Document:

Prepared by MERRILL CORPORATION

 

CONTRACT MANUFACTURING AGREEMENT

This CONTRACT

MANUFACTURING AGREEMENT (the “Agreement”) is entered into as of August 1, 2001

(the “Effective Date”), by and between ICOS Corporation (“ICOS”), a corporation

organized and existing under the laws of the State of Delaware and having its

principal place of business at 22021 20th Avenue S E, Bothell, WA

98021 USA and Seattle Genetics, Inc. (“SGI”), a corporation organized and

existing under the laws of the State of Delaware and having its principal place

of business at 22215 26th Avenue S.E., Suite 3000, Bothell, WA

98021.

RECITALS

WHEREAS, ICOS is in the

business of manufacturing and testing pharmaceutical products; and

WHEREAS, SGI is

the proprietor of a certain hybridoma that produce the monoclonal antibody chimeric

BR96 (cBR96) and other material described in Appendix B; and

WHEREAS, ICOS has

expertise in the development, evaluation and production of monoclonal

antibodies for therapeutic use using cell lines; and

WHEREAS, subject

to the terms and conditions set forth in this Agreement, SGI wishes to have

ICOS manufacture for SGI a pre-commercial pharmaceutical Product (hereinafter

defined); and

WHEREAS, subject to the

terms and conditions set forth in this Agreement, ICOS wishes to manufacture

Product for SGI.

NOW, THEREFORE, the

parties hereto, intending to be legally bound, hereby agree as follows:

1.               Definitions

For purposes of this

Agreement, the following terms will have the meanings set forth below:

1.1          “Affiliates” means, with

respect to any Person, another Person that, directly or indirectly, controls,

is controlled by or is under common control with such Person.  The term "control" means the

possession, directly or indirectly, of the power to direct or cause the

direction of the management and policies of a Person, whether through the

ownership of voting securities, by contract or otherwise.  The direct or indirect ownership of at least

fifty percent (50%) or, if smaller, the maximum allowed by applicable law, of the

voting securities of a business entity or of an interest in the assets, profits

or earnings of a Person shall be deemed to constitute "control" of

the Person.

 

1.2          “Applicable Laws” means all

ordinances, rules and regulations of any kind whatsoever of any governmental or

regulatory authority, including, without limitation, the FDCA, that are

applicable with respect to the context in which the term is used.

1.3          “Audit” means a review by SGI

or their appointed representatives (such representatives to be reasonably

acceptable to ICOS) of processes, procedures and documents of ICOS that are

used or maintained by ICOS to provide the Services.

1.4          “Calendar Quarter” means the

three-month period ending on March 31, June 30, September 30 or December

31.  The initial Calendar Quarter will

be deemed to begin on the Effective Date and end on the first to occur of March

31, June 30, September 30 or December 31 of such same year.

1.5          “Calendar Year” means the

twelve (12) month period ending on December 31.  The initial Calendar Year will be deemed to begin on the

Effective Date and end on December 31 of such same year.

1.6          “Cell Line” means a hybridoma

expressing cBR96 antibody as described in Appendix B, and will be used to

provide the Services herein.

1.7          “cGMP”

means Good Manufacturing Practices and General Biologics Products Standards as

promulgated under the US Federal Food Drug and Cosmetic Act at 21CFR (Chapters

210, 211, 600 and 610).

1.8          “Damages” means any and all

reasonable costs, losses, claims, actions, liabilities, fines, penalties, costs

and expenses, court costs, and reasonable fees and disbursements of counsel,

consultants and expert witnesses incurred by a party hereto (including interest

which may be imposed in connection therewith).

1.9          “FDA”

means the United States Food and Drug Administration, any comparable agency in

any Foreign Jurisdiction, and any successor agency or entity to any of the

foregoing that may be established hereafter.

1.10        “FDCA” means the Federal Food,

Drug and Cosmetic Act (21 U.S.C. § 301 et seq.).

