AMENDMENT #1 TO COLLABORATION, LICENSE AND DEVELOPMENT AGREEMENT

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 [***].

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

ASOs that are designed to bind to the RNA that encodes the Amendment-Additional Collaboration Target, where such ASO is discovered by ▇▇▇▇ 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;

An Amendment-Additional Collaboration Target Compound that is determined by ▇▇▇▇’ 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;

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;

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;

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

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

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.

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.

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 ▇▇▇▇ to AstraZeneca under Section 3.5 for the Amendment-Additional Collaboration Target within 30 days after the Amendment Date;

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-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

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).

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.

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.

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

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.

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 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.

Isis Pharmaceuticals, Inc.

By: 

Name: 

Title:

Date:

AstraZeneca AB

By: 

Name: 

Title: 

Date: