to
ARTICLE 6 (Financial Provisions) solely with respect to the Collaboration
Program that is the subject of the Ionis Breach Event [***] (the “Setoff
Amount”). If Biogen exercises its setoff right under this Section 10.4.5(b),
Biogen will provide Ionis with a written certificate, signed by Biogen’s Chief
Financial Officer, certifying that the amount setoff by Biogen represents [***].
Notwithstanding the foregoing, if Ionis notifies Biogen in writing (a “Setoff
Dispute Notice”) that it disputes Biogen’s assertion that Ionis is in material
breach of this Agreement or the amount setoff by Biogen (a “Setoff Dispute”),
then (i) both Parties will participate in the dispute resolution process set
forth on Schedule 10.4.5(b), and (ii) pending the Parties' agreement regarding
the appropriate setoff (if any) or a determination by the Advisory Panel of the
proper amount that Biogen may setoff (if any) in accordance with Schedule
10.4.5(b), Biogen will pay the Setoff Amount into an interest-bearing escrow
account established for the purpose at a bank. If the Parties cannot settle
their dispute by mutual agreement, then, in accordance with Schedule 10.4.5(b)
the Advisory Panel will determine (1) the amount (if any) that Biogen may setoff
against future payments solely with respect to the Collaboration Program that is
the subject of the Ionis Breach Event to Ionis going forward, and (2) whether
any portion of the escrow account should be released to Ionis or returned to
Biogen, provided that any decision or determination by the Advisory Panel (a
“Panel Decision”) will not be treated as an arbitral award but will be binding
on the Parties until and unless a court of competent jurisdiction (the “Trial
Court”) has determined in a judgment regarding some or all of the issues decided
in the Panel Decision, and in any Action contemplated by the next sentence
hereof the Trial Court will determine the facts and the law de novo, and will
give a Panel Decision only such persuasive effect, if any, that after review of
all of the facts and the law presented to the Trial Court by the Parties, the
Trial Court deems appropriate, provided that the escrow agent will comply with a
Panel Decision that determines that any portion of the escrow account should be
released to Ionis or returned to Biogen. If it is determined in a judgment by
the Trial Court that Ionis owes Biogen any damages, then, during the pendency of
any appeal of the Trial Court’s decision (or, if the Trial Court’s decision is
not appealed, until Biogen recoups such amount), Biogen may setoff against any
future payments solely with respect to the Collaboration Programs that are the
subject of the Ionis Breach Event to Ionis under this Agreement the amount of
any such damages not paid by Ionis.  If it is determined in a Trial Court that
Biogen has setoff an amount that exceeds the amount of losses, damages and
expenses actually incurred by Biogen as a result of Ionis’ breach of this
Agreement, then Biogen will promptly pay Ionis the amount of such excess, plus
interest on such amount as provided for in Section 6.17 (Interest on Late
Payments), with interest accruing from the time Biogen applied such excess
setoff.  If, with respect to a Setoff Dispute, Ionis provides a Setoff Dispute
Notice to Biogen and Biogen fails to do any of the following: (X) appoint a
member of the Advisory Panel to the extent required in Section 2 of Schedule
10.4.5(b); (Y) meet with the Advisory Panel as required in Section 3 of Schedule
10.4.5(b); or (Z) pay the Setoff Amount into an interest-bearing escrow account
established for the purpose at a bank, then Biogen will forfeit its right to set
off under this Section 10.4.5(b) and Schedule 10.4.5(b) with respect to any and
all Setoff Disputes.

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10.4.6.
Transition Services.

(a)
In the case where (i) Biogen terminates the Agreement under Section 10.2.1
(Biogen’s Termination for Convenience) or (ii) Ionis terminates this Agreement
under Section 10.2.4(b) (Ionis’ Right to Terminate) or Section 10.2.5 (Remedies
for Failure to Use Commercially Reasonable Efforts) with respect to one or more
Products, the terms of this Section 10.4.6 shall apply.

(b)
In such event, the Parties wish to provide a mechanism to ensure that patients
who were being treated with the applicable Product prior to such termination or
who desire access to such Product can continue to have access to such Product
until the regulatory and commercial responsibilities for the Product are
transitioned from Biogen to Ionis following the termination of the applicable
Product. As such, Ionis may request Biogen perform transition services as listed
on Schedule 10.4.6 and such other transition services that the Parties mutually
agree in writing to (i) provide patients with continued access to the applicable
Products, (ii) following the termination of this Agreement with respect to the
applicable Product, transition the responsibilities under all Approvals and
ongoing Clinical Studies for the applicable Product to Ionis or its designee and
(iii) following termination of this Agreement with respect to the applicable
Collaboration Target, transition the then-current supply process and
responsibilities for the Product to Ionis or its designee (collectively, the
“Transition Services”). Subject to the Parties agreeing on a transition plan as
described in Section 10.4.6(c), Biogen will perform such Transition Services
using reasonable efforts for a period not to exceed [***] months from the
termination date; provided that Biogen and Ionis may mutually agree to conduct
the Transition Services for a longer period of time. Notwithstanding the
provision of the Transition Services under this Section 10.4.6(b), Ionis shall
not conduct activities with respect to any Discontinued Products to the extent
prohibited by ARTICLE 2 of this Agreement.

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

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

(e)
Ionis or its designee will be sufficiently prepared to accept the transition of
Development, Manufacturing and Commercialization activities with respect to the
Products to Ionis or such designee on the timelines set forth on Schedule 10.4.6
for the Transition Services.  Biogen will have no liability under this Agreement
with respect to a failure of or delay in the Transition Services to the extent
caused by any failure or delay by Ionis or its designee in accepting the
transition of Development, Manufacturing and Commercialization activities with
respect to the Products.  In the event that Biogen encounters any delays beyond
Biogen’s reasonable control, the Parties shall discuss in good faith and agree
upon extended timelines for completion of the Transition Services.

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ARTICLE 11.
CONFIDENTIALITY

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

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

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

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11.4.
Press Release; Publications; Disclosure of Agreement.

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

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

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

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

11.4.5.
Prior to License Grant. Prior to the date Biogen has been granted a license
under Section 4.1.1(a) or Section 4.1.1(b) (as applicable) with respect to a
Product, such Product is the sole property of Ionis and, subject to any
communication plan for such Product mutually agreed to by the Parties in
accordance with Section 1.10.2(d) and to the provisions of this Section 11.4.5
and Section 11.4.7, Ionis will have the sole right to issue press releases,
publish, present or otherwise disclose the progress and results regarding such
Product to the public, which shall be consistent with its practice with its
other compounds and products; provided that, with respect to any proposed press
release or other similar public communication by Ionis disclosing regulatory
discussions, the efficacy or safety data or clinical results related to such
Product, (i) Ionis will submit such proposed communication to Biogen for review
at least two Business Days in advance of such proposed public disclosure, (ii)
Biogen will have the right to review and recommend changes to such
communication, and (iii) Ionis will in good faith consider any changes that are
timely recommended by Biogen; and provided further that, if Biogen conducted or
co-conducted a Clinical Study that is the subject of such public announcement,
press release or other public disclosure, then any such public announcement,
press release or other public disclosure shall be jointly issued by the Parties
(unless Biogen expressly waives in writing its right to jointly issue such
public announcement, press release or other public disclosure). If Biogen
desires to make any public announcement, issue a press release or make any other
public disclosure with respect to a Clinical Study that was conducted or
co-conducted by Biogen prior to the date Biogen has been granted a license under
Section 4.1.1(a) or Section 4.1.1(b) (as applicable) with respect to a Product,
Biogen shall so notify Ionis and shall provide Ionis with a draft thereof at
least two Business Days prior to the proposed publication thereof. Ionis may
review and provide comments to Biogen and the Parties shall discuss in good
faith any such comments and seek to mutually agree on a final version of such
proposed public announcement, press release or other public disclosure.
Notwithstanding the foregoing, Ionis shall, pursuant to this Section 11.4.5,
retain final decision-making authority over (x) whether such proposed public
announcement, press release or other public disclosure shall be issued or made,
and (y) the content thereof, and in no event shall Biogen issue any such public
announcement, press release or other public disclosure under this Section 11.4.5
except in the final version approved by Ionis.

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11.4.6.
After License Grant. After the date Biogen has been granted a license under
Section 4.1.1(a) or Section 4.1.1(b) (as applicable) with respect to a Product,
subject to the provisions of this Section 11.4.6 and Section 11.4.7, Biogen will
have the sole right to issue press releases, publish, present or otherwise
disclose the progress and results regarding such Product to the public, which
shall be consistent with its practice with its other compounds and products;
provided that with respect to any proposed press release or other similar public
communication by Biogen disclosing regulatory discussions, the efficacy or
safety data or results related to such Product or Biogen’s sales projections,
(a) Biogen will submit such proposed communication to Ionis for review at least
two Business Days in advance of such proposed public disclosure, (b) Ionis will
have the right to review and recommend changes to such communication and (c)
Biogen will in good faith consider any changes that are timely recommended by
Ionis; and provided further that, if Ionis conducted or co-conducted a Clinical
Study that is the subject of such public announcement, press release or other
public disclosure, then any such public announcement, press release or other
public disclosure shall be jointly issued by the Parties (unless Ionis expressly
waives in writing its right to jointly issue such public announcement, press
release or other public disclosure). If Ionis desires to make any public
announcement, issue a press release or make any other public disclosure with
respect to a Clinical Study that was conducted or co-conducted by Ionis, Ionis
shall so notify Biogen and shall provide Biogen with a draft thereof at least
two Business Days prior to the proposed publication thereof. Biogen may review
and provide comments to Ionis and the Parties shall discuss in good faith any
such comments and seek to mutually agree on a final version of such proposed
public announcement, press release or other public disclosure. Notwithstanding
the foregoing, Biogen shall, pursuant to this Section 11.4.6, retain final
decision-making authority over  (i) whether such proposed public announcement,
press release or other public disclosure shall be issued or made and (ii) the
content thereof, and in no event shall Ionis issue any such public announcement,
press release or other public disclosure under this Section 11.4.6 except in the
final version approved by Biogen.

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

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11.4.8.
Scientific or Clinical Presentations for Collaboration Products. Regarding any
proposed scientific publications or public presentations related to summaries of
results from any Clinical Studies generated by Ionis or Biogen for a
Collaboration Product, the Parties acknowledge that scientific lead time is a
key element of the value of the Collaboration Products under this Agreement and
further agree to use Commercially Reasonable Efforts to control public
scientific disclosures of the results of the Development activities under this
Agreement to prevent any potential adverse effect of any premature public
disclosure of such results. The Parties will establish a procedure for
publication review and each Party will first submit to the other Party through
the Joint Patent Committee an early draft of all such publications or
presentations, whether they are to be presented orally or in written form, at
least [***] days prior to submission for publication including to facilitate the
publication of any summaries of Clinical Studies data and results as required on
the clinical trial registry of each respective Party. Each Party will review
such proposed publication in order to avoid the unauthorized disclosure of a
Party’s Confidential Information and to preserve the patentability of inventions
arising from the Collaboration Programs. If, during such [***] day period, the
other Party informs such Party that its proposed publication contains
Confidential Information of the other Party, then such Party will delete such
Confidential Information from its proposed publication. In addition, if at any
time during such [***] day period, the other Party informs such Party that its
proposed publication discloses inventions made by either Party in the course of
the Development under this Agreement that have not yet been protected through
the filing of a patent application, or the public disclosure of such proposed
publication could be expected to have a material adverse effect on any Patent
Rights or Know-How solely owned or Controlled by such other Party, then such
Party will either (a) delay such proposed publication for up to [***] days from
the date the other Party informed such Party of its objection to the proposed
publication, to permit the timely preparation and first filing of patent
application(s) on the information involved or (b) remove the identified
disclosures prior to publication. With respect to each Clinical Study, (i) if
such Clinical Study is Initiated prior to the date Biogen has been granted a
license under Section 4.1.1(a) or Section 4.1.1(b) (as applicable) with respect
to the applicable Product, Ionis shall determine authorship or attribution with
respect to any proposed publications regarding the results of such Clinical
Study and (ii) if such Clinical Study is Initiated after the date Biogen has
been granted a license under Section 4.1.1(a) or Section 4.1.1(b) (as
applicable) with respect to the applicable Product, Biogen shall determine
authorship or attribution with respect to any proposed publications regarding
the results of such Clinical Study, in each case ((i) and (ii)), by interpreting
and applying the authorship and attribution principles of the International
Committee of Medical Journal Editors’ Recommendations for the Conduct,
Reporting, Editing and Publication of Scholarly Work in Medical Journals,
provided that (A) in each case, the Party that has the right to determine
attribution or authorship in accordance with this Section 11.4.7 shall consider
in good faith any reasonable comments timely made by the other Party with
respect thereto, (B) any determination of authorship or attribution under this
Section 11.4.7 shall be in compliance with the requirements of the applicable
journal of the proposed publication and (C) the Party that does not have the
right to determine attribution or authorship in accordance with this Section
11.4.7 for any such proposed publication will have the right to have at least
one author listed in such publication if such Party conducted or co-conducted
such Clinical Study.

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

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

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

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

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

ARTICLE 12.
MISCELLANEOUS

12.1.
Dispute Resolution.

12.1.1.
Escalation. In the event of any Dispute (other than a Setoff Dispute, which
Setoff Dispute will be resolved pursuant to Section 12.1.3, or dispute regarding
the construction, validity or enforcement of either Party’s Patent Rights, which
disputes will be resolved pursuant to Section 12.2), either Party may, within
[***] days after either Party notifies the other Party that the Dispute has not
been resolved (provided, that such notice cannot be given less than [***] days
after the Dispute has arisen), make a written request that the Dispute be
referred for resolution to the Executive Vice President, Business Development of
Biogen and the Chief Operating Officer of Ionis (the “Executives”). Within [***]
days of either Party’s written request that the Dispute be referred to the
Executives, the Executives will meet in person at a mutually acceptable time and
location or by means of telephone or video conference to negotiate a settlement
of a Dispute. Each Party may elect to have such Party’s CSC representatives
participate in such meeting, if desired, provided that it provides the other
Party with reasonable advance notice of such intent so as to enable the other
Party to have its CSC representatives also participate in such meeting, if
desired. If the Executives fail to resolve the Dispute within such [***] day
period, then the Dispute will be referred to mediation under Section 12.1.2.

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

12.1.3.
Setoff Disputes. Setoff Disputes will be resolved in accordance with Section
10.4.5(b) and Schedule 10.4.5(b).

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12.1.4.
Expert Resolution. In the event that a matter is referred for expert resolution
under this Section 12.1.4 pursuant to Section 1.10.2(d) or under Appendix 3, the
matter will be resolved by a panel of three (3) industry experts experienced in
the issues comprising such dispute.  One expert will be chosen by Ionis, one
expert will be chosen by Biogen and the third expert will be chosen by mutual
agreement of the experts chosen by Ionis and Biogen.  The place of such expert
resolution will be in Chicago, Illinois. Within [***] days after the selection
of the third expert (which will occur not later than [***] days after a Party
notifies the other Party that it elects to have a dispute resolved pursuant to
this Section 12.1.4), the Parties will each simultaneously submit to the expert
panel and one another a written statement of their respective positions on the
relevant dispute.  Each Party will have [***] days from receipt of the other
Party’s submission to submit a written response thereto, which will include any
scientific and technical information in support thereof.  The expert panel will
conduct at least one hearing at which each Party will have the opportunity to
advocate its position before the other Party and the expert panel.  The expert
panel will have the right to further meet with both Parties together, as
necessary to make a determination.  There will be no ex parte communications
between an individual Party and either the expert panel or one or more experts. 
All documents submitted will be in the English language.  Further, the expert
panel will have the right to request information and materials and to require
and facilitate discovery as it will determine is appropriate in the
circumstances, taking into account the needs of the Parties and the desirability
of making discovery expeditious and cost-effective determinations.  No later
than 90 days after the designation of the third expert or as otherwise agreed by
the Parties, the expert panel will make a determination.  The expert panel will
provide the Parties with a written statement setting forth the basis of the
determination in connection therewith.  The decision of the expert panel will be
final, binding and conclusive, absent manifest error.  Each Party will bear its
attorneys’ fees, costs and disbursements (including, for example, expert witness
fees and expenses, photocopy charges, travel expenses, etc.) and the Parties
will share equally (50/50) the fees and costs of the expert panel.  Judgment
upon any award rendered pursuant to this Section 12.1.4 may be entered by any
court having jurisdiction over the Parties’ assets.  Except to the extent
necessary to confirm or enforce an award or as may be required by law, neither
Party nor any of the experts may disclose the existence, content or results of
any proceeding under this Section 12.1.4 without the prior written consent of
both Parties.

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

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

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12.2.2.
Subject to the provisions of Section 12.1, each Party by its execution hereof,
(a) hereby irrevocably submits to the exclusive jurisdiction of the United
States District Court for the District of Delaware (or, if but only if such
court lacks, or will not exercise, subject matter jurisdiction over the entirety
of a Dispute, the Court of Chancery of  the State of Delaware, or, if but only
if such court lacks, or will not exercise, subject matter jurisdiction over the
entirety of a Dispute, the Superior Court of the State of Delaware, with respect
to the Dispute) for the purpose of any Dispute arising between the Parties in
connection with this Agreement (each, an “Action”) and (b) hereby waives to the
extent not prohibited by Applicable Law, and agrees not to assert, by way of
motion, as a defense or otherwise, in any such Action, any claim that it is not
subject personally to the jurisdiction of the above-named courts, that venue in
the above-named courts  is improper, that its property is exempt or immune from
attachment or execution, that any such Action brought in the above-named courts
should be dismissed on grounds of forum non conveniens, should be transferred or
removed to any court other than the above-named courts, or should be stayed by
reason of the pendency of some other proceeding in any other court other than
the above-named courts, or that this Agreement or the subject matter hereof may
not be enforced in or by such courts and (c) hereby agrees not to commence any
such Action other than before the above-named courts.  Notwithstanding the
previous sentence, a Party may commence any Action in a court other than the
above-named court solely for the purpose of enforcing an order or judgment
issued by the above-named court.

12.2.3.
Each Party hereby agrees that service of process: (a) made in any manner
permitted by Delaware law, or (b) made by overnight express courier service
(signature required), prepaid, at its address specified pursuant to Section
12.8, will constitute good and valid service of process in any such Action and
(c) waives and agrees not to assert (by way of motion, as a defense, or
otherwise) in any such Action any claim that service of process made in
accordance with clause (a) or (b) does not constitute good and valid service of
process.

12.3.
Remedies. Notwithstanding anything to the contrary in this Agreement, each Party
will be entitled to seek, in addition to any other right or remedy it may have,
at law or in equity, a temporary restraining order or a preliminary injunction,
without the posting of any bond or other security, enjoining or restraining the
other Party from any violation or threatened violation of this Agreement, and
the Parties agree that in the event of a threatened or actual material breach of
this Agreement injunctive relief would be appropriate. Neither Party will be
entitled to recover any Losses relating to any matter arising under one
provision of this Agreement to the extent that such Party has already recovered
Losses with respect to such matter pursuant to other provisions of this
Agreement (including recoveries under Section 9.1 or Section 9.2, and the
offsets under Section 6.13.3(c)).  Except for the offsets and credits explicitly
set forth in Section 1.8.3, Section 6.15, Section 6.13.3(b), Section 6.13.3(d)
and Section 10.4.5(b), neither Party will have the right to setoff any amount it
is owed or believes it is owed against payments due or payable to the other
Party under this Agreement.

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

The [***].

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

12.5.
Change of Control.

12.5.1.
Research Activities. If, at any time during the Research Term, a Change of
Control of Ionis occurs, then at any time prior to the [***] anniversary of the
closing of such Change of Control, upon written notice to Ionis, Biogen may
either:

(a)
Extend the Research Term until such time as Ionis has completed target
validating activities that are Ionis Activities under the Neurological Disease
Research Plan for a total of [***] High Interest Targets;

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(b)
Terminate the Research Term, in which case: (i) Ionis will complete all ongoing
target validation work that are Ionis Activities under the Neurological Disease
Research Plan and advance each such target to Target Sanction (but for clarity,
no target validation work will be initiated for any new target under the
Neurological Disease Research Plan); (ii) Ionis will complete all ongoing Ionis
Activities under the Core Research Plan (but for clarity, no new work will be
initiated under the Core Research Plan); (iii) for each Collaboration Target
that is not an ALS Target that reaches Target Sanction or each ALS Target
designated a Collaboration Target, an ASO Development Candidate Identification
Plan will be prepared and Ionis will carry out its obligations under such plan,
all in accordance with Section 1.10.1; (iv) Ionis will continue to perform its
obligations under each ongoing ASO Development Candidate Identification Plan
until the end of the applicable ASO Development Candidate Identification Term
and under each ongoing Initial Development Plan until completion of all Ionis
Activities thereunder; (v) for each Collaboration Program for which a
Development Candidate is identified as provided herein, Biogen may, upon written
notice to Ionis, such notice to be delivered within [***] days after designating
a Development Candidate for the applicable Collaboration Program, elect to
either (A) exercise the applicable Option by notifying Ionis in writing of
Biogen’s election to license the Collaboration Product [***] and will be paid to
Ionis within [***] days after Biogen’s election under clause (A) of this Section
12.5.1(b), and after such exercise, Biogen will not be obligated [***], or (B)
establish an Initial Development Plan for such Collaboration Program pursuant to
Section 1.10.2(d), in which case Ionis and Biogen will continue to exercise
their rights and perform their respective obligations with respect to the
applicable Collaboration Program under the terms of this Agreement; (vi) the
Research Term will end upon Ionis’ completion of all Ionis Activities under
clauses (i), (ii) and (iii) above; and (vii) within [***] days after the end of
the Research Term, Ionis will [***]; or

(c)
Allow such [***] period to lapse without providing any such notice of election
under this Section 12.5.1, in which case Ionis and Biogen will continue to
exercise their rights and perform their respective obligations under the terms
of this Agreement.

12.5.2.
Pre-Existing Competitive Collaboration Programs of an Acquirer. If, at any time
during the Agreement Term, a Change of Control of a Party occurs involving a
Person that, at the time of the execution of such Change of Control, is (A)
developing or commercializing a (1) Competitive Product or (2) Competitive
Indication Collaboration Product within the Field (such pre-existing Competitive
Collaboration Products and Competitive Indication Products, each, a
“Pre-Existing Competitive Collaboration Product”) or (B) is engaged in a (1)
Competitive Collaboration Program or (2) Competitive Indication Program (such
pre-existing Competitive Collaboration Programs and Competitive Indication
Collaboration Programs, each, a “Pre-Existing Competitive Collaboration
Program,” and such Person being hereinafter referred to as a “Competing
Collaboration Acquirer”), then in each case ((A) and (B)):

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

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

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

(d)
the research, development, manufacture or commercialization of any Pre-Existing
Competitive Collaboration Product(s) by a Competing Collaboration Acquirer will
not be a violation of such Party’s exclusivity covenants under Section 2.1.1 and
Section 12.5.3(a) will not apply to any such Pre-Existing Competitive
Collaboration Product or Pre-Existing Competitive Collaboration Program;
provided that the conditions of Section 12.5.2(a) and Section 12.5.2(c) are
satisfied.

12.5.3.
Acquired Competitive Programs; Acquired Associated Programs.

(a)
If, at any time during the Agreement Term, either Party acquires a Third Party
or a portion of the business of a Third Party (whether by merger, stock purchase
or purchase of assets) that is, prior to such acquisition, engaged in
discovering, researching, developing or commercializing a Competitive
Collaboration Product within the Field or is engaged in a Competitive
Collaboration Program, in each case that would violate the provisions of ARTICLE
2 if conducted by such Party (such acquired Competitive Collaboration Product an
“Acquired Competitive Product” and such acquired Competitive Collaboration
Program an “Acquired Competitive Program”), then the limited continuation of the
research, development, manufacture or commercialization of the Acquired
Competitive Product(s) or Acquired Competitive Programs by the acquiring Party
as permitted in this Section 12.5.3(a) in a manner that would have been in the
ordinary course of business of such Third Party will not be a violation of such
acquiring Party’s exclusivity covenants under Section 2.1.1, provided that,
following the closing of such acquisition, the conditions set forth in Sections
12.5.3(a)(i) through 12.5.3(a)(iv) are met:

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

(ii)
Such acquiring Party shall use reasonable efforts to divest all such Acquired
Competitive Products and Acquired Competitive Programs promptly following the
closing of such acquisition, and in any event such Party shall complete such
divestment within [***] after the closing of such acquisition (the
“Collaboration Divestiture Period”); provided that such Collaboration
Divestiture Period shall be extended, and such Party shall not be in breach of
this Section 12.5.3(a) if, at the expiration thereof (and any extensions
thereto), such Party provides competent evidence of reasonable ongoing efforts
to divest such Acquired Competitive Products and Acquired Competitive Programs;
provided, further, that such Party shall cease all development and
commercialization activities with respect to all such Acquired Competitive
Products and Acquired Competitive Programs if such Party has not completed such
divestiture within [***] after the closing of such acquisition (it being
understood that such Party may thereafter continue its efforts to divest such
asset);

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

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

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

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(c)
In addition, without limiting Section 12.5.3(a)(iv), if at any time during the
Agreement Term, (i) Ionis acquires a Third Party or a portion of the business of
a Third Party (whether by merger, stock purchase or purchase of assets) that is,
prior to such acquisition, engaged (A) in [***] (an “Associated Product”) or any
Competitive Indication Collaboration Product, or (B) is engaged in [***] (an
“Associated Program”) or a Competitive Indication Collaboration Program, (ii)
Ionis or an Ionis Affiliate [***] or (iii) Ionis or an Ionis Affiliate
[***] then, in each case ((i) through (iii)) with respect to any Collaboration
Program directed to the Collaboration Target to which the Associated Product,
Associated Program, Competitive Collaboration Product or Competitive
Collaboration Program is directed and with respect to any Collaboration Program
intended for the same indication as the Competitive Indication Collaboration
Product or the Competitive Indication Collaboration Program, Biogen may elect
that [***] and Ionis shall comply with the same procedures as under Section
12.6 to separate its Development activities under this Agreement from its
development activities relating to any such Associated Product, Associated
Program, Competitive Collaboration Product, Competitive Collaboration Program,
Competitive Indication Collaboration Product or Competitive Indication
Collaboration Program.

12.5.4.
Biogen Alternate Modality Programs. On a Biogen Alternate Modality
Product-by-Biogen Alternate Modality Product basis, if, at any time during the
Agreement Term, a Change of Control occurs involving Ionis and a Person that, at
the time of the closing of such Change of Control, is developing in human
clinical trials or commercializing a Directly Competitive Biogen Alternate
Modality Product within the Field or is engaged in a Directly Competitive Biogen
Alternate Modality Program or, at any time during the Agreement Term after such
closing of the Change of Control, develops or acquires a Directly Competitive
Biogen Alternate Modality Product or begins a Directly Competitive Biogen
Alternate Modality Program (such Person being hereinafter referred to as a
“Competing Alternate Modality Acquirer”) and such Competing Alternate Modality
Acquirer has not, within [***] of either (i) closing of the Change of Control in
the event the Directly Competitive Biogen Alternate Modality Product is being
developed in human clinical trials or commercialized, or the Directly
Competitive Biogen Alternate Modality Program exists, as of such closing date or
(ii) the date of first development or acquisition of such Directly Competitive
Biogen Alternate Modality Product or the date on which such Competing Alternate
Modality Acquirer begins such Directly Competitive Biogen Alternate Modality
Program (the “Alternate Modality Divestiture Period”) divested itself of the
Directly Competitive Biogen Alternate Modality Product or Directly Competitive
Biogen Alternate Modality Program, terminated development and commercialization
of such Directly Competitive Biogen Alternate Modality Product or such Biogen
Alternate Modality Program or assigned this Agreement pursuant to Section 12.4
to a Third Party that is not itself developing or commercializing a Directly
Competitive Collaboration Product or engaged in a Directly Competitive Biogen
Alternate Modality Program, then (i) Ionis will provide written notice to Biogen
of the closing of such Change of Control or Alternate Modality Divestiture
Period, as applicable, and (ii) [***].  For clarity, Biogen’s rights as set
forth in this Section 12.5.4 shall be Biogen’s exclusive remedies for the
failure of a Competing Alternate Modality Acquirer to divest or terminate
development and commercialization of a Directly Competitive Biogen Alternate
Modality Product or Directly Competitive Collaboration Program or assigned this
Agreement to an applicable Third Party, in each case, during the Alternate
Modality Divestiture Period in accordance with this Section 12.5.4.

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

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

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

If to Ionis, addressed to:
Ionis Pharmaceuticals, Inc.
 
2855 Gazelle Court
 
Carlsbad, CA  92010
 
Attention:  Chief Operating Officer
 
E-mail: [***]
   
with a copy to:
Ionis Pharmaceuticals, Inc.
 
2855 Gazelle Court
 
Carlsbad, CA  92010
 
Attention:  General Counsel
 
E-mail: [***]
   
If to Biogen, addressed to:
Biogen MA Inc.
 
225 Binney Street
 
Cambridge, MA 02142
 
Attention: Chief Legal Officer
 
E-mail: [***]
   
with a copy to:
Ropes & Gray LLP
 
Prudential Tower
 
800 Boylston Street
 
Boston, MA 02199-3600
 
Attention: Mark Bellomy, Esq.
 
Email: mark.bellomy@ropesgray.com

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

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

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

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

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

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

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

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

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

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

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

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

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

[SIGNATURE PAGE FOLLOWS]

* - * - * - *

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

BIOGEN MA INC.
 
By:
/s/ Michael Ehlers
 
Name: Michael Ehlers
Title: EVP, Research & Development

Signature Page to Second Amended and Restated Strategic Neurology Drug Discovery
and Development Collaboration, Option and License Agreement

--------------------------------------------------------------------------------

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

IONIS PHARMACEUTICALS, INC.
 
By:
/s/ Brett P. Monia
 

Name:
 Brett P. Monia
 

Title:
Chief Operating Officer/SVP Translational Medicine
 

Signature Page to Second Amended and Restated Strategic Neurology Drug Discovery
and Development Collaboration, Option and License Agreement

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List of Appendices and Schedules

Appendix 1 – Definitions

Appendix 2 – Development Candidate Checklist

Appendix 3 – Multi-Indication Target Process

Appendix 4 – Form of Side Letter

Schedule 1.1.4 – Biogen Conducted Non-ALS Targets

Schedule 1.2.4 – Terms and Conditions for Provision of Research ASOs to Biogen

Schedule 1.6.1 – ALS Letter Agreement

Schedule 1.10.2(c) – Ionis’ Standard IND-Enabling Toxicology Studies

Schedule 1.10.2(d) – Initial Development Plan Requirements

Schedule 1.10.2(d)(v) – Study Synopsis Requirements

Schedule 1.10.2(e) – Apportionment of Certain Milestone Payments and
Biogen-Approved Costs

Schedule 1.10.6 – Ionis API Supply for ALS Collaboration Programs and Biogen
Conducted Non-ALS Collaboration Programs

Schedule 1.18.1 – Collaboration Steering Committee Governance

Schedule 1.18.2 – Neurology JRC Governance

Schedule 1.18.3 – Neurology JDC Governance

Schedule 1.18.6 – Alliance Management Activities

Schedule 4.3.1(a) – Drug Substance Process and Formulation Development
Activities

Schedule 4.8.2(c) – Ionis’ Fully Absorbed Cost of Goods Methodology

Schedule 5.1.4 – Biogen’s Development and Commercialization Activities

Schedule 5.1.6 – Integrated Development Plan Content

Schedule 6.10.2(e) – Royalty Calculation Examples

Schedule 6.10.2(f) – Allocation of Net Sales

Schedule 6.13.1 – Certain Ionis In-License Agreements

Schedule 8.2.4(a) – Ionis Core Technology Patents

Schedule 8.2.4(b) – Ionis Manufacturing and Analytical Patents

Schedule 8.2.4(c) – Ionis Product-Specific Patents

Schedule 8.2.8 – Prior Agreements

Schedule 10.4.5(b) – Advisory Panel Regarding Setoff Disputes

Schedule 10.4.6 – Transition Services

Schedule 12.1.2 – Mediation

Schedule 12.5 – Applicable License Fee Payments in Change of Control for
Collaboration Products, and [***]

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Appendix 1

DEFINITIONS

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

“Accelerated Target” has the meaning set forth in Section 1.8.4.

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

 “Acquired Competitive Product” has the meaning set forth in Section 12.5.3(a).

“Acquired Competitive Program” has the meaning set forth in Section 12.5.3(a).

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

“Actual Biogen-Approved Costs” has the meaning set forth in Section 1.14.1(e).

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

“Additional Plan Costs” means [***].

“Advisory Panel” has the meaning in Schedule 10.4.5(b) of this Agreement.

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

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

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

“Alliance Manager” has the meaning set forth in Section 1.18.6.

“ALS” means the disease amyotrophic lateral sclerosis.

“ALS Collaboration Program” means a Collaboration Program focused on an ALS
Target.

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

“ALS Pre-Licensing Milestone Event” has the meaning set forth in Section 6.5.

“ALS Target” means the initial ALS-associated High Interest Targets identified
as ALS Targets on Schedule 1.2.3(a) on the Effective Date, plus any
ALS-associated High Interest Target that is designated as an ALS Target in
accordance with Section 1.2.3(a).

“ALS Target List” means the list of ALS-associated High Interest Targets
identified as ALS Targets on the High Interest Target List.  For clarity, at any
given time, if a gene target is not on the ALS Target List at such time, then
such gene target is not an ALS Target.

“Alternate Modality” means a therapeutic approach for a gene target that is not
an Oligonucleotide approach.

“Alternate Modality Divestiture Period” has the meaning set forth in Section
12.5.4.

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

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

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

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

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“Approval” means, with respect to a Product in any regulatory jurisdiction,
approval from the applicable Regulatory Authority sufficient for the
manufacture, distribution, use, marketing and sale of such Product in such
jurisdiction in accordance with Applicable Laws. In jurisdictions where the
applicable Regulatory Authority sets the pricing or reimbursement authorizations
necessary for the general marketing and sale of such Product in the marketplace,
Approval will not be deemed to have occurred if the final approval to market and
sell such Product is being withheld because Biogen (or its Affiliate or
Sublicensee) and the Regulatory Authority have not yet determined pricing or
reimbursement even if all other approvals, licenses, registrations or
authorizations necessary for marketing, sale or use of such Product in such
jurisdiction have been obtained. “Approval” does not include authorization by a
Regulatory Authority to conduct named patient, compassionate use or other
similar activities.

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

“ASO Development Candidate Identification Plan” has the meaning set forth in
Section 1.10.1(a).

“ASO Development Candidate Identification Term” has the meaning set forth in
Section 1.10.1(b).

“Associated Product” has the meaning set forth in Section 12.5.3(c).

“Associated Program” has the meaning set forth in Section 12.5.3(c).

“Audit Report” has the meaning set forth in Section 6.15.

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

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

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

“Biogen Alternate Modality Milestone Event” has the meaning set forth in Section
6.3.

“Biogen Alternate Modality Product” means a finished drug product that contains
a molecule that is (i) not an Oligonucleotide, (ii) designed to bind, mimic or
otherwise affect a protein or RNA that is encoded by a Biogen Alternate Modality
Target, and (iii) discovered by Biogen or its Affiliates or any Third Party
acting on their behalf.

“Biogen Alternate Modality Program” means a program to discover, Develop,
Manufacture and Commercialize a Biogen Alternate Modality Product.

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“Biogen Alternate Modality Royalty” has the meaning set forth in Section 6.9.1.

“Biogen Alternate Modality Royalty Period” has the meaning set forth in Section
6.9.2.

“Biogen Alternate Modality Target” is either (i) a High Interest Target that is
designated as a Biogen Alternate Modality Target under Section 1.3, Section 1.4
or Section 1.8, (ii) a Collaboration Target that is changed to a Biogen
Alternate Modality Target under Section 3.2.2, or (v) a Collaboration Target
that is added as a Biogen Alternate Modality Target under Section 3.2.4.2.

“Biogen-Approved Changes” means any changes (including number of subjects,
duration of dosing, additional studies, additional endpoints, additional
analysis, etc.) to the applicable Neurology Plan for a Product that are
requested by either Party after the Parties have set the initial Cost Estimates
for such Neurology Plan under Section 1.10.2(e), and (i) required by a
Regulatory Authority or (ii) agreed to be paid for by Biogen.

“Biogen-Approved Costs” has the meaning set forth in Section 1.14.1

“Biogen Conducted Non-ALS Collaboration Program” means a Collaboration Program
focused on a Biogen Conducted Non-ALS Target.

“Biogen Conducted Non-ALS Option Deadline” has the meaning set forth in Section
3.1.3.

“Biogen Conducted Non-ALS Target” means each of the High Interest Targets listed
on Schedule 1.1.4, which may be updated by mutual written agreement of the
Parties to include additional High Interest Targets relating to [***].

“Biogen Full Royalty” has the meaning set forth in Section 6.10.1.

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

“Biogen Manufacturing Program Patents” has the meaning set forth in Section
4.8.3.

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

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

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

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

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

“Biogen-Prosecuted Patents” has the meaning set forth in Section 7.2.5(c).

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“Biogen Reduced Participation and Information Obligations” means solely with
respect to the [***] (a) Biogen may [***], (b) Biogen will [***], (c) Biogen may
[***] and (d) Biogen’s obligation to [***], other than (i) reports required by
Section 5.2.7, Section 6.14.1 and Section 10.4.4 (if applicable) (ii) upon
Ionis’ reasonable request, information to the extent required to confirm
Biogen’s compliance with its obligations under Section 5.1 and (iii) as
reasonably required to permit Ionis to perform its obligations under this
Agreement. The Biogen Reduced Participation and Information Obligations will not
limit or diminish the scope of any licenses granted by Biogen to Ionis under
this Agreement.

“Biogen Reduced Royalty” has the meaning set forth in Section 6.10.2(c).

“Biogen Results” has the meaning set forth in Section 4.8.3.

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

“Biogen Technology” means the Biogen Program Technology, Jointly-Owned Program
Technology, Biogen Product-Specific Patents and any trademarks described in
Section 4.1.6, owned, used, developed by, or licensed to Biogen or its
Affiliates that is necessary or useful to Develop, register, Manufacture or
Commercialize a Product.

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

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

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

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

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

“Calendar Year” means a year beginning on January 1 (or, with respect to 2013,
the Effective Date) and ending on December 31.

“Carryover Development Candidate” has the meaning set forth in Section
1.10.1(e).

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

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

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

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

“Clinical Supplies” means API and finished drug Collaboration Product for use in
a Clinical Study.

“CMC” has the meaning set forth in Section 1.13.1(c).

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

“Collaboration” means the conduct of the Neurology Plans in accordance with this
Agreement.

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

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

“Collaboration Program” has the meaning set forth in Section 1.6.1.

“Collaboration Target” means a gene target for which the Parties wish to start
an ASO drug discovery program that is either (i) a High Interest Target that is
not an ALS Target and is designated as a Collaboration Target under Section 1.3
or Section 1.8, (ii) an ALS Target designated as a Collaboration Target under
Section 1.5, (iii) an Ionis Neurology Target designated as a Collaboration
Target under Section 1.4, (iv) a Biogen Alternate Modality Target that is
changed to a Collaboration Target under Section 3.2.1, or (v) a Neurology Target
that is added as a Collaboration Target under Section 3.2.4(a).  As of the
Effective Date SOD-1 is a Collaboration Target that is an ALS Target and is not
a Multi-Indication Target.

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

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

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

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

“Commercially Reasonable Efforts” means the carrying out of discovery, research,
development or commercialization activities using good-faith commercially
reasonable and diligent efforts that the applicable Party would reasonably
devote to a compound or product of similar market potential or profit potential
at a similar stage in development or product life resulting from its own
research efforts, based on conditions then prevailing and taking into account,
without limitation, issues of safety and efficacy, regulatory authority-approved
labeling, product profile, the competitiveness of alternative products in the
marketplace, the likely timing of the product’s entry into the market, the
patent and other proprietary position, the likelihood of Approval and other
relevant scientific, technical and commercial factors. Without limiting any of
the foregoing, Commercially Reasonable Efforts as it applies to Biogen’s
Development or Commercialization of a Product hereunder includes the use of
Commercially Reasonable Efforts to perform (i) any Biogen Activities in a
Neurology Plan, and (ii) the “General Activities” described in Schedule 5.1.4,
and Commercially Reasonable Efforts as it applies to Ionis’ Development of a
Product hereunder includes use of Commercially Reasonable Efforts to adhere to
the activities and timelines set forth in each Neurology Plan.

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

“Competing Alternate Modality Acquirer” has the meaning set forth in Section
12.5.4.

“Competing Collaboration Acquirer” has the meaning set forth in Section 12.5.2.

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

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

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

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

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

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

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

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

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

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

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

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

“Conflicting Patent Right” has the meaning set forth in Section 7.2.5(d).

“Contracting Party” has the meaning set forth in Section 1.10.7.

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

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“Core Research Plan” has the meaning set forth in Section 1.2.

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

“Cost Estimate” has the meaning set forth in Section 1.10.2(e).

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

“CSC” has the meaning set forth in Section 1.18.1.

“CTD” has the meaning set forth in Section 4.4.

“Deferral Notice” has the meaning set forth in Section 1.8.1.

“Deferral Period” has the meaning set forth in Section 1.8.1.

“Deferred Target” has the meaning set forth in Section 1.8.1.

“Deferred Target Development Candidate” means a Development Candidate identified
in accordance with Section 1.8.4.

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

“Design Notice” has the meaning set forth in Section 6.2.1.

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

“Development Candidate” means a Compound that is reasonably determined by Ionis’
RMC in accordance with Ionis’ standard procedures for designating development
candidates [***] as ready to start IND-Enabling Toxicology Studies; provided,
however, that with respect to any Primarily Neuro Multi-Indication Target, such
Compound will be reasonably selected by Biogen (giving good faith consideration
to the input of Ionis’ representatives on the Neurology JRC) as a Development
Candidate from the body of work Ionis used to determine the applicable Compound
Ionis believes is ready to start IND-Enabling Toxicology Studies. The checklist
Ionis uses as of the Effective Date when reviewing potential development
candidates for approval is attached hereto as Appendix 2.

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

“Diagnostic Option” has the meaning set forth in Section 3.3.1.

“Directly Competitive Biogen Alternate Modality Product” means with respect to a
Biogen Alternate Modality Product, a product designed to bind to or directly
modulate the Biogen Alternate Modality Target targeted by such Biogen Alternate
Modality Program, other than a Biogen Alternate Modality Product that is being
pursued under this Agreement.

“Directly Competitive Biogen Alternate Modality Program” means any internal
research program for which [***] or [***], with the goal of discovering and
developing a Directly Competitive Biogen Alternate Modality Product for which
drug discovery activities have been initiated.

“Directly Competitive Collaboration Product” means with respect to a
Collaboration Product, any product, other than such Collaboration Product, that
is designed to bind to or directly modulate the Collaboration Target targeted by
such Collaboration Product.

“Directly Competitive Collaboration Program” means any internal research program
for which [***] or [***], with the goal of discovering and developing a Directly
Competitive Collaboration Product for which drug discovery activities have been
initiated.

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

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

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

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

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

“Drug Development Program” means the aggregate drug development activities
related to each Development Candidate through completion of the first Phase 2
PoC Trial under a Collaboration Program in accordance with the applicable
Initial Development Plan for all Collaboration Programs under this Agreement.

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

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

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

“Equal Multi-Indication Target” has the meaning set forth in Appendix 3.

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

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

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

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

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

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

“[***]” means any form of the [***].

“[***] Collaboration Program” means an [***] Collaboration Program solely and
exclusively focused on [***].

“Field” means, except as may be limited under Section 4.1.5, any prophylactic or
therapeutic use or form of administration for any indication.

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

“First Amended and Restated Agreement” has the meaning set forth in the Preamble
of this Agreement.

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

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

“Follow-On Agreement” has the meaning set forth in Section 2.2.1.

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

“Follow-On Interest Notice” has the meaning set forth in Section 2.2.1.

“Follow-On Negotiation Notice” has the meaning set forth in Section 2.2.1.

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

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

“FTE Costs” has the meaning set forth in Section 1.14.1.

“FTE Rate” means $[***] for the Calendar Year 2013. The FTE Rate will be
increased each Calendar Year thereafter by the [***].

“Full Royalty Period” has the meaning set forth in Section 6.10.2(a).

“Fully Absorbed Cost of Goods” means the costs incurred by Ionis as determined
using the methodology set forth in Schedule 4.8.2(c) fairly applied and as
employed on a consistent basis throughout Ionis’ operations.

“GAAP” means generally accepted accounting principles in the United States,
consistently applied.

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

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

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

“High Interest Target” has the meaning set forth in Section 1.2.3(a).  For
clarity, at any given time, if a gene target is not on the High Interest Target
List at such time, then such gene target is not a High Interest Target.

“High Interest Target List” has the meaning set forth in Section 1.2.3(a).

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

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

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

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

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

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

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

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

“Initial Development Plan” has the meaning set forth in Section 1.10.2(d).

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

“Integrated Development Plan” or “IDP” has the meaning set forth in Section
5.1.6.

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

“Ionis Activities” means the research, pre-clinical and/or clinical activities
for which Ionis is designated as responsible under any Neurology Plan.

“Ionis Activities Data” has the meaning set forth in Section 1.10.2(d)(i).

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

“Ionis/Biogen Additional Agreements” means the (i) SMN Agreement, (ii) DMPK
Agreement, (iii) the Neurology Drug Discovery and Development Collaboration,
Option and License Agreement between the Parties dated December 10, 2012, (iv)
the Research Collaboration, Option and License Agreement between the Parties
dated December 19, 2017 and (v) the Neurology III Agreement, in each case, as
amended and/or restated from time to time

“Ionis Breach Event” has the meaning set forth in Section 10.4.5(a).

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

“Ionis In-License Agreements” has the meaning set forth in Section 6.13.1(a).

“Ionis Internal ASO Safety Database” has the meaning set forth in Section 5.2.7.

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

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

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

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“Ionis Multi-Indication Compound” has the meaning set forth in Appendix 3.

“Ionis Neurology Target” means a Neurology Target that (1) is not (i) a High
Interest Target for which target validating activities are planned under the
then-current Neurological Disease Research Plan, (ii) an ALS Target, (iii) a
Collaboration Target, or (iv) a Biogen Alternate Modality Target and (2) has a
Neurological Disease as its primary disease association.

“Ionis Non-Exclusive Product” has the meaning set forth in Section 2.1.1(c).

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

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

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

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

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

“Ionis Results” has the meaning set forth in Section 4.8.3.

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

“Japan NDA” or “JNDA” means the Japanese equivalent of an NDA filed with the
Koseisho (i.e., the Japanese Ministry of Health and Welfare, or any successor
agency thereto).

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

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

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

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

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

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

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

“License Effective Date” means, on an Option-by-Option and Program-by-Program
basis, the date on which Biogen notifies Ionis in writing that it wishes to
exercise the Option and pays to Ionis the applicable license fee set forth in
Section 6.6 (in the event Biogen wishes to exercise its Option for a
Collaboration Program) or Section 6.2.2  (in the event Biogen wishes to exercise
its Option for a Biogen Alternate Modality Program) for such Program.

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

“Licensed Patents” means the Ionis Product-Specific Patents, Ionis Core
Technology Patents, Ionis Manufacturing and Analytical Patents and Ionis’
interest in Jointly-Owned Program Patents. For clarity, Licensed Patents do not
include any Patent Rights claiming formulation technology or delivery devices
unless such Patent Rights are included in the Jointly-Owned Program Patents. 
For clarity, Licensed Patents that are jointly-owned by Ionis and Biogen will
count toward the calculation of the Full Royalty Period in a particular country
if the use or sale of a Product by an unauthorized Third Party in such country
would infringe a Valid Claim of such Licensed Patent.

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

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

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

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

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

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

“Manufacturing Process Development Terms” means Section 4.1.3(b), Section
4.3.1(a), Section 4.3.2, Section 4.4, Section 4.5, Section 4.7.2 and Section
4.8.3 of this Agreement.

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“Measurement Period” has the meaning set forth in Section 1.14.1(c) or Section
1.14.1(d), as applicable.

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

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

“[***]” means a disease that has, as its [***].

“Multi-Indication Product” means a product for a Non-Neurological Indication
associated with a Multi-Indication Target.

“Multi-Indication Product-Specific Patent” has the meaning set forth in Section
7.2.4.

“Multi-Indication Target” has the meaning set forth in Section 1.2.3(b).

“Multi-Indication Target Notice” has the meaning set forth in Section 1.2.3(b).

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

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

“Negotiation Period” has the meaning set forth in Section 2.2.2.

“Net Sales” means the gross amount billed or invoiced on sales of a Product by
Biogen, its Affiliates and Sublicensees, less the following: (a) customary
trade, quantity, or cash discounts to non-affiliated brokers or agents to the
extent actually allowed and taken; (b) amounts repaid or credited by reason of
rejection or return; (c) to the extent separately stated on purchase orders,
invoices, or other documents of sale, any taxes or other governmental charges
levied on the production, sale, transportation, delivery, or use of such Product
which is paid by or on behalf of Biogen; and (d) outbound transportation costs
prepaid or allowed and costs of insurance in transit.

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

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

“Neurological Disease Research Plan” has the meaning set forth in Section 1.2.

“Neurological Disease Research Program” has the meaning set forth in Section
1.2.

“Neurology III Agreement” means that certain New Strategic Neurology Drug
Discovery and Development Collaboration, Option and License Agreement between
the Parties dated April 19, 2018, as amended or restated from time to time.

“Neurology JDC” has the meaning set forth in Section 1.18.3.

“Neurology JRC” has the meaning set forth in Section 1.18.2.

“Neurology Plan” means any of the following plans: (i) the Core Research Plan,
(ii) the Neurological Disease Research Plan, (iii) any ASO Development Candidate
Identification Plans, or (iv) any Initial Development Plans.

“Neurology Target” means any gene target that (i) as of the Effective Date, (y)
has not been encumbered by Ionis under an agreement with a Third Party that
would prevent Ionis from granting Biogen the license under Section 4.1.1 of this
Agreement with respect to such gene target, and (z) has not yet achieved Target
Sanction status, and (ii) as of the Effective Date or during the Research Term,
the expression or activity of the gene in neurons is demonstrated to have an
association to any one of the following (each of (a) through (e) below, a
“Neurological Disease”):

[***].

For purposes of clarity, [***] are expressly excluded from the above-listed
[***] and therefore any gene target that has as its primary disease association
an association to [***] will not be a Neurology Target, and any [***] will not
be a Product under this Agreement. In addition, [***] or [***] are expressly
excluded from the above-listed [***] and therefore any gene target that has as
its [***] will not be a Neurology Target.  For purposes of further clarity, a
gene target that has as its [***] would not be considered a Neurology Target.

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

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

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

“NPV” has the meaning set forth in Appendix 3.

“[***]” means diseases that have, as their [***].

“Oligonucleotide” means a synthetic compound that comprises or consists of at
least 5 linked nucleosides (including any analog, variant, mimic, or mimetic
thereof). For clarity, the [***] of Oligonucleotides [***].  Oligonucleotides
[***].  Oligonucleotides may be single-stranded or multi-stranded.

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

“Option Acceleration Deadline” has the meaning set forth in Section 1.10.2(g).

“Option Acceleration Notice” has the meaning set forth in Section 1.10.2(g).

“Option Deadline” means the Standard Option Deadline, the ALS Option Deadline or
the Biogen Conducted Non-ALS Option Deadline, as applicable.

“Option Period” means, with respect to a Collaboration Program, the period
beginning on the date a Neurology Target is designated as a Collaboration
Program hereunder and ending on the License Effective Date or the expiration or
earlier termination of the Option with respect to such Collaboration Program.

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

“Panel Decision” has the meaning set forth in Section 10.4.5(b).

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

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

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

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“Permitted Licenses” means (1) licenses granted by Ionis before or after the
Effective Date to any Third Party under the Ionis Core Technology Patents, the
Ionis Manufacturing and Analytical Patents, or the Ionis Manufacturing and
Analytical Know-How (but not under the Ionis Product-Specific Patents) to (a)
use Oligonucleotides (or supply Oligonucleotides to end users) solely to conduct
pre-clinical research, or (b) enable such Third Party to manufacture or
formulate Oligonucleotides, where (i) such Third Party is primarily engaged in
providing contract manufacturing or services and is not primarily engaged in
drug discovery, development or commercialization of therapeutics; and (ii) Ionis
does not assist such Third Party to identify, discover or make a Compound or
Product; and (2) material transfer agreements with academic collaborators or
non-profit institutions solely to conduct non-commercial research.

“Person” will mean any corporation, limited or general partnership, limited
liability company, joint venture, trust, unincorporated association,
governmental body, authority, bureau or agency, any other entity or body, or an
individual.

“Pharmacovigilance Agreement” has the meaning set forth in Section 5.2.2.

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

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

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

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

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

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

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

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

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

“Post-Licensing Milestone Event” has the meaning set forth in Section 6.7.

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

“Pre-Existing Competitive Collaboration Product” has the meaning set forth in
Section 12.5.2.

“Pre-Existing Competitive Collaboration Program” has the meaning set forth in
Section 12.5.2.

“Pre-Existing Target” has the meaning set forth in Section 1.2.3(c).

“Pre-Licensing Milestone Event” means an ALS Pre-Licensing Milestone Event or a
Standard Pre-Licensing Milestone Event, as applicable.

“Primarily Neuro Multi-Indication Target” has the meaning set forth in Appendix
3.

“Primarily Other Multi-Indication Target” has the meaning set forth in Appendix
3.

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

“Proceeding” means an action, suit or proceeding.

“Product” means (i) a Biogen Alternate Modality Product, or (ii) a Collaboration
Product.

“Product-Specific Patents” means, with respect to a Product, Patent Rights
Controlled by a Party or any of its Affiliates on or after the Effective Date,
including any Program Patents, claiming (a) the specific composition of matter
of such Product, (b) methods of using such Product as a prophylactic or
therapeutic or (c) the specific method of manufacture of such Product (unless in
the case of (c), such Patent Rights also claim any other product or services of
Ionis); provided however, Patent Rights Controlled by Ionis or any of its
Affiliates that (i) include claims that are directed to subject matter
applicable to ASOs or products in general, or (ii) include an ASO, the sequence
of which targets the RNA that encodes a Collaboration Target and the RNA of a
gene that does not encode a Collaboration Target (or similarly, a non-ASO
molecule that binds, mimics or otherwise affects a protein or RNA that is
encoded by a Biogen Alternate Modality Target and the RNA of a gene that does
not encode a Biogen Alternate Modality Target), will not be considered
Product-Specific Patents, and in the case of (i) and (ii), such Patent Rights
will be considered Ionis Core Technology Patents.

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“Program” has the meaning set forth in Section 7.2.2.

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

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

“[***]” means a [***].

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

“Reduced Royalty Period” has the meaning set forth in Section 6.10.2(d).

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

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

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

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

“Research Term” has the meaning set forth in Section 1.2.1.

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“Results” has the meaning set forth in Section 4.8.3.

“Reverse Royalties” has the meaning set forth in Section 6.12.1.

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

“ROFN Period” has the meaning set forth in Section 2.2.

“Royalty Quotient” has the meaning set forth in Section 6.10.2(c).

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

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

“Setoff Amount” has the meaning set forth in Section 10.4.5(b).

“Setoff Dispute” has the meaning set forth in Section 10.4.5(b).

“Setoff Dispute Notice” has the meaning set forth in Section 10.4.5(b).

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

“Specific Performance Milestone Events” has the meaning set forth in Section
5.1.4.

“[***]” means the form of the [***].

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

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

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

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

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

“Superior Patent Right” has the meaning set forth in Section 7.2.5(d).

“Target Related Biogen Program Claim” has the meaning set forth in Section
4.3.4.

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

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

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“Target Sanction Data Package” means, with respect to a Neurology Target, the
data package Ionis presented to its RMC to obtain approval to justify expending
resources to identify a human Development Candidate, all in accordance with
Ionis’ standard processes; provided such package contains the same level of
detail as the data packages Ionis currently presents to its Research Management
Committee to approve Ionis’ own internal gene targets.

“Technical Failure” has the meaning set forth in Section 1.10.1(b).

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

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

“Transition Services” has the meaning set forth in Section 10.4.6.

“Trial Court” has the meaning set forth in Section 10.4.5(b).

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

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

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Appendix 2

Development Candidate Checklist

[***]

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Appendix 3

Multi-Indication Target Process

Neurology Targets with Broader Therapeutic Benefit.

(a)
If, pursuant to Section 1.2.3(d), the CSC is unable to agree upon whether a
Multi-Indication Target is a Primarily Neuro Multi-Indication Target, Equal
Multi-Indication Target or Primarily Other Multi-Indication Target, the Parties
will engage an expert panel under Section 12.1.4 to make such determination.
Such expert panel will first determine the net present value (“NPV”) of a
therapeutic targeting such Multi-Indication Target and allocate such NPV between
the markets for Neurological Disease indications and for Non-Neurological
Indications, where such NPV calculations and allocations will take into
consideration, and risk-adjust for, the relevant market sizes, competitive
landscapes, scientific rationale for each market and any other factors deemed
relevant by such expert panel.  Based on such NPV calculations and allocations,
Multi-Indication Targets will be classified as either “Primarily Neuro
Multi-Indication Targets”; “Equal Multi-Indication Targets” or “Primarily Other
Multi-Indication Targets”, where (1) a Multi-Indication Target with [***]% or
more of its NPV allocated to the market for Neurological Disease indications
will be a Primarily Neuro Multi-Indication Target, (2) a Multi-Indication Target
with less than [***]% but more than [***]% of its NPV allocated to the market
for Neurological Disease indications will be an Equal Multi-Indication Target,
and (3) a Multi-Indication Target with [***]% or less of its NPV allocated to
the market for Neurological Disease indications will be Primarily Other
Multi-Indication Target.

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 (b)
Primarily Neuro Multi-Indication Targets.  If a Multi-Indication Target is
classified as a Primarily Neuro Multi-Indication Target, then within [***] days
of such classification, Biogen will send Ionis a written notice either (1)
electing to negotiate in good faith with Ionis a development plan and [***]
(i.e., [***]) for the Non-Neurological Indications if Developed and
Commercialized under this Agreement, which plan and provisions will be
recommended to the CSC for approval; (2) granting Ionis and its Affiliates the
right to work on their own or with a Third Party to discover, develop and
commercialize an Oligonucleotide against such Multi-Indication Target for
primarily Non-Neurological Indications (an “Ionis Multi-Indication Compound”);
or (3) precluding Ionis and its Affiliates from working on their own or with a
Third Party to discover, develop commercialize an Ionis Multi-Indication
Compound.  If under this clause (b) Ionis or any of its Affiliates or licensees
Commercializes a product incorporating an Ionis Multi-Indication Compound, and
Biogen has paid the applicable license fee under Section 6.6 for the applicable
Collaboration Program, then until the earlier of (i) the [***] anniversary of
the date of First Commercial Sale of such product or (ii) the date Biogen, its
Affiliates and Sublicensees stop Commercializing the Product related to such
Multi-Indication Target, Ionis will pay Biogen a royalty of [***]% of Annual
worldwide Net Sales of such product sold by Ionis, its Affiliates or
Sublicensees. The definition of Net Sales in Appendix 1 and the other provisions
contained in Sections 6.14, 6.15, 6.16, and 6.17 governing payment of royalties
from Biogen to Ionis will govern the payment of such royalty from Ionis to
Biogen under this clause (b), mutatis mutandis.  If within [***] days of Biogen
making an election under clause (1) of this clause (b) to pursue the
Non-Neurological Indication, the CSC has not agreed on a development plan and
enhanced economic provisions to be paid by Biogen for the Non-Neurological
Indication, then (I) Ionis and its Affiliates will not work on their own or with
a Third Party to discover, develop and commercialize in the Field an Ionis
Multi-Indication Compound unless otherwise permitted under this Agreement and
(II) Biogen and its Affiliates will not work on their own or with a Third Party
to discover, develop or commercialize Compounds related to such Multi-Indication
Target for Non-Neurological Indications.

(c)
Equal Multi-Indication Targets. If a Multi-Indication Target is classified as an
Equal Multi-Indication Target, neither Party nor its respective Affiliates,
licensees or Sublicensees may develop or commercialize a product targeting such
Multi-Indication Target for any indication unless and until Ionis and Biogen
have agreed on (i) a development plan and enhanced economic provisions to be
paid by Biogen (i.e., multi-indication filing and approval milestone payments,
but not additional license fees) for the Non-Neurological Indications, and (ii)
the restrictions under which Ionis or Biogen (as applicable) would develop or
commercialize a product targeting such Multi-Indication Target (which terms may
include the requirements set forth under clause (d)(2) below).

180

--------------------------------------------------------------------------------

(d)
Primarily Other Multi-Indication Targets.  If a Multi-Indication Target is
classified as a Primarily Other Multi-Indication Target, then (A) Biogen may
continue to Develop and Commercialize Products for Neurological Disease
indications pursuant to the terms of this Agreement, and (B) within [***] days
of such classification, Biogen will send Ionis a written notice either (1)
electing to negotiate in good faith with Ionis and agree on a development plan
and [***] (i.e., [***]) for the Non-Neurological Indications if Developed and
Commercialized under this Agreement, which plan and provisions will be
recommended to the CSC for approval; or (2) granting Ionis and its Affiliates
the right to work on their own or with a Third Party to discover, develop and
commercialize an Ionis Multi-Indication Compound so long as such Ionis
Multi-Indication Compound [***], provided, in addition to the foregoing
provisions, if the Development Candidate targeting such Multi-Indication Target
being Developed or Commercialized by Biogen, its Affiliates or Sublicensees
under this Agreement is [***], Ionis cannot develop or commercialize such Ionis
Multi-Indication Compound for [***].

(e)
If within [***] days of Biogen making an election under clause (b)(1) of this
Appendix 3 to pursue the Non-Neurological Indication, the CSC has not agreed on
a development plan and [***] (i.e., [***]) for the Non-Neurological Indications,
then Ionis and its Affiliates will have the right to work on their own or with a
Third Party to discover, develop and commercialize an Ionis Multi-Indication
Compound so long as such Ionis Multi-Indication Compound [***].

181

--------------------------------------------------------------------------------

[image10.jpg]

Appendix 4

Form of Side Letter

[Date]

Ionis Pharmaceuticals, Inc.
2855 Gazelle Court
Carlsbad, CA 92010
Attention:  Chief Operating Officer
E-mail: [***]

Re:  Establishment of Cost Estimates and Milestone Payments

Dear [Chief Operating Officer]:
 

Reference is hereby made to that certain Second Amended and Restated Strategic
Neurology Drug Discovery and Development Collaboration, Option and License
Agreement by and between Ionis and Biogen dated _________ ___, [2018] (the
“Neurology II Agreement”), as supplemented and/or amended to date.  Any
capitalized terms not defined herein will have the meaning set forth in the
Neurology II Agreement.
 

This letter memorializes the Cost Estimates and corresponding milestone payments
set forth on the exhibit attached hereto as Exhibit A for the Collaboration
Program and Development Candidate specified on Exhibit A, which Cost Estimates
and corresponding milestone payments have been agreed by the applicable
Neurology JDC in accordance with Section 1.10.2(e) of the Neurology II
Agreement. Exhibit A hereto supersedes and replaces any previously approved Cost
Estimates and corresponding milestone payments for the Collaboration Program and
Development Candidate set forth on Exhibit A.
 

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

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

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

--------------------------------------------------------------------------------

 
Sincerely,          
[VP of Corporate Development]
  Vice President, Corporate Development  
Biogen MA Inc.

CONFIRMED ON BEHALF OF IONIS PHARMACEUTICALS, INC.:

By:
         
Name:
         
Title:
         
Date:
   

Cc:
Ionis Pharmaceuticals, Inc.
 
2855 Gazelle Court
 
Carlsbad, CA 92010
 
Attention:  General Counsel
 
E-mail: [***]

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

--------------------------------------------------------------------------------

Exhibit A

Collaboration Program:
         
Development Candidate:

         
[***]
   

184

--------------------------------------------------------------------------------

[image10.jpg]

[Date]

Ionis Pharmaceuticals, Inc.
2855 Gazelle Court
Carlsbad, CA 92010
Attention:  Chief Operating Officer
E-mail: [***]

Re:  Establishment of Biogen-Approved Costs

Dear [Chief Operating Officer]:
 

Reference is hereby made to that certain Second Amended and Restated Strategic
Neurology Drug Discovery and Development Collaboration, Option and License
Agreement by and between Ionis and Biogen dated _________ ___, 2018 (the
“Neurology II Agreement”), as supplemented and/or amended to date.  Any
capitalized terms not defined herein will have the meaning set forth in the
Neurology II Agreement.
 

This letter memorializes certain Biogen-Approved Costs set forth on the exhibit
attached hereto as Exhibit A for the Collaboration Program and Development
Candidate specified on Exhibit A, which Biogen-Approved Costs have been mutually
agreed by the Parties (including, if applicable, through the applicable
Neurology JDC) in accordance with Section 1.14.1 of the Neurology II Agreement.
 

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

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

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

--------------------------------------------------------------------------------

 
Sincerely,
         
[VP of Corporate Development]
 
Vice President, Corporate Development
 
Biogen MA Inc.

CONFIRMED ON BEHALF OF IONIS PHARMACEUTICALS, INC.:

By:
         
Name:
         
Title:
         
Date:
   

Cc:
Ionis Pharmaceuticals, Inc.
 
2855 Gazelle Court
 
Carlsbad, CA 92010
 
Attention:  General Counsel
 
E-mail: [***]

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

--------------------------------------------------------------------------------

Exhibit A

Collaboration Program:
         
Development Candidate:
   

[***]
Biogen-Approved Costs
Apportionment of
Biogen-Approved Costs
under Section 1.14.1(a)
[***]
                 

187

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Schedule 1.1.4

Biogen Conducted Non-ALS Targets

  1.
[***]

2.
[***]

3.
[***]

4.
[***]

188

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Schedule 1.2.3(a)

ALS Targets

1.
SOD-1

2.
[***]

3.
[***]

4.
[***]

5.
[***]

6.
[***]

189

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Schedule 1.2.4

Terms and Conditions for Provision of Research ASOs to Biogen

ARTICLE 1
DEFINITIONS

The terms used in this Schedule 1.2.4 with initial letters capitalized, whether
used in the singular or the plural, will have the meaning set forth in
Attachment 1, or if not listed in Attachment 1, the meaning designated in places
throughout the Agreement (or Appendix 1 to the Agreement).

ARTICLE 2
PROVISION OF RESEARCH ASOS OUTSIDE OF THE DISEASE RESEARCH PROGRAM

2.1. Scope of Collaboration.

 
a)
Ionis will generate Research ASOs for Accepted Gene Targets in accordance with
the terms and conditions of this Schedule 1.2.4.

b)
Each Party will devote commercially reasonable efforts to performing its
obligations under the Target Validation Plan.

ARTICLE 3
CONDUCT OF THE TARGET VALIDATION OUTSIDE OF THE DISEASE RESEARCH PROGRAM

3.1. Selection of Biogen TV Targets; Target Validation Activities.

a)
During the Research Term, Biogen will have the right to propose gene targets
that are the focus of Biogen programs that are not part of the Collaboration
(each, a “Biogen TV Target”) for up to a total of [***] Accepted Gene Targets
per [***] period. Biogen will propose such Biogen TV Targets by written notice
to the Ionis Alliance Manager.

b)
Ionis may reject a proposed Biogen TV Target if, at the time of such proposal,
[***].

c)
Each Biogen TV Target that is not rejected by Ionis will be an “Accepted Gene
Target.” During the Research Term, Ionis and Biogen will use Commercially
Reasonable Efforts to perform the activities outlined in the Target Validation
Plan on each Accepted Gene Target.

190

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3.2. Biogen’s Use of Research ASOs and Information.

a)
The Research ASOs and any related Confidential Information provided to Biogen by
Ionis hereunder are proprietary to Ionis.  Biogen will not distribute or release
the Research ASOs to any Person other than its employees, academic
collaborators, Affiliates, agents or (sub)contractors, solely for purposes of
performing work in support of Biogen’s drug discovery activities. Subject to the
terms and conditions of this Schedule 1.2.4, Ionis hereby grants Biogen a
non-exclusive, fully paid, license to use the Ionis Confidential Information
(including data generated by Ionis with Research ASOs in the performance of the
Target Validation Plan) and Research ASOs solely for use in support of Biogen'
drug discovery purposes. In exercising its rights under this Schedule 1.2.4,
Biogen may use data generated by Biogen using the Research ASOs (the “Biogen
Data”) to support Patent Rights filed by or on behalf of Biogen, including
Patent Rights that claim methods of treating disease by modulating the
applicable Accepted Gene Target. The claims of any such Biogen Patent Right
using such Biogen Data that generically claims methods of treating disease by
modulating the applicable Accepted Gene Target, but are not directed to specific
compounds or agents, are referred to as the “Biogen Licensed Claims.”
Notwithstanding the foregoing, Biogen will not use such Biogen Data to support
claims directed to one or more Oligonucleotides as a composition of matter or
one or more Oligonucleotides as a pharmaceutical product, without the prior
written consent of Ionis. In addition, Biogen may not use Ionis data disclosed
to Biogen in connection with this Schedule 1.2.4 or the Research ASOs to make
products that incorporate Oligonucleotides.

b)
Biogen hereby grants Ionis a non-exclusive, fully-paid sublicensable license
under any Biogen Licensed Claims solely for the purpose of discovering,
developing or commercializing an Oligonucleotide(s) as a pharmaceutical product,
provided, however, that such license will only be sublicensable by Ionis to a
Third Party licensee in connection with the grant of an exclusive license to
such Third Party under other Ionis intellectual property with respect to such
Oligonucleotide. No other license is granted to Ionis under any Biogen-owned or
controlled Patent Right or other intellectual property under this Schedule
1.2.4.  For avoidance of doubt, no rights are granted by Biogen to Ionis under
this Schedule 1.2.4 (expressly or by implication or otherwise) with respect to
any compounds, materials or agents (or any method of use or manufacture
thereof).

c)
Ionis hereby grants Biogen a non-exclusive, fully-paid sublicensable license
under any Ionis Licensed Claims solely for the purpose of discovering,
developing or commercializing a non-Oligonucleotide compound(s) as a
pharmaceutical product, provided, however, that such license will only be
sublicensable by Biogen to a Third Party licensee in connection with the grant
of an exclusive license to such Third Party under other Biogen intellectual
property with respect to any such non‑Oligonucleotide compound. “Ionis Licensed
Claims” means the claims of any Ionis Invention that generically claims methods
of treating disease by modulating an Accepted Gene Target, but are not directed
to any specific compound or agent (including any Oligonucleotide).  Except as
set forth in Section 3.2(a) and (c), no other license is granted to Biogen under
any Ionis-owned or controlled Patent Right or other intellectual property under
this Schedule 1.2.4.

3.3. Non-exclusive Collaboration.

a)
Ionis will perform target validation activities and will provide Research ASOs
to Biogen as set forth in the Target Validation Plan on a non-exclusive basis.
Ionis may collaborate with Third Parties for target validation studies on any
gene targets, including Accepted Gene Targets. In addition, this Schedule 1.2.4
will not limit Ionis from conducting research, discovery and development work on
any and all Oligonucleotides, for itself or with or on behalf of a Third Party.

b)
If an Oligonucleotide to an Accepted Gene Target hereunder becomes a drug
development candidate of Ionis or a Third Party collaborator of Ionis, Ionis
will notify Biogen. Upon receipt of such notice from Ionis, Biogen will return
to Ionis all unused quantities of applicable TV Compound within [***] days after
the date on which Biogen received such notice.  After such time, Ionis will not
have any obligation to provide additional quantities of the originally supplied
TV Compound to Biogen under this Schedule 1.2.4.

191

--------------------------------------------------------------------------------

  c)
If Ionis achieves Target Sanction for an Accepted Gene Target, and Ionis does
not at such time have any obligations to any Third Party with respect to such
Accepted Gene Target that would conflict with Ionis’ compliance with this
Section 3.3(c), Ionis will provide to Biogen a Target Sanction Data Package for
such Accepted Gene Target (an “AGT Target Sanction Data Package”) and Biogen
will have [***] days following receipt of such AGT Target Sanction Data Package
to decide whether to negotiate with Ionis regarding an agreement with respect to
such Accepted Gene Target (an “AGT Agreement”).  Following delivery of an AGT
Target Sanction Data Package, Ionis will not initiate negotiations regarding or
enter into an AGT Agreement with any Third Party until the earlier to occur of:
(1) Biogen notifying Ionis that it declines the opportunity to negotiate with
Ionis regarding such AGT Agreement; (2) Biogen not responding to Ionis within
[***] days after receipt of such AGT Target Sanction Data Package; or (3) the
AGT Negotiation Period expiring before Biogen and Ionis have entered into such
AGT Agreement.  If Biogen or one of its Affiliates responds within 30 days after
its receipt of the AGT Target Sanction Data Package indicating that Biogen or
one of its Affiliates desires to negotiate with Ionis regarding the proposed AGT
Agreement, Ionis and Biogen or one of its Affiliates will negotiate in good
faith for 180 days thereafter (or such other period as mutually agreed by the
Parties) (the “AGT Negotiation Period”) regarding a mutually satisfactory AGT
Agreement. During the AGT Negotiation Period, Biogen or its Affiliate will make
the first written proposal to Ionis setting forth all material business and
legal terms on which Biogen or its Affiliate would be willing to enter into the
proposed AGT Agreement with Ionis; provided that neither Party will have any
obligation to enter into an AGT Agreement. If the AGT Negotiation Period expires
before Biogen or its Affiliate and Ionis have entered into such AGT Agreement,
Ionis will have no further obligation to negotiate with Biogen or its Affiliates
with respect to such AGT Agreement and Ionis will be free to negotiate and enter
an agreement with a Third Party with respect to an AGT Agreement [***];
provided, however, that Ionis will not enter into any such AGT Agreement with
any Third Party unless the terms and pricing of such AGT Agreement, [***].

3.4. Biogen Materials.

Any materials provided by Biogen to Ionis in connection with a Biogen TV Target
or Accepted Gene Target, including any biological materials with respect to
screening assays, including any progeny, expression products, mutants,
replicates, derivatives and modifications thereof, (such materials being
individually and collectively referred to as the “Biogen Materials”) will be
used by Ionis solely for purposes of performing activities in accordance with
the  Target Validation Plan and any remaining Biogen Materials will be returned
to Biogen (or destroyed as may be requested by Biogen in writing) promptly
following the end of the applicable activities under the Target Validation Plan
or earlier upon request by Biogen. All information related to such Biogen
Materials will be Biogen Confidential Information. All such materials must be
used with prudence and appropriate caution in any experimental work, since all
of their characteristics may not be known.

ARTICLE 4
INTELLECTUAL PROPERTY

4.1. Ownership of Inventions.

a)
Title to any inventions, technology, discoveries, or other proprietary property
made or discovered (as determined by the U.S. laws of inventorship) by employees
of or consultants or contractors of a Party pursuant to the performance Target
Validation Plan (collectively, “Inventions”) are retained by the Party that is
the employer of the inventor (or, in the case of consultants or contractors, the
Party for which such consultant or contractor is providing services). Ionis will
own Inventions invented solely by employees or consultants or contractors of
Ionis and any Patent Rights claiming such Invention (collectively, the “Ionis
Inventions”). Biogen will own Inventions invented solely by employees or
consultants or contractors of Biogen and any Patent Rights claiming such
Invention.

192

--------------------------------------------------------------------------------

b)
Except as provided otherwise herein, Ionis and Biogen will jointly hold title to
all Inventions, made or discovered (as determined by the U.S. laws of
inventorship) jointly by employees or consultants or contractors of Ionis and
Biogen (“Joint Inventions”). Patent Rights claiming such Joint Inventions will
be “Joint Patents.”  Ionis and Biogen will promptly provide each other with
notice whenever a Joint Invention is made or discovered.

c)
The Parties agree, upon reasonable request, to execute any documents reasonably
necessary to effect and perfect each other’s ownership of any Invention or
Patent Right claiming such Invention.

4.2. Patent Prosecution; Infringement of Joint Patents.

a)
Each Party has the right to file, prosecute, maintain, enforce and defend Patent
Rights on Inventions owned by such Party, at its own expense.

b)
Ionis and Biogen will mutually agree on the filing, prosecution and maintenance
of any Joint Patents and the expenses of such prosecution and maintenance will
be shared equally. If either Party elects not to participate in the filing,
prosecution or maintenance of a Joint Patent, it will notify the other Party of
such election not later than [***] days before the applicable deadline for
filing, prosecution or maintenance, and the other Party will thereafter have the
right to undertake such filing, prosecution or maintenance, at its own expense.

c)
A Party whose rights in a Joint Patent are impacted by the infringement of such
Joint Patent by a Third Party will have the right to enforce that Joint Patent
at its own discretion and at its own expense. The non-enforcing Party agrees to
provide the enforcing Party all reasonable assistance (including joining such
action as a Party plaintiff), at the enforcing Party’s expense. Any damages or
other recovery, whether by settlement or otherwise, from an action hereunder to
enforce a Joint Patent will be paid first to each Party to reimburse the costs
of enforcement and then prorated to the Party(ies) based on damages incurred.

ARTICLE 5
TERM AND TERMINATION

5.1. Agreement Term.

Unless the Agreement is earlier terminated (in which case this Schedule 1.2.4
will also terminate), this Schedule 1.2.4 will remain in effect until the end of
the Research Term (the “Term”), at which time it will expire.

5.2. Survival.

Section 3.2 (Biogen’s Use of Research ASOs and Information), Section 5.2
(Survival) and ARTICLE 4 (Intellectual Property) will survive the expiration or
termination of this Schedule 1.2.4.

193

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Attachment 1 to Schedule 1.2.4

Definitions

“Accepted Gene Target” has the meaning set forth in Section 3.1(c).

“AGT Agreement” has the meaning set forth in Section 3.3(c).

“AGT Negotiation Period” has the meaning set forth in Section 3.3(c).

“AGT Target Sanction Data Package” has the meaning set forth in Section 3.3(c).

“Biogen Data” has the meaning set forth in Section 3.2(a).

“Biogen Licensed Claims” has the meaning set forth in Section 3.2(a).

“Biogen Materials” has the meaning set forth in Section 3.4.

“Biogen TV Target” has the meaning set forth in Section 3.1(a).

“Inventions” has the meaning set forth in Section 4.1(a).

“Ionis Inventions” has the meaning set forth in Section 4.1(a).

“Ionis Licensed Claims” has the meaning set forth in Section 3.2(c).

“Joint Invention” has the meaning set forth in Section 4.1(b).

“Joint Patents” has the meaning set forth in Section 4.1(b).

“Target Validation Plan” means the collaborative Target Validation Plan
undertaken by the Parties pursuant to this Schedule 1.2.4, as further described
in Attachment 2.

“Term” has the meaning set forth in Section 5.1.

“TV Compound” means an Oligonucleotide delivered to Biogen by Ionis under this
Schedule 1.2.4 directed to an Accepted Gene Target.

194

--------------------------------------------------------------------------------

Attachment 2 to Schedule 1.2.4

Target Validation Plan

[***]

195

--------------------------------------------------------------------------------

Schedule 1.6.1

ALS Letter Agreement

[***]

196

--------------------------------------------------------------------------------

Schedule 1.10.2(c)

Ionis’ Standard IND-Enabling Toxicology Studies

[***]

197

--------------------------------------------------------------------------------

Schedule 1.10.2(d)

Initial Development Plan Requirements

[***]

198

--------------------------------------------------------------------------------

Schedule 1.10.2(d)(v)

Study Synopsis Requirements

[***]

199

--------------------------------------------------------------------------------

Schedule 1.10.2(e)

Apportionment of Certain Milestone Payments and Biogen-Approved Costs

In the event that either (I) a milestone payment established under Section
1.10.2(e) or (II) Biogen-Approved Costs resulting from [***], such milestone
payment or Biogen-Approved Costs, as applicable, shall be apportioned into
smaller milestone payments and paid by Biogen to Ionis as follows:

[***].

Each payment due under this Schedule 1.10.2(e) shall be payable by Biogen within
[***] days after receipt of the applicable invoice by Biogen following the event
that triggered such milestone payment.

200

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Schedule 1.10.6

Ionis API Supply for ALS Collaboration Programs and Biogen Conducted Non-ALS
Collaboration Programs

[***]

201

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Schedule 1.18.1

Collaboration Steering Committee Governance

CSC Representatives

Ionis

Lynne Parshall, Senior Strategic Advisor

Frank Bennett, SVP, Head of Research

Richard Geary, SVP, Head of Development

Biogen

Michael Ehlers, EVP, Research and Development

Katherine Dawson, VP, Late Stage Clinical Development

Anabella Villalobos, SVP, Biotherapeutic and Medicinal Sciences

Daniel Karp, EVP Corporate Development

202

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Schedule 1.18.2

Neurology JRC Governance

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

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

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

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

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

203

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Schedule 1.18.3

Neurology JDC Governance

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

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

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

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

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

204

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Schedule 1.18.6

Alliance Management Activities

Each Alliance Manager is responsible for:

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

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

(c)
Organizing CSC, Neurology JRC and Neurology JDC meetings, including agendas,
drafting minutes, and publishing final minutes;

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

(e)
Preparing status and progress reports on the above as determined necessary by
the CSC, Neurology JRC and Neurology JDC;

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

(g)
Manage and coordinate the target validation activities under Schedule 1.2.4;

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

(i)
Determining an appropriate format for summaries of resource and FTE utilization,
and ensuring such summarized are timely provided to the Neurology JRC as
outlined in Section 1.11.

205

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Schedule 4.3.1(a)

Drug Substance Process and Formulation Development Activities

[***]

206

--------------------------------------------------------------------------------

Schedule 4.8.2(c)

Ionis’ Fully Absorbed Cost of Goods Methodology
Cost Estimate of API Cost per Kilogram
(OOO’s)

[***]

207

--------------------------------------------------------------------------------

Schedule 5.1.4

Biogen’s Development and Commercialization Activities

[***]

208

--------------------------------------------------------------------------------

Schedule 5.1.6

Integrated Development Plan Content

[***]
[***]
[***]
[***]
[***]

[***]

[***]

[***]
[***]
 
[***]
       

[***]
   
[***]

[***]
         

[***]
[***]

[***]
        

[***]

209

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Schedule 6.10.2(e)
Royalty Calculation Examples
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210

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Schedule 6.10.2(f)

Allocation of Net Sales

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211

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Schedule 6.13.1

Certain Ionis In-License Agreements

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

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212

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Schedule 8.2.4(a)

Ionis Core Technology Patents

 
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213

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Schedule 8.2.4(b)

Ionis Manufacturing and Analytical Patents

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214

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Schedule 8.2.4(c)

Ionis Product-Specific Patents

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Schedule 8.2.8

Prior Agreements

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Schedule 10.4.5(b)

Advisory Panel Regarding Setoff Disputes

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Schedule 10.4.6

Transition Services

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Schedule 12.1.2

Mediation

1.
Mediation.

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

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

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Schedule 12.5

Table A
Applicable License Fee Payments in Change of Control for Collaboration Products

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Schedule 12.5

Table B
Applicable [***] under Section 12.5.1(b) in Change of Control

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