1.11        “FAS” means the delivery term

Free Along Side, meaning that ICOS has fulfilled its obligation to deliver when

it has made the object of delivery available at its premises to SGI or SGI’s

agent (or to SGI’s carrier).  For the

avoidance of doubt, unless otherwise agreed in writing, ICOS is not responsible

for loading the object of delivery on to the vehicle provided by SGI or SGI’s

agent (or to ICOS's nominated carrier) or for any risk of loss during shipment.

1.12        “Foreign

Jurisdiction” means any jurisdiction, not governed by the United States or

any political subdivision thereof, as agreed upon by the parties.

1.13        “ICOS Know-How” means unpatented

and/or unpatentable technical information, including ideas, concepts,

inventions, discoveries, data, designs, formulas, specifications, procedures

for experiments and tests and other protocols, results of experimentation and

testing, fermentation and purification techniques, and assay protocols owned by

ICOS as of the Effective Date which may be necessary for the performance of the

Services.  All ICOS Know-How shall be

Confidential Information of ICOS.

1.14        “Manufacturing Specifications”

means the specifications for manufacturing the Product.  Prior to the initiation of the first cGMP

manufacturing run, an Appendix C-1 signed by both parties setting forth the

initial Manufacturing Specifications shall be appended to this Agreement and

shall contain at a minimum a collection of documents containing certain

specifications, procedures, assay methods (QC Release Tests), personnel contacts

and any other information as may be needed and agreed by the parties relating

to the manufacture of Product by ICOS for SGI. 

This Appendix C-1 shall also contain a statement to be agreed and

acknowledged by ICOS and SGI that SGI adopts the initial Manufacturing

Specifications as its own specification in conformance with Clause 6.7

herein.  Any changes or additions to the

Manufacturing Specifications shall be made by the written agreement of ICOS and

SGI.

1.15        “NDA” means New Drug Application

or any comparable application required by a Foreign Jurisdiction filed for the

Product by SGI with the FDA and all subsequent submissions, supplements or

amendments related thereto.

1.16        “Person”

means a natural person, a corporation, a partnership, a trust, a joint venture,

a limited liability company, any governmental authority or any other entity or

organization.

1.17        “Price” means the price specified

in Appendix E for the Services.

1.18        “Process” means the process for

the production of the Product from the Cell Line using the Manufacturing

Specifications, including any improvements thereto from time to time made as a

result of the Services.

1.19        “Product” means a  monoclonal antibody derived from the Cell

Line manufactured through ICOS's use of the Process.

1.20        “Product Specifications” means

the product specifications listed under the column "Acceptance

Criteria" as listed in Appendix C.

1.21        “Services” means all or any part

of the services to be provided by ICOS (or any permitted subcontractor) for the

benefit of SGI pursuant to this Agreement as further described in Appendix A.

1.22        “SGI-Patent Rights” means all

patents and patent applications of any kind throughout the world relating to

the Process which from time to time SGI is the owner of or is entitled to use.

1.23        “SGI Information” means all

confidential and proprietary technical information not in the public domain

relating to the Cell Line, the Process and the Product, from time to time

supplied by SGI to ICOS, or arranged by SGI to be supplied by a third party

(such as a prior manufacturer) to ICOS.

1.24        “SGI

Know-How” means all information relating to the Process known to SGI from

time to time other than confidential SGI Information and information in the

public domain.

1.25        “SGI

Materials” means the Materials supplied by SGI to ICOS (if any) and

identified as such by Appendix B hereto.

1.26        “SGI Technology” means all of

SGI’s Patent Rights,  SGI Know-How and

SGI Information necessary to manufacture the Product.

1.27        “SGI Tests” means the tests to be

carried out on the Product immediately following receipt of the Product by SGI,

particulars of which are set out in Appendix C.

1.28        “Terms of Payment” means the

terms of payment specified in Appendix E.

1.29        “Testing Laboratories” means any

third party instructed by ICOS to carry out tests on the Cell Line or the

Product.

1.30        “United States” means the fifty

(50) states, the District of Columbia and all of the territories of the United

States of America.

