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Execution Copy

CONFIDENTIAL TREATMENT REQUESTED
UNDER 17 C.F.R §§ 200.80(B)4, AND 240.24B-2

Exhibit 10.3

AMENDMENT NUMBER ONE
TO THE
SECOND AMENDED AND RESTATED
STRATEGIC COLLABORATION AND LICENSE AGREEMENT

THIS AMENDMENT NUMBER ONE (the “Amendment”) to the Second Amended and Restated
Strategic Collaboration and License Agreement is entered into as of the 13 day
of July, 2015 (the “Amendment Effective Date”) by and among Alnylam
Pharmaceuticals, Inc., a Delaware corporation, with its principal place of
business at 300 Third Street, Cambridge, Massachusetts 02142 (“Alnylam”), and
Isis Pharmaceuticals, Inc., a Delaware corporation, with its principal place of
business at 2855 Gazelle Court, Carlsbad, California 92010 (“Isis”).
 
RECITALS
 
WHEREAS, Isis and Alnylam granted to each other certain exclusive rights with
respect to certain targets pursuant to that certain Second Amended and Restated
Strategic Collaboration and License Agreement dated January 8, 2015 (the “Second
Restated Agreement”);
 
WHEREAS, Isis and Alnylam now desire to amend the Second Restated Agreement to
expand such cross-license of exclusive rights to include additional targets as
provided herein.
 
AGREEMENT
 
NOW, THEREFORE, in consideration of the mutual covenants contained herein, and
other good and valuable consideration, the receipt and sufficiency of which is
hereby acknowledged, Isis and Alnylam each agrees as follows:
 

1. DEFINITIONS

 
Capitalized terms used herein and not defined elsewhere herein have the meanings
set forth in the Second Restated Agreement.
 

2. AMENDMENTS

 
2.1                Section 12 of Exhibit 1.1 of the Second Restated Agreement is
deleted and replaced in its entirety by the following:
 
“Alnylam Exclusive Target” means an RNA Target or protein product of (a) the
antithrombin gene (AT, also known as AT3), (b) the aminolevulinate synthase 1
gene (AS1), (c) the hydroxyacid oxidase 1 gene (GO1) or (d) the alpha-1
antitrypsin gene (AAT), which genes are further identified and described on
Exhibit B.
 
2.2                Section 58 of Exhibit 1.1 of the Second Restated Agreement is
deleted and replaced in its entirety by the following:
 

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“Isis Exclusive Target” means an RNA Target or protein product of (a) the Factor
XI gene (FXI), (b) the Apo(a) gene (Apoa1), (c) the diglyceride acyltransferase
gene 2 (DGAT2) or (d) the growth hormone receptor gene (GHR), which genes are
further identified and described on Exhibit A.
 
2.3                Section 100 of Exhibit 1.1 of the Second Restated Agreement
is deleted and replaced in its entirety by the following:
 
“RNA Target” means a ribonucleic acid transcript with a defined sequence and/or
function, including, for example, non-coding transcripts, pre-mRNA transcripts,
and mRNA transcripts, including all splice variants and mutant forms of any such
transcripts. RNA Targets may be identified by reference to a gene encoding such
ribonucleic acid transcripts or, for transcripts that encode a protein, by
reference to a protein encoded by such transcripts.
 
2.4                Exhibit A (Isis Exclusive Targets), Exhibit B (Alnylam
Exclusive Targets), and Exhibit 5.3(d) (Isis Third Party Agreements) to the
Second Restated Agreement are deleted and replaced with Exhibit A, Exhibit B and
Exhibit 5.3(d) attached hereto, respectively. Schedules 1-8 (Alnylam Current
Chemistry Patents), 1-9 (Alnylam Current Motif and Mechanism Patents), 1-14
(Alnylam Exclusive Target Patents), 1-17 (Alnylam Extended Field Patents), 1-52
(Isis Current Chemistry Patents), 1-53 (Isis Current Motif and Mechanism
Patents), 1-60 (Isis Exclusive Target Patents) and 1-63 (Isis Extended Field
Patents) to the Second Restated Agreement are deleted and replaced with
Schedules 1-8, 1-9, 1-14, 1-17, 1-52, 1-53, 1-60 and 1-63 attached hereto,
respectively.
 
2.5                Notwithstanding the provisions of Section 5.3(d) of the
Second Restated Agreement, licenses to Isis Exclusive Target Patents that cover
the manufacture, use or sale of an Alnylam Exclusive Target Product that
hybridizes to and modulates the Alnylam Exclusive Target known as GO1 or the
Alnylam Exclusive Target known as AAT (described in clause (c) and (d) of the
definition of “Alnylam Exclusive Target”, respectively) and that are subject to
contractual obligations between Isis and Third Parties in effect as of the
Amendment Effective Date are licensed subject to the restrictions and other
terms described in the Isis Third Party Agreements. Prior to the Amendment
Effective Date, Isis has provided Alnylam with copies of the Isis Third Party
Agreements, provided, that Isis may redact copies of out-licenses Isis has
granted Third Parties so long as the redacted terms do not limit Alnylam’s
rights hereunder or create obligations for Alnylam. Alnylam hereby agrees to
comply, and to cause its sublicensees to comply, with such restrictions and
other terms.
 
2.6                The license to Isis Exclusive Target Patents granted in
Section 5.1(h) with respect to the Alnylam Exclusive Target known as [***]
 
2.7               Notwithstanding the provisions of Section 6.5(c), licenses to
Alnylam Exclusive Target Patents that cover the manufacture, use or sale of an
Isis Exclusive Target Product that hybridizes to and modulates an Isis Exclusive
Target known as [***]
 

3. MISCELLANEOUS

 
3.1                Other Terms. All other terms and conditions of the Second
Restated Agreement shall remain in full force and effect.
 
3.2                Representations and Warranties of the Parties. Each Party
represents and warrants to the other Party that, as of the Amendment Effective
Date:
 
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(a)            Such Party is duly organized and validly existing under the laws
of the state of its incorporation and has full corporate power and authority to
enter into this Amendment and to carry out the provisions hereof;
 
(b)            Such Party has taken all corporate action necessary to authorize
the execution and delivery of this Amendment and the performance of its
obligations under this Amendment;
 
(c)            This Amendment is a legal and valid obligation of such Party,
binding upon such Party and enforceable against such Party in accordance with
the terms of this Amendment. The execution, delivery and performance of this
Amendment by such Party does not conflict with any agreement, instrument or
understanding, oral or written, to which such Party is a Party or by which such
Party may be bound, and does not violate any law or regulation of any court,
governmental body or administrative or other agency having authority over such
Party. All consents, approvals and authorizations from all governmental
authorities or other Third Parties required to be obtained by such Party in
connection with this Amendment have been obtained; and
 
(d)            Such Party has sufficient right, power and authority to enter
into this Amendment, to perform its obligations under this Amendment and to
grant the licenses granted hereunder.
 
3.3               Counterparts. This Agreement may be executed in any number of
counterparts, each of which will be deemed an original, and all of which
together will constitute one and the same instrument.
 
[Remainder of Page Intentionally Left Blank]
 
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IN WITNESS WHEREOF, the Parties hereby execute this Amendment Number One to the
Second Amended and Restated Strategic Collaboration and License Agreement as of
the date first written above.
 

 
ALNYLAM PHARMACEUTICALS, INC.

 

  By:
 /s/ John Maraganore

  Name:
John Maraganore

  Title:
Chief Executive Officer

 

 
ISIS PHARMACEUTICALS, INC.

 

  By:
 /s/ B. Lynne Parshall

  Name:
B. Lynne Parshall

  Title:
Chief Operating Officer

 
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Exhibit A

Isis Exclusive Targets
 

1. The human Factor XI gene (also known as coagulation factor XI, plasma
thromboplastin antecedent, F11, FXI). As of the Second Restatement Date, an
example of an identifier for the Factor XI gene is NCBI Gene ID 2160.

 

2. The human Apo(a) gene (also known as apolipoprotein(a); LPA; Lipoprotein,
Lp(a); Lp(a); Apo A-I; Apoa1). As of the Second Restatement Date, an example of
an identifier for the Apo(a) gene is NCBI Gene ID 4018.

 

3. The human diacylglycerol acyltransferase 2 gene (also known as DGAT2,
Acyl-CoA and diacylglycerol O-acyltransferase 2). As of the Amendment Effective
Date, an example of an identifier for the DGAT2 gene is NCBI Gene ID 84649.

 

4. The human growth hormone receptor gene (also known as GHR, GHBP and GHIP). As
of the Amendment Effective Date, an example of an identifier for the GHR gene is
NCBI Gene ID 2690.

 
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Exhibit B

Alnylam Exclusive Targets

 

1. The human antithrombin gene (also known asSERPINC1, antithrombin3, AT3 and
ATIII). As of the Second Restatement Date, an example of an identifier for the
antithrombin gene is NCBI Gene ID 462.

2. The human aminolevulinate delta-synthase gene (also known as ALAS-1,
ALAS, ALAS3, ALASH, aminolevulinate delta-synthase, Delta-ALA synthase,
Delta-Aminolevulinate synthase 1, 5-aminolevulinic acid synthase 1, ALAS-H,
5-aminolevulinate synthase, MIG4, aminolevulinate synthase-1, AS1). As of the
Second Restatement Date, an example of an identifier for the ALAS-1 gene is NCBI
Gene ID 211.

3. The human Alpha-1 antitrypsin gene (also known as AAT, SERPINA1, PI, A1A,
PI1, A1AT, PRO2275, alpha1AT). As of the Amendment Effective Date, an example of
an identifier for the AAT gene is NCBI Gene ID 5265.

4. The human hydroxyacid oxidase 1 gene (also known as HAO1, GO, GO1, GOX, GOX1
and HAOX1). As of the Amendment Effective Date an example of an identifier for
the HAO1 gene is NCBI Gene ID 54363.

 
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Exhibit C

[***]
 
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Exhibit 5.3(d)
 
Isis Third Party Agreements

The following schedule of Isis Third Party Agreements is provided by Isis to
Alnylam, in connection with the Agreement.  Capitalized terms used but not
otherwise defined herein have the meanings given to such terms in the Agreement.

This schedule and the information and disclosures contained in this schedule are
intended only to qualify and limit the licenses granted by Isis to Alnylam in
the Agreement and do not expand in any way the scope or effect of any such
licenses.

Agreements Providing Rights to Third Parties in Certain Isis Patent Rights

[***]

Agreements Granting Third Parties Rights to Conduct Target Validation

[***]

Research License Agreements

[***]

Agreements Containing Cross-Licenses to New Technology Arising from Partner
Collaborations

[***]

Government Rights in Isis IP

1. Government Rights - Inventions claimed in US Patent Applications: [***] were
funded in part by a Small Business Innovation Research grant administered by the
National Institutes of Health.  Accordingly, the U.S. Federal Government retains
certain rights to those inventions.

 
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Schedule 1-8
Alnylam Current Chemistry Patents

[***]
 
9

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Schedule 1-9
Alnylam Current Motif and Mechanism Patents

[***]
 
10

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Schedule 1-14
Alnylam Exclusive Target Patents

[***]
 
11

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Schedule 1-17
Alnylam Extended Field Patents

[***]
 
12

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Schedule 1-52
Isis Current Chemistry Patents

[***]
 
13

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Schedule 1-53
Isis Current Motif and Mechanism Patents

[***]
 
14

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Schedule 1-60
Isis Exclusive Target Patents

[***]
 
15

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Schedule 1-63
Isis Extended Field Patents

[***]
 
 
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