EXHIBIT 10.2

 

CONFIDENTIAL

EXECUTION COPY

 

CONFIDENTIAL TREATMENT REQUESTED

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

 

AMENDMENT #1 TO COLLABORATION, LICENSE AND DEVELOPMENT AGREEMENT

 

This AMENDMENT #1 TO COLLABORATION, LICENSE AND DEVELOPMENT AGREEMENT (this
“Amendment”) is entered into as of the date of last signature hereof (the
“Amendment Date”) by and between ISIS PHARMACEUTICALS, INC., a Delaware
corporation, having its principal place of business at 2855 Gazelle Court,
Carlsbad, CA 92010 (“Isis”), and ASTRAZENECA AB, a company incorporated in
Sweden under no. 556011-7482 (“AstraZeneca”).  Isis and AstraZeneca are each
referred to herein by name or as a “Party” or, collectively, as “Parties.”

 

RECITALS

 

WHEREAS, Isis and AstraZeneca are parties to the Collaboration, License and
Development Agreement dated December 7, 2012 (the “Agreement”);

 

WHEREAS, Isis and AstraZeneca desire to amend the Agreement to add an additional
research program focused on the gene target [***] (GenBank accession # [***]) or
any alternative splice variants, mutants, polymorphisms and fragments thereof
(the “Amendment-Additional Collaboration Target”); and

 

NOW, THEREFORE, in consideration of the premises and mutual covenants herein
contained, and for other good and valuable consideration, the receipt and
sufficiency of which are hereby acknowledged, and solely with respect to the
newly created program focused on the Amendment-Additional Collaboration Target,
the Parties, intending to be legally bound, do hereby agree as follows:

 

1.                                      Amendment-Additional Collaboration
Target Program.  In addition to the three Oncology Collaboration Programs under
the Agreement, the Parties will conduct a research and development program on
the Amendment-Additional Collaboration Target (the “Amendment-Additional
Collaboration Target Program”) in accordance with this Amendment and the plan
for the research and development of the Amendment-Additional Collaboration
Target (the “Amendment-Additional Collaboration Target Research and Development
Plan”).  The initial Amendment-Additional Collaboration Target Research and
Development Plan is attached hereto as ATTACHMENT 1 and sets forth the
activities to be conducted by each Party to reach Target Sanction for the
Amendment-Additional Collaboration Target.  Once the Amendment-Additional
Collaboration Target has reached Target Sanction, within [***] days the Parties
will mutually agree to updates to the Amendment-Additional Collaboration Target
Research and Development Plan to include the specific activities and studies
under the Amendment-Additional Collaboration Target Research and Development
Plan each Party

 

1

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

 

will perform to identify a Development Candidate for the Amendment-Additional
Collaboration Target.  This Amendment is without prejudice to AstraZeneca’s
rights under Section 2.2.4(b) of the Agreement to add an additional Oncology
Target to the Oncology Collaboration as set out therein.

 

2.                                      Amendment-Additional Collaboration
Target Rights and Obligations.  For purposes of the Agreement (except as
explicitly set forth in this Amendment):

 

a.                                      the Amendment-Additional Collaboration
Target will be considered a Gene Target under the Agreement and will be treated
the same as an Oncology Target under the Agreement, including but not limited to
Article 5 of the Agreement except that in Article 5.2 of the Agreement as it
applies to the Amendment-Additional Collaboration Target the references to
cancer shall be read as references to [***].

 

b.                                      the Amendment-Additional Collaboration
Target Research and Development Plan will be treated the same as an Oncology
Research and Development Plan;

 

c.                                       ASOs that are designed to bind to the
RNA that encodes the Amendment-Additional Collaboration Target, where such ASO
is discovered by Isis prior to the Amendment Date or in the performance of the
Amendment-Additional Collaboration Target Research and Development Plan
(“Amendment-Additional Collaboration Target Compounds”) will be treated the same
as Oncology Compounds; the discovery research program focused on discovering
Amendment-Additional Collaboration Target Compounds to select an
Amendment-Additional Collaboration Target Development Candidate in accordance
with the Amendment-Additional Collaboration Target Research and Development Plan
will be treated the same as an Oncology Collaboration Program;

 

d.                                      An Amendment-Additional Collaboration
Target Compound that is determined by Isis’ RMC in accordance with Isis’
standard procedures for designating development candidates as ready to start
IND-Enabling Toxicology Studies, will be treated the same as a Lead Candidate;

 

e.                                       A Development Candidate selected by
AstraZeneca arising out of the work conducted under the Amendment-Additional
Collaboration Target Research and Development Plan (an “Amendment-Additional
Collaboration Development Candidate”) will be treated the same as an Oncology
Development Candidate;

 

f.                                        A finished product containing an
Amendment-Additional Collaboration Target Compound as an active pharmaceutical
ingredient (including any salt, hydrate, solvate or prodrug thereof) (a
“Amendment-Additional Collaboration Target Product”) will be treated the same as
an Oncology Product;

 

And as such, except as explicitly set forth in this Amendment, each Party will
have the same rights and obligations with respect to Amendment-Additional
Collaboration Target Compounds and Amendment-Additional Collaboration Target
Products as each has under

 

2

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

 

the Agreement with respect to Oncology Compounds and Oncology Products,
including but not limited to:

 

a.              the Option under Section 3.5 of the Agreement to obtain the
license set forth in Section 6.1.3 of the Agreement;

 

b.              and the applicable financial provisions under Article 8 of the
Agreement as specified in Section 7 of this Amendment.

 

And the terms of the Agreement as they apply to the Amendment-Additional
Collaboration Target, except where the context otherwise requires, shall be
construed such that the Effective Date is replaced with the Amendment Date,
including but not limited to Section 6.1.4 (e), 6.1.7, 6.2 of the Agreement and
relevant definitions, including but not limited to “AstraZeneca Background IP”;
and with respect to Section 3.2.2 of the Agreement where the Oncology
Collaboration Term as it applies to the Amendment-Additional Collaboration
Target will begin on the Amendment Date and will end on [***] (for the purposes
of this Amendment herein referred to as the “Amendment-Additional Collaboration
Term”).

 

3.                                      No Substitution Rights.  The rights of
substitution in Section 3.3.7 of the Agreement shall continue to apply to the
Oncology Targets as set out therein but AstraZeneca will have no rights of
substitution under the Agreement or this Amendment with respect to the
Amendment-Additional Collaboration Target Program.

 

4.                                      Performing the Amendment-Additional
Collaboration Target Research and Development Plan; Costs.

 

a.                                      Isis will use Commercially Reasonable
Efforts to conduct the activities to be conducted by Isis designated under the
Amendment-Additional Collaboration Target Research and Development Plan.  Such
activities will be treated the same as Isis Conducted Activities under the
Agreement and the costs for such activities will be handled the same as the
costs under Section 4.5.2 of the Agreement.

 

b.                                      AstraZeneca will use Commercially
Reasonable Efforts to conduct all other activities as described in the
Amendment-Additional Collaboration Target Research and Development Plan. Such
activities will be treated the same as AstraZeneca Conducted Activities under
the Agreement and the costs for such activities will be handled the same as the
costs under Section 4.5.2 of the Agreement.

 

5.                                      Manufacturing and Supply.

 

The provisions of Section 4.6.1 (a) of the Agreement shall apply to Isis
Conducted Activities designated under the Amendment-Additional Collaboration
Target Research and Development Plan.

 

The provisions of Section 4.6.1 (b)(iii) (including the last two paragraphs of
Section 4.6.1(b)) of the Agreement shall apply to AstraZeneca Conducted
Activities under the

 

3

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

 

Amendment-Additional Collaboration Target Research and Development Plan, as more
specifically set out herein:

 

a.                                      Research Compound Supply.  Isis will
provide up to [***] of bulk unformulated research-grade Compound for
Amendment-Additional Collaboration Target Compounds for up to [***] for each of
[***] ([***] total) [***].  In addition, should AstraZeneca require additional
research-grade Compound for the Amendment-Additional Collaboration Target
Program for pre-clinical studies, then, at AstraZeneca’s reasonable
request, Isis will use its reasonable endeavors to provide such research-grade
Compound for such pre-clinical studies at [***].

 

b.                                      Development API Supply.  Isis will
supply (at AstraZeneca’s expense at [***] within 60 days after AstraZeneca’s
receipt of the applicable invoice) bulk unformulated API for the
Amendment-Additional Collaboration Development Candidate sufficient to support
the IND Enabling Toxicology Studies for the Amendment-Additional Collaboration
Target Development Candidate, and the quantity of API determined by the JSC when
the protocol is available for the first Clinical Study, consistent with Isis’
obligations to supply the Oncology Programs under Section 4.6.1(b)(iii) of the
Agreement.

 

c.                                       Formulation.  AstraZeneca will be
responsible for conducting and paying for all formulation work to conduct the
Amendment-Additional Collaboration Target Program. If requested by AstraZeneca,
during the Amendment-Additional Collaboration Term Isis will provide reasonable
assistance to AstraZeneca for such work as set out in the Amendment-Additional
Collaboration Target Research and Development Plan.  Isis will provide such
assistance on an hourly basis [***] up to a reasonable maximum number of hours
set by the Amendment-Additional Collaboration Target Working Group for each year
of the Amendment-Additional Collaboration Term, and thereafter at Isis’ then
current FTE Rate. AstraZeneca will resupply any finished Product necessary to
support any Isis Conducted Activities, AstraZeneca Conducted Activities, IND
toxicology studies and the Phase 1 Study for the Amendment-Additional
Collaboration Target Program.

 

d.                                      Manufacturing Services Agreement. The
Parties have entered into a Manufacturing Services Agreement with effective date
of 7 March 2013 as provided by Section 4.6.1 (b) of the Agreement and the
Parties agree that they will use the MSA to facilitate the supply arrangements
herein.

 

6.                                      Amendment-Additional Collaboration
Target Working Group.

 

a.                                      Formation of the Amendment-Additional
Collaboration Target Working Group. Within [***] ([***]) days after the
Amendment Date, with respect to the Amendment-Additional Collaboration Target
Program, the Parties will establish an Amendment-Additional Collaboration Target
Working Group (“Amendment-Additional Collaboration Target Working Group”) that
will be separate and

 

4

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

 

independent from the JSC, and will be responsible for the coordination and
management of activities under the Amendment-Additional Collaboration Target
Research and Development Plan. The Amendment-Additional Collaboration Target
Working Group will consist of an equal number of representatives of each Party. 
The Amendment-Additional Collaboration Target Working Group will report into the
JSC and will make decisions and resolve disputes in the same manner as the JSC.

 

b.                                      Term of Amendment-Additional
Collaboration Target Working Group. The Amendment-Additional Collaboration
Target Working Group (and any of its sub-teams and working groups) under this
Amendment will cease to exist upon the earlier of Isis ceasing to participate in
the JSC in respect of the Amendment-Additional Collaboration Target Program or
the JSC ceasing to be responsible for making decisions in respect thereof, in
each case as provided in Section 4.1.4 of the Agreement.

 

c.                                       Meeting Coordination. The
Amendment-Additional Collaboration Target Working Group will meet at least once
per quarter in person or via video conference or teleconference and more
frequently whenever necessary and will meet in person at least twice a year.
Isis and AstraZeneca will use commercially reasonable efforts to schedule
meetings of the JSC and Amendment-Additional Collaboration Target Working Group
to take place at the same location and on the same dates to maximize the use of
each Party’s time, increase information sharing efficiencies and reduce the cost
of additional travel, lodging and related expenses.

 

7.                                      FTE hours.  Sections 6.5.1 and 7.1.5 of
the Agreement will apply to the Amendment-Additional Collaboration Target in the
same manner as applied to each Oncology Product, except the reference in those
Sections to [***]. Instead, under each of Sections 6.5.1 and 7.1.5 of the
Agreement up to [***] of Isis’ time shall be available [***] to AstraZeneca
(being [***] in total) specifically in respect of the Amendment-Additional
Collaboration Target.

 

8.                                      Additional Financial Provisions.  The
financial provisions set forth in Article 8 of the Agreement applicable to
Oncology Products (including but not limited to Section 8.6 and Section 8.8)
will apply to the Amendment-Additional Collaboration Target Products in the same
manner as applied to each Oncology Product except that:

 

a.                                      Section 8.1(iii) of the Agreement shall
not apply with respect to the Amendment-Additional Collaboration Target Program,
and instead Section 8.1 of the Agreement shall be amended to add that
AstraZeneca shall pay Isis an additional up-front fee of $[***] in partial
consideration for the Option granted by Isis to AstraZeneca under Section 3.5
for the Amendment-Additional Collaboration Target within 30 days after the
Amendment Date;

 

b.                                      In partial consideration for the Option
granted by Isis to AstraZeneca under Section 3.5 of the Agreement in respect of
the Amendment-Additional Collaboration Target, AstraZeneca will pay Isis $[***]
when the Amendment-

 

5

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

 

Additional Collaboration Target Program achieves Target Sanction, such payment
to be due within 30 days following receipt of an invoice from Isis following
such achievement; and

 

c.                                       Section 8.2 of the Agreement shall be
amended such that up to a total of $[***] may become due and payable thereunder
for a total of five Options (if AstraZeneca exercises all of its Options under
the Agreement and under this Amendment and if a fourth Oncology Collaboration
Program is added under Section 2.2.4 of the Agreement).

 

9.                                      Termination.  If the
Amendment-Additional Collaboration Target Program has not achieved Target
Sanction by [***], then either Party may terminate this Amendment by providing
the other party a written notice thereof by [***] with the consequences thereof
as set forth in Section 3.4 of the Agreement.  The Amendment-Additional
Collaboration Target Program (and therefore this Amendment) will terminate at
the end of the Amendment-Additional Collaboration Term if, despite the Parties’
Commercially Reasonable Efforts, by the expiration of the Amendment-Additional
Collaboration term, Isis has not designated an Amendment-Additional
Collaboration Target Lead Candidate, with the consequences thereof as set forth
in Section 3.4 of the Agreement.  The licenses under the Cross-Licensed
Collaboration Formulation IP granted by each Party under Section 11.c of this
Amendment will survive termination of this Amendment or the Agreement.

 

10.                               Representations and Warranties.

 

a.                                      Each Party hereby makes, as of the
Amendment Date and solely with respect to the Amendment-Additional Collaboration
Target Program, the same representations and warranties set forth in
Section 10.1 of the Agreement.

 

b.                                      Isis hereby makes to AstraZeneca, as of
the Amendment Date and solely with respect to the Amendment-Additional
Collaboration Target Program, the same representations and warranties set forth
in Section 10.2 of the Agreement.

 

11.                               Intellectual Property Rights.

 

a.                                      Isis Patents.  Solely with respect to
the Amendment-Additional Collaboration Target Program, the Patent Rights listed
on ATTACHMENT 2 to this Amendment (i) are part of the Isis Core Technology
Patents and (ii) will not be considered formulation technology excluded under
the definitions of Licensed Know-How or Licensed Patents, except that the Patent
Rights listed on ATTACHMENT 2 to this Amendment (A) will be considered
formulation technology for purposes of Section 8.9.3, 8.9.4 of the Agreement and
the definition of Additional Core IP under the Agreement, and (B) [***]. The
Patent Rights listed on ATTACHMENT 3 to this Amendment are part of the Isis
Product-Specific Patents, solely with respect to the Amendment-Additional
Collaboration Target Program.

 

b.                                      [***] Agreements.  It is agreed by
AstraZeneca and Isis that the Amendment-Additional Collaboration Target
Compounds will be treated as [***] under

 

6

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

 

AstraZeneca’s agreements with [***] (the [***]), as such term is defined
therein.  As such, if clause (iv) of Section 3.4 of the Agreement or clause
(i)(1) of Section 12.3.2 of the Agreement become applicable with respect to the
Amendment-Additional Collaboration Target Program, then, subject to [***] right
to use such results for research purposes as reserved to it in the [***], any
results related to Amendment-Additional Collaboration Target Compounds owned by
AstraZeneca under the [***] would be licensed to Isis under clause (iv) of
Section 3.4 of the Agreement or clause (i)(1) of Section 12.3.2 of the
Agreement, as the case may be.  AstraZeneca will not provide [***] with any
Amendment-Additional Collaboration Target Compounds unless and until [***]
agrees in writing that such Compounds will be treated as [***] under the [***],
and AstraZeneca will provide Isis such written agreement if requested by Isis. 
AstraZeneca will not amend (or waive any rights under) the [***] in any way that
diminishes Isis’ rights under this Section 11b without Isis’ prior written
consent.

 

c.                                       Cross-Licenses to Collaboration
Formulation IP.  For purposes of this Amendment, “Cross-Licensed Collaboration
Formulation IP” means (A) Patent Rights claiming formulation technology that is
discovered, developed, invented, created or reduced to practice by or on behalf
of a Party during the Agreement Term (i) in the performance of the
Amendment-Additional Collaboration Target Plan, (ii) using the
Amendment-Additional Collaboration Target Compounds, or (iii) using the
inventions described in the Patent Rights listed on ATTACHMENT 2 to this
Amendment, and (B) any Know-How related thereto, in each case to the extent
Controlled by a Party at any time during the Agreement Term.  Claims within a
Patent Right claiming a specific combination of an Amendment-Additional
Collaboration Target Compound and formulation technology will be
Product-Specific Patents and will not be Cross-Licensed Collaboration
Formulation IP.  For purposes of the definition of Cross-Licensed Collaboration
Formulation IP, [***].

 

i                                             Isis hereby grants to AstraZeneca
a perpetual, worldwide, non-exclusive, fully-paid, royalty-free, sublicensable
license under the Cross-Licensed Collaboration Formulation IP to research,
develop, manufacture, have manufactured, register, market and commercialize
products.

 

ii                                          AstraZeneca hereby grants to Isis a
perpetual, worldwide, non-exclusive,  sublicensable license under the
Cross-Licensed Collaboration Formulation IP to research, develop, manufacture,
have manufactured, register, market and commercialize products.  Notwithstanding
the foregoing, until the earlier of the [***] anniversary of the Amendment Date
and the date Section 3.4 or Section 12.3.2 of the Agreement becomes applicable
with respect to the Amendment-Additional Collaboration Target Program, Isis
agrees that it will not (A) practice its license from AstraZeneca under any
Patent Right within the Cross-Licensed Collaboration Formulation IP that is
solely owned by AstraZeneca to develop, manufacture, have manufactured,
register, market or commercialize products that [***] (such product, a
“Restricted Product”); provided that the restriction set forth in

 

7

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

 

this clause (A) will not preclude Isis from conducting research on any ASOs
prior to designation of such ASOs as a development candidate; or (B) [***] a
Restricted Product as [***] where such Restricted Product is Covered by a Patent
Right within the Cross-Licensed Collaboration Formulation IP that is solely
owned by AstraZeneca.

 

12.                               No Impact on Other Collaboration Programs.
Except as otherwise expressly amended by this Amendment, the Agreement remains
in full force and effect in accordance with its terms. For the avoidance of
doubt, this Amendment is solely intended to modify certain terms of the
Agreement regarding the Amendment-Additional Collaboration Target Program, and
does not amend the Agreement in any way with respect to the [***] Program, [***]
Program or any of the Oncology Collaboration Programs.

 

13.                               Entire Agreement and Governing Law.
Section 14.9 of the Agreement shall be construed as including this Amendment.
This Amendment shall be construed and interpreted as per the Agreement,
including but not limited to governing law and jurisdiction, and defined terms
set out in the Agreement shall have the same meaning in this Amendment unless
otherwise provided by this Amendment.

 

* - * - * - *

 

[Signature page follows]

 

8

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

 

IN WITNESS WHEREOF, the Parties have caused this Amendment to be executed by
their duly authorized representatives.

 

ISIS PHARMACEUTICALS, INC.

 

By:

/s/ B. Lynne Parshall

 

 

 

 

Name:

B. Lynne Parshall

 

 

 

 

Title:

 

 

 

 

 

Date:

 

 

 

 

 

 

 

 

ASTRAZENECA AB

 

 

 

 

By:

/s/ Jan-Olof Jacke

 

 

 

 

Name:

Jan-Olaf Jacke

 

 

 

 

Title:

CFO, AstraZeneca AB

 

 

 

 

Date:

2013-08-13

 

 

9

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

 

ATTACHMENT 1

 

Amendment-Additional Collaboration Target Research and Development Plan

 

[***]

 

10

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

 

ATTACHMENT 2

 

Amendment-Additional Collaboration Target Isis Core Technology Patents

 

[***]

 

11

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

 

ATTACHMENT 3

 

Amendment-Additional Collaboration Target Isis Product Specific Patents

 

[***]

 

12

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