2.              Supply

by SGI

2.1          Prior

to or immediately following the Effective Date of this Agreement SGI shall

supply to ICOS SGI Information necessary for ICOS to perform the Services.  SGI shall also provide to ICOS on an ongoing

basis throughout the term of this Agreement full details of any hazards

relating to SGI Materials and Cell Line, including with respect to their

storage and use.  On review of this SGI

Information and details SGI Materials shall be provided to ICOS at ICOS's

request when ICOS has satisfactorily determined that SGI Materials do not pose

a hazard to ICOS.  SGI shall assist ICOS

in making such determination, but in no way be responsible for deciding the

safety of the SGI Materials to ICOS’s facilities.  All property rights in the SGI Information, SGI Technology and/or

SGI Materials supplied to ICOS shall remain vested in SGI.

2.2          SGI

hereby grants ICOS the non-exclusive right to use the SGI Materials, SGI

Information, SGI Know-How and SGI Technology for the sole purpose of providing

the Services.  ICOS hereby undertakes

not to use SGI Materials, SGI Information, SGI Know-how or SGI Technology (or

any part thereof) for any other purpose.

2.3          ICOS

shall:

2.3.1       at all

times use all reasonable efforts to keep the SGI Materials secure and safe from

loss or damage but in no case in a lesser manner than ICOS stores its own

material of similar nature;

2.3.2       not

transfer to a third party any part of the SGI Materials or the Product, except

for the purpose of any tests at the Testing Laboratories, provided, that, SGI

is given prior notification or if SGI has given prior written consent to such

transfer; and

2.3.3       provide

that such Testing Laboratories are subject to obligations of confidence

materially in the form of those obligations of confidence imposed on ICOS under

this Agreement.

2.4          SGI

warrants to ICOS that SGI is and shall at all times throughout the duration of

this Agreement remain entitled to supply the SGI Materials, SGI Information and

SGI Know-How to ICOS for the performance of the Services.

2.5           SGI

warrants that the use by ICOS of SGI Materials, SGI Information and SGI

Know-How for the Services will not infringe or is not alleged to infringe any

rights (including, without limitation, any intellectual or other proprietary

rights) vested in any third party.

2.6          SGI

shall indemnify, defend and hold harmless ICOS against any loss, damage, costs

and expenses of any nature (including court costs and legal fees incurred by

ICOS or ordered as payable by ICOS), whether or not foreseeable or in the

contemplation of ICOS or SGI, that ICOS may suffer as a result of any third

party claims, suits or actions arising out of or incidental to (a) any

breach of the warranties given in Clauses 2.4 and 2.5 above, (b) the

distribution or use of the Product, except to the extent such loss, damage,

costs and expenses are caused by ICOS's gross negligence or willful misconduct,

or (c) any claims by third parties alleging ICOS's use of the Cell Line,

SGI Materials, SGI Information, SGI Know-How, or the Manufacturing

Specifications infringes any rights (including, without limitation, any

intellectual or other proprietary rights) vested in any third party (whether or

not SGI knew or should have known about such alleged infringement) except to

the extent ICOS infringes any rights of any third parties by application of its

production techniques while performing the Services unless such application or

production technique has been developed as part of the Services.  For the purposes of Clauses 2.6 and 2.7, the

term, production technique(s), is limited to all and any physical arrangement

and use of plant and equipment in the provision of Services.

2.7          ICOS shall indemnify, defend and hold harmless SGI against

any loss, damage, costs and expenses of any nature (including court costs and

legal fees incurred by SGI or ordered as payable by SGI), whether or not

foreseeable or in the contemplation of SGI or ICOS, that SGI may suffer as a

result of any third party claims, suits or actions arising from ICOS’s

performance of the Services except to the extent the loss or damage is a result

of (a) SGI's negligence or willful misconduct or (b) ICOS's use of an

application or production technique that has been developed as part of the

Services for SGI or is supplied by SGI. 

For the avoidance of doubt where ICOS’s application or production

techniques, existed prior to the effective date of this Agreement, are not

developed as part of the Services hereto and whether or not included in the

Manufacturing Specifications, then they are covered by ICