execution version   
 Exhibit 10.3
 
AMENDMENT #5 TO THE RESEARCH, DEVELOPMENT AND LICENSE AGREEMENT
This AMENDMENT #5 TO THE RESEARCH, DEVELOPMENT AND LICENSE AGREEMENT (this
"Amendment No. 5") is entered into and made effective as of the 27th day of
June, 2014 (the "Amendment No. 5 Effective 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 Glaxo Group
Limited, a company existing under the laws of England and Wales, having its
registered office at 980 Great West Road, Brentford London TW8 9GS, United
Kingdom ("GGL"), and GlaxoSmithKline Intellectual Property Development Limited, 
a company existing under the laws of England and Wales, having its registered
office at 980 Great West Road, Brentford London TW8 9GS, United Kingdom ("GSK
IPDL"). GGL and GSK IPDL are referred to together as "GSK".  Isis and GSK are
each referred to herein by name or as a "Party" or, collectively, as "Parties."
RECITALS
Whereas, Isis and GGL are parties to the Research, Development and License
Agreement dated March 30, 2010, as amended (the "Agreement") and (to the extent
applicable) GGL has sub-licensed its rights under the Agreement to GSK IPDL;
Whereas, Isis and GSK are Developing the molecule known as [***] under the
Collaboration Program focused on [***] (the "[***] Program"); and
Whereas, Isis and GSK desire to amend certain terms of the Agreement solely with
respect to the [***] Program, and to amend the activities being conducted under
the [***] Program to include work on [***] ASOs discovered by Isis that bind to
[***] and [***] (the "[***] Compounds");
WHEREAS, Isis and GSK wish to conduct research and development activities to
identify and advance, [***], an [***] on the terms and conditions set forth
herein.
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
[***] Program, the Parties, intending to be legally bound, do hereby agree as
follows:
Capitalized terms used but not defined herein will have the meaning ascribed to
such terms in the Agreement.
1.
Amendment of Activities under [***] Program. The [***] Program is hereby amended
to include work on the compounds listed on Appendix 4 attached hereto (each, a
"Research Lead") which (unless excluded under Section 11(a) of this Amendment
No. 5) are acknowledged to be Compounds under the [***] Program.

2.
***] DC Development Plan.  The initial Development plan for the potential [***]
DC is attached hereto as Appendix 1.  After the selection of the [***] DC in
accordance with Section 3 of this Amendment No.5, GSK will promptly provide Isis
with an updated Development plan for the [***] DC, and thereafter will update
such Development plan on at least [***] basis until such time as the [***]
Option is exercised (or otherwise expires).  After Option exercise, GSK will
provide updates as required under Section 4.3.2 and Section 4.3.3 of the
Agreement.

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3.
Research Activities; Selection of [***] DC.   Isis will use Commercially
Reasonable Efforts to conduct the [***] DC Confirmation Activities set out in
Column 3 of Appendix 2 attached hereto, with the goal of achieving the [***] DC
Criteria, as follows:

a.
Isis will use Commercially Reasonable Efforts to complete a study testing [***]
(as further described and in accordance with Column 3 of Appendix 2 of this
Amendment No.5) to provide [***] (the "Research Lead Study").

b.
Once the Research Lead Study has been completed, Isis will provide GSK written
notice thereof, including a summary of the results of the Research Lead Study
(such notice and summary the "Research Lead Data Package").  Within [***]
([***]) days of its receipt of the Research Lead Data Package, GSK will
designate [***] (the "Prioritized Lead") to advance as described in Section 3.c.
of this Amendment No. 5.

c.
For the Prioritized Lead, Isis will use Commercially Reasonable Efforts to
complete (i) [***], and (ii) [***], (all as further described and in accordance
with Column 3 of Appendix 2 of this Amendment No.5) such [***] to be agreed and
finalized in advance by the JSC (the "Prioritized Lead Studies").  Once the
Prioritized Lead Studies have been completed, Isis will provide the JSC written
notice thereof, including the data and results of the Prioritized Lead Studies
(the "Prioritized Lead Data Package").  Within [***] days of its receipt of the
Prioritized Lead Data Package, [***] will determine whether the Prioritized Lead
meets the applicable criteria for designating a development candidate under
Column 3 of Appendix 2 (the "[***] DC Selection Criteria").  Unless within such
[***] day period [***] determines (or by written notice GSK informs Isis that)
the Prioritized Lead has not met the [***] DC Selection Criteria, then the
Prioritized Lead will be the [***] DC.  If within such [***] day period [***]
determines (or by written notice GSK informs Isis that) the Prioritized Lead has
not met the [***] DC Selection Criteria, then within [***] days of such
determination, GSK may designate an additional Research Lead as a Prioritized
Lead, and Isis and GSK will repeat the process set forth in this Section 3.c. of
this Amendment No. 5 until the earlier of the date (y) an [***] DC is
designated, or (z) each Research Lead has been tested in the studies set forth
in this Section 3.c of this Amendment No. 5, but no such Research Lead has been
designated an [***] DC.  If the Parties do not designate an [***] DC under this
Section 3.c. of this Amendment No. 5 then, unless otherwise mutually agreed to
by the Parties in writing, no Compound will be an [***] DC and Isis will have no
further obligations under this Amendment No. 5.

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d.
Isis will be responsible for all costs and expenses associated with the studies
under this Section 3 of this Amendment No. 5.

4.
[***] DC Development Activities Conducted by Isis and Paid for by GSK.

a.
Isis' Manufacturing Responsibilities; CMC Characterization.

i.
Isis will manufacture [***] of API for the Research Lead known as [***], to
generate [***] of API.  Isis will begin such activities within [***] ([***])
Business Days of Isis' receipt of the $[***] payment under clause (i) of Section
4.c. of this Amendment No. 5.  Such API will be manufactured in accordance with
cGMP and [***].  In addition, Isis will formulate an amount of such API into
drug product that is sufficient (but no more than is necessary) to conduct the
[***] and the [***] for the [***] DC, and which meets the requirements of cGLP. 
As soon as reasonably practicable (and using Commercially Reasonable Efforts  to
meet such timeframe as necessary to meet the scheduled start of the [***] as
agreed between the Parties), Isis will deliver such drug product to the CRO, and
deliver the remaining quantity of API to GSK, in each case [***].  GSK will pay
Isis for its [***] to manufacture such API and drug product (subject to the
principles set out in Section 4(a)(ii) below with respect to failed batches) as
set out in Rows A and B of Appendix 3 attached hereto, which include the actual
cost charged by its appointed Third Party contract manufacturing organization to
perform the conjugation work for such API and Isis' [***].

ii.
If Isis encounters any difficulties or hazards during the  manufacture of such
API that prevents Isis from successfully manufacturing API that meets the
requirements of Section 4(a)(i) above with respect to quality and quantity, Isis
will notify GSK within [***] days of such failure and will use Commercially
Reasonable Efforts to manufacture a replacement batch of API, such that the CRO
receives the formulated API in accordance with the requirements of Section
4(a)(i) above as close to the originally-scheduled delivery date as possible. 
For any such failed batch, the cost of the manufacture incurred by Isis will be
[***] as follows:  [***]; and, to the extent [***], [***]; except, that [***]. 
Any such [***] under Section 4.a.i of this Amendment No. 5.

iii.
Isis will also use Commercially Reasonable Efforts to [***] (and perform the
related [***] for the [***] for the [***] for the [***] DC.  GSK will pay Isis
for its internal FTE costs reasonably estimated to conduct such activities which
have been calculated in accordance with [***] set out in Section 4(d) of this
Amendment No. 5 and included in the costs outlined in Row A of Appendix 3
hereto.

iv.
Isis and GSK will agree to a technology transfer plan and schedule pursuant to
which Isis will provide to GSK (or to a Third Party manufacturer selected by GSK
and reasonably agreed to by Isis) a technology transfer under Section 4.2.1 of
the Agreement solely to the extent necessary to enable GSK to fulfill its
obligations to Develop the [***] DC under Section 5 of this Amendment No. 5
prior to the [***] Option Deadline (including use of the API and formulated
product supplied by Isis according to this Amendment No.5), and solely for the
sole purpose of Developing the [***] DC.  Isis will provide such transfer in a
timely manner to facilitate GSK's activities in accordance with the [***] DC
Development plan.   If GSK believes in good faith that additional API for the
[***] DC is necessary for GSK to fulfill its obligations to Develop the [***] DC
under Section 5 of this Amendment No. 5, then GSK will provide Isis written
notice thereof, and the technology transfer plan will be expanded accordingly by
mutual agreement.  Isis will provide the first [***] ([***]) hours of such
technology transfer [***], and thereafter GSK will pay Isis for [***] and any
out-of-pocket costs to perform such activities ([***] in accordance with the
principles set out in Section 4(d) of this Amendment No. 5). Isis will provide
GSK an [***] GSK pursuant to this Section 4(a)(iv) in advance of initiating such
activities.  Until GSK approves the estimated cost to perform such an activity,
Isis will not incur such cost and Isis will not be obligated to perform such
activity.

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v.
At GSK's request, Isis will use its Commercially Reasonable Efforts to refer the
conduct of [***] for the [***] and [***] for the [***] DC manufactured by Isis
to an established contract research organization Isis uses to perform such work;
provided GSK will be solely responsible for managing such studies and the cost
of such studies.

vi.
If a Compound that is not [***] is designated as the [***] DC, then at the same
time as such designation, GSK will (i) pay Isis the Remaining Payment Due under
Section 4.c (iii) of this Amendment No. 5 related to [***], and (ii) notify Isis
if GSK intends to manufacture the API and drug product for such [***] DC itself
or if GSK intends Isis to manufacture such API and drug product for such [***]
DC.  If GSK notifies Isis that GSK intends Isis to manufacture such API for such
[***] DC, then at GSK's expense, as soon as reasonably practicable Isis will
manufacture [***] of the API and related drug product for such [***] DC under
the same terms and conditions as set forth in Section 4.a. of this Amendment No.
5 by adding such [***] DC to Isis' then existing queue for manufacturing
compounds at Isis' facility [***] and the Parties will adjust the planned start
of the [***] and [***] accordingly.

b.
[***].  Following [***], Isis will contract for the conduct of [***] and the
[***] under the initial [***] DC Development Plan with an established contract
research organization (the "CRO") consistent with the requirements of Section
4.1.7 and other applicable terms of the Agreement (with respect to
sub-contracting), and will monitor the performance of such [***] by such CRO,
including compliance with all Applicable Law.  GSK will pay Isis for all of
[***] and [***], as set out in Row D of Appendix 3.

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Isis will also use Commercially Reasonable Efforts to [***] for the [***] DC. 
GSK will pay Isis [***].
Isis will provide GSK an estimate of all such costs to be charged to GSK
pursuant to this Section 4(b) in advance of initiating such activities.  Until
GSK approves the estimated cost to perform such an activity, Isis will not incur
such cost and Isis will not be obligated to perform such activity.  Isis
currently estimates that it will use [***] to conduct the work under this
Section 4.b. of this Amendment No. 5.  For clarity, Isis will only be required
to conduct the activities under this Section 4.b for [***].
c.
Payment by GSK.  GSK will pay Isis for the activities under this Section 4 in
accordance with the amounts set forth in Appendix 3 attached hereto, as follows,
(i) with respect to the payments due under Section 4(a) of this Amendment No. 5,
upon [***], Isis will issue an invoice to GSK for $[***] (being the total amount
due under the Initial Payment Column for Rows A, B and C of Appendix 3), and GSK
will pay such invoice within [***] ([***]) Business Days following receipt of
such invoice by GSK, (ii) with respect to the payments due under Section 4(b) of
this Amendment No. 5, upon [***], Isis will invoice GSK for [***]% of the [***]
and [***]% of the [***] to conduct the work under Section 4.b of this Amendment
No. 5 (as described in the Initial Payment Column of Row D of Appendix 3), and
GSK will pay such invoice within [***] ([***]) days of receipt of such invoice
by GSK, and (iii) upon the occurrence of the applicable "Event Triggering
Remaining Payment" listed on Appendix 3 for the relevant activity, Isis will
issue an invoice to GSK for the balance of any remaining payment due in respect
of such activity as shown in the Remaining Payment Due column of Appendix 3, and
GSK will pay such invoice within [***] ([***]) days of receipt of such invoice
by GSK; provided always that in the case of remaining payments under this
sub-section  (iii)  of this Section 4(c), such payments will only be due from
GSK to Isis to the extent that [***].

d.
FTEs.  With respect to activities under this Amendment No. 5 that require GSK to
reimburse Isis FTE costs, Isis will [***], and the then applicable [***] will
apply. Isis' applicable [***] for the 2014 Calendar Year is $[***].

5.
GSK's Manufacturing and  Development  Responsibilities.

a.
Except as expressly set forth in Section 3 and Section 4 of this Amendment No.
5, without prejudice to GSK's obligations under Section 4.3 of the Agreement, as
from the Amendment No.5 Effective Date until such time as GSK exercises its
Option to the [***] Program (or until such Option expires), and provided Isis
has fulfilled its obligations under Section 4.a and Section 4.b of this
Amendment No. 5 (to the extent necessary for GSK to perform its obligations),
GSK will use Commercially Reasonable Efforts to conduct all activities related
to [***] the [***] DC, including but not limited to (i) [***] and [***] for the
[***], (ii) [***], including the [***], (iii) [***], (iv) [***].  GSK will be
responsible for all costs and expenses associated with the activities under this
Section 5.  Following GSK's exercise of its Option to the [***] Program, GSK's
Development and Commercialization obligations shall be as set forth in Section
4.3 of the Agreement.

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b.
Commitment to Develop [***] DC. Without limiting GSK's obligations under Section
2.2 of the Agreement and except as otherwise required for GSK to fulfil its
obligations under the Agreement or as otherwise requested by Isis, prior to
GSK's exercise of its Option to the [***] Program, GSK will [***] without Isis'
prior written consent.

c.
Development of Alternative [***] DC.  If based on the results of the [***] or
the [***] for the first [***] DC, GSK in good faith (acting in accordance with
its Commercially Reasonable Efforts) determines Development of such [***] DC
should be terminated, GSK may terminate the Development of such [***] DC by
providing Isis a written notice thereof within [***] ([***]) days following the
completion of the [***] of such [***], or completion of the [***] (as
applicable).  In such case, the Parties will, as soon as reasonably practicable,
hold a meeting of the JSC to discuss the merits of Developing a different
Research Lead.  Within [***] ([***]) days following such meeting of the JSC (or,
in any event if the JSC has not met within [***] ([***]) days of the termination
notice from GSK), GSK may provide Isis a written notice designating a Research
Lead as a replacement [***] DC, in which case (i) such Research Lead will be the
[***] DC, (ii) Isis will have no obligation to research, Develop or Manufacture
such [***] DC, and (iii) GSK will use Commercially Reasonable Efforts to Develop
such [***] DC up through the [***] Option Deadline [***].

6.
Safety Reporting; Data Integrity.

a.
Safety Reporting.  GSK will report to Isis any serious adverse events (SAEs) and
suspected unexpected serious adverse reactions (SUSARs) under any Clinical Study
for the [***] DC being conducted by or on behalf of GSK prior to the date of
[***] Option exercise, strictly in accordance with the timelines set out in the
Safety Data Exchange Agreement (such timelines to ensure that each Party is able
to meet all applicable legal and regulatory obligations in line with its own
respective internal processes).  In addition, GSK will provide Isis with [***]
and [***] regarding adverse events and material lab findings under any Clinical
Study for the [***] DC being conducted by or on behalf of GSK prior to the date
of [***] Option exercise.

b.
Safety Data Exchange Agreement (or equivalent).  As soon as reasonably
practicable following the Amendment No. 5 Effective Date, and in any event no
later than [***] days prior to the expected start of the first Clinical Study of
the [***] DC (or such other date as may be agreed between the Parties), the
pharmacovigilance representatives of each of Isis and GSK will meet and
determine the appropriate approach to be taken for the collection, review,
assessment, tracking, exchange and filing of information related to adverse
events and safety data associated with a [***] DC during the period prior to
GSK's exercise of its Option to the [***] Program, based on the activities being
conducted by each Party under the Agreement and this Amendment No.5. Such
approach will be documented between the Parties in writing in a separate safety
data exchange agreement (to the extent such agreement is necessary) or other
appropriate documentation, which will control with respect to the subject matter
covered therein. Such documentation will be in accordance with, and will enable
the Parties to fulfill, local and international regulatory reporting obligations
to Regulatory Authorities and other Applicable Law as well as to meet their own
respective internal policy requirements.  After GSK's exercise of its Option to
the [***] Program, the Parties will wind-down and discontinue the activities
provided for under any such arrangements, but GSK will continue to provide Isis
the cooperation and information described in Section 4.4.1 of the Agreement as
it relates to the [***] Program.

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c.
Isis  Database.  Notwithstanding the fact that GSK has not exercised its Option
for the [***] Program, GSK will provide Isis the cooperation and information
described in Section 4.4.1 of the Agreement as it relates to activities
undertaken by GSK in relation to the [***] DC prior to the date of [***] Option
exercise.

d.
Data Integrity.  GSK agrees that it will carry out its activities under the
[***] Program and collect and record any data generated therefrom in a manner
consistent with Good Data Management Practices.  Prior to GSK's exercise of its
Option for the [***] Program, GSK will, upon reasonable request by Isis permit
review of relevant notebooks and records in GSK's possession or control by Isis
during normal business hours. 

7.
Option.

a.
Once Isis has obtained the data generated under the statistical analyses plan
for the Phase 2 PoC Trial for [***], Isis will provide GSK with (i) a notice
from Isis that the PoC Trial is completed, and (ii) the Phase 2 PoC Data Package
for [***] (such notice and package, the "[***] PoC Trial Completion Package") in
accordance with Section 3.1 of the Agreement.  Once the data are generated under
the statistical analysis plan for the Phase 2 PoC Trial for the [***] DC, GSK
will notify Isis and provide a copy of the data package through the JSC.   GSK
will provide written notice to Isis of its decision whether to exercise its
Option to the [***] Program on or before 5:00 p.m. (US Eastern time) on the
[***] day following the earlier of (y) GSK's receipt of the [***] PoC Trial
Completion Package, and (z) the data are generated under the statistical
analyses plan for the Phase 2 PoC Trial for the [***] DC (the "[***] Option
Deadline").  If GSK does not provide written notice to Isis of GSK's exercise of
the Option for the [***] Program before the [***] Option Deadline, then GSK's
Option to the [***] Program will expire and, subject to Section 5.10 of the
Agreement, Isis will be free to Develop and Commercialize any Compounds that had
been  included in the [***] Program on its own or with a Third Party and, except
as specified in Section 5.10 of the Agreement, GSK will have no further rights
to the [***] Program (including all Compounds included therein) and [***] will
no longer be a Collaboration Target. For the avoidance of doubt, if GSK
exercises its Option for the [***] Program, then the license granted to GSK
pursuant to Section 4.1 of the Agreement will include all Compounds within the
[***] Program, including the Research Leads, but will not include any Compounds
that are excluded under Section 11 of this Amendment No. 5.

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b.
Early Exercise of an Option. For the avoidance of doubt, notwithstanding
anything to the contrary in this Amendment No. 5 or in the Agreement, GSK will
have the right to exercise its Option for the [***] Program at any time prior to
the [***] Option Deadline.

8.
Financial Provisions. The following revised financial provisions will apply
solely to the [***] Program:

a.
Upfront Payment. Upon execution of this Amendment No. 5, in consideration for
the amended scope of activities under the [***] Program described in this
Amendment No.5, Isis will issue to GSK an invoice for, and GSK will pay to Isis
within [***] ([***]) Business Days following the receipt of such invoice for, a
payment equal to $[***] ([***] US Dollars).

b.
Milestone Payments for First Achievement of Development Milestone Event. Solely
with respect to Compounds under the [***] Program that first achieve a
Development Milestone Event as a result of activities by or on behalf of GSK or
its Affiliates or Sublicensees, Table 3 set forth in Section 5.6.1 (Milestone
Payments for First Achievement of Development Milestone Event) of the Agreement
is hereby deleted in its entirety and replaced with Table 3A below.

Table 3A
Development Milestone Events for the [***] Program
Milestone Payment 1st Indication
Milestone Payment 2nd Indication
 
[***]
$[***]
 ([***])
$[***]
[***]
$[***] ([***])
$[***]
[***]
$[***]
$[***]
[***]
 
$[***] ([***])
$[***]
[***]
$[***]
$[***]
[***]†
 
$[***]
$[***]
[***]†
 
$[***]
$[***]
[***]
 
$[***]
$[***]
[***]††
$[***]
$[***]
[***]††
$[***]
$[***]
[***]†††
$[***]
$[***]
[***]
$[***]
$[***]
Total Development Milestone Payments for the [***] Program
$[***]
$[***]

 
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†  In the unlikely event that the [***] with a [***] DC is achieved prior to the
[***] by [***], GSK will pay a total of $[***] at the time that the [***] with a
[***] DC is achieved, consisting of the $[***] milestone payment and the $[***]
with the [***] DC milestone payment.
†† For clarity with respect to this Milestone Event, "[***]" by the applicable
Regulatory Authority in [***] (or any other [***] such as [***] or the [***]) of
the equivalent of [***] in [***] (or any other [***] such as [***] or the [***])
will satisfy the requirements for achievement of this Development Milestone
Event.
††† For clarity with respect to this Milestone Event, "[***]" by the applicable
Regulatory Authority in [***] (or any other [***] such as [***] or the [***]) of
the equivalent of [***] in [***] (or any other [***] such as [***] or the [***])
will satisfy the requirements for achievement of this Development Milestone
Event.
Except as expressly set forth in Section 5.6.2 of the Agreement (as Section
5.6.2 of the Agreement relates to Compounds that are not [***] or the [***]),
each milestone set forth in Table 3A above will be paid only once for the [***]
Program upon the first achievement of the Milestone Event, regardless of the
number of Licensed Compounds, Follow-On Compounds or Licensed Products resulting
under the [***] Program.
For avoidance of doubt, except as expressly amended by this Amendment No. 5, the
terms and conditions of Section 5.6.2 of the Agreement continue to apply to the
[***] Program with respect to Compounds that are not [***] or the [***] DC.
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c.
Milestone Payments for First Achievement of Sales Milestone Event for [***] DC.
GSK will pay to Isis the applicable one-time milestone payments as set forth in
Table 4B below after a Licensed [***] Product first achieves the listed events
(as set forth in  Table 4B) as a result of sales by or on behalf of GSK, its
Affiliates or Sublicensees:

 
Table 4B
Sales Milestones for each Licensed [***] Product
Milestone Payment
$[***] in worldwide Annual Net Sales
 
$[***]
$[***] in worldwide Annual Net Sales
 
$[***]
$[***] in worldwide Annual Net Sales
 
$[***]
Total Sales Milestone Payments for the [***] DC Program
$[***]

 
9.
[***] DC Program Royalties.  Solely with respect to the Licensed [***] Products
sold by GSK, its Affiliates or Sublicensees, Table 5 set forth in Section 5.9.1
(GSK Patent Royalty) of the Agreement is deleted in its entirety and replaced
with Table 5B below:

Table 5B
Worldwide Annual Net Sales of each Licensed [***] Product
Royalty Rate
For the portion up to and including $[***]
 
[***]%
 
For the portion above $[***] and up to and including $[***]
 
[***]%
For the portion above $[***]
 
[***]%

10.
No Impact on Other Collaboration Programs. Except as otherwise expressly amended
by this Amendment No. 5, the Agreement (including Section 5.7.1 and Section
5.9.1 as it applies to Licensed Products under the [***] Program that are not
Licensed [***] Products) remains in full force and effect in accordance with its
terms. For the avoidance of doubt, this Amendment No. 5 is solely intended to
modify certain terms of the Agreement regarding the [***] Program, and does not
amend the Agreement in any way with respect to the other Collaboration Programs.

11.
Termination by Isis of Rights to [***] DC.   (a) If GSK, in Isis' reasonable
determination, fails to use Commercially Reasonable Efforts under Section 5(a)
of this Amendment No.5, Isis will notify GSK and within [***] ([***]) days
thereafter, Isis and GSK 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 GSK's use of Commercially Reasonable Efforts in
Section 5(a).  Following such a meeting, if GSK fails to use Commercially
Reasonable Efforts as contemplated by Section 5(a), then subject to Section
11(b) below, Isis will have the right, at its sole discretion, to terminate
GSK's rights under this Amendment No. 5 and the Agreement with respect to the
[***] DC and the other Research Leads.  In the case of such a termination, the
[***] DC and other Research Leads will be excluded from the [***] Program,
including GSK's Option and licenses to the [***] Program under Sections 3.1 and
Section 4.1 under the Agreement.

(b) This Section 11 and Section 12 below of this Amendment No. 5 set forth Isis'
sole and exclusive remedy for GSK's breach of its obligation to use Commercially
Reasonable Efforts under Section 5(a) of this Amendment No.5.
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12.
Special Consequences for Termination by Isis or Voluntary Termination  by GSK. 
In addition to the consequences set forth in Section 9.3.2 of the Agreement (as
applicable), in the event of (i) a termination of the Agreement either in its
entirety or with respect to the [***] Program by Isis pursuant to Section 9.2.2
or by GSK pursuant to Section 9.2.1, or (ii) a termination by Isis pursuant to
Section 11 above of this Amendment No.5, in each case ((i) and (ii)) prior to
GSK's exercise of its Option for the [***] Program by GSK or upon the
unexercised expiration of GSK's Option for the [***] Program and solely with
respect to the [***] DC:

a.
GSK will perform the obligations under Section 4.2.1 of the Agreement , as
though such obligations under Section 4.2.1 were obligations owed by GSK to
Isis, mutatis mutandis, with respect to the [***] DC, except for such
information as is already in Isis' possession at the date of termination;

b.
GSK will, at GSK's election and at its sole cost and expense, either (i)
complete any ongoing Clinical Study for the [***] DC or (ii) subject to
applicable law and regulatory consents, transfer sponsorship of any ongoing
Clinical Study for the [***] DC  to Isis together with the transfer of all of
the rights and responsibilities thereunder, except as described in Section 12(c)
below;

c.
If as part of terminating the [***] Program GSK terminates a Clinical Study for
a [***] DC due to safety reasons as confirmed by GSK's Global Product Safety
Board, then GSK cannot elect to complete such Clinical Study under Section
12(b)(i)  above but will: (i) take such action consistent with its internal
policies and applicable regulatory requirements to close out such Clinical Study
(including, without limitation, notification to the FDA and withdrawal of the
IND), and  (ii) provide to Isis all data and information contained within or
referenced in the IND and such other data and information within GSK's
possession or control generated under the [***] Program (except for such
information as is already in Isis' possession at the date of termination or as a
result of the technology transfer under Section 12.a. above), at GSK's sole cost
and expense. For clarity, in the circumstances described in this Section 12(c),
GSK will not be required to transfer the sponsorship of such terminated Clinical
Study pursuant to Section 12(b)(ii) above.

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d.
If GSK elects to transfer sponsorship to Isis under Section 12(b)(ii) above, the
Parties agree to, as soon as practicable following the date of such termination
or expiration according to this Section 12, negotiate in good faith a separate
agreement to effect such transfer consistent with industry standards under
similar circumstances and in accordance with each Party's respective internal
policies.

13.
Governing Law; Counterparts.  This Amendment No. 5 and any dispute arising from
the performance or breach hereof 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.  This Amendment No. 5 may be signed in
counterparts, each and every one of which will be deemed an original,
notwithstanding variations in format or file designation which may result from
the electronic transmission, storage and printing of copies of this Amendment
No. 5 from separate computers or printers.  Facsimile signatures and signatures
transmitted via PDF will be treated as original signatures.

14.
Definitions.  Capitalized terms used in this Amendment No. 5 will have the
meaning set forth in Appendix A attached hereto.

* - * - * - *
[Signature page follows]
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execution version    Exhibit 10.3

IN WITNESS WHEREOF, the Parties have caused this Amendment No. 5 to be executed
by their duly authorized representatives as of the Amendment No. 5 Effective
Date.
Isis Pharmaceuticals, Inc.
By: /s/ B. Lynne Parshall
Name: B. Lynne Parshall
Title: Chief Operating Officer
Date: __                             

 
Glaxo Group Limited
By: /s/ Paul Williamson  
Name: Paul Williamson   
Title: Authorised Signatory For and on behalf
Of Edinburgh Pharmaceutical Industries Limited
Corporate Director  
Date: __                             

                      
Glaxosmithkline intellectual property
development limited

By: /s/ Paul Williamson  
Name: Paul Williamson     
Title: Authorised Signatory For and on behalf
Of Edinburgh Pharmaceutical Industries Limited
Corporate Director    
Date: __                             
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execution version    Exhibit 10.3

Appendix A
Defined Terms
Capitalized terms used in this Amendment No. 5 but not otherwise defined herein
will have the meanings given in the Agreement. For purposes of this Amendment
No. 5, the following capitalized terms will have the following meanings:
a.
"CRO" has the meaning set forth in Section 4.b of this Amendment No. 5.

b.
"[***] DC Development Plan" means the Development plan attached to this
Amendment No. 5 as Appendix 1, which may be amended from time to time by the
JSC.

c.
"[***] DC" means the Compound designated as the [***] DC under Section 3.c. of
this Amendment No. 5.

d.
"[***] DC Selection Criteria" has the meaning set forth in Section 3.c of this
Amendment No. 5.

e.
[***]

f.
"[***] Option Deadline" has the meaning set forth in Section 7 of this Amendment
No. 5.

g.
"[***] PoC Trial Completion Package" has the meaning set forth in Section 7 of
this Amendment No. 5.

h.
"[***] Program" has the meaning set forth in the recitals of this Amendment No.
5.

i.
"[***]" means the compound known as [***] (which is ISIS [***]).

j.
"Licensed [***] Product" means a Licensed Product having the [***] DC as an
active ingredient.

k.
"Prioritized Lead" has the meaning set forth in Section 3.b of this Amendment
No. 5.

l.
"Prioritized Lead Studies" has the meaning set forth in Section 3.c of this
Amendment No. 5.

m.
 "Prioritized Lead Data Package" has the meaning set forth in Section 3.c of
this Amendment No. 5.

n.
 "Research Leads" has the meaning set forth in Section 1 of this Amendment No.
5.

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o.
"Research Lead Study" has the meaning set forth in Section 3.a. of this
Amendment No. 5.

p.
"Research Lead Data Package" has the meaning set forth in Section 3.b. of this
Amendment No. 5.

15

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execution version    Exhibit 10.3

Appendix 1
[***] DC Development Plan
[***]

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execution version    Exhibit 10.3

Appendix 2 
Isis' Development Candidate Criteria and Activities for [***] DC
[***]
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execution version    Exhibit 10.3

Appendix 3
Payment Schedule for [***] DC Development Activities Managed or Conducted by
Isis
[***]

18

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Appendix 4
Research Leads
[***]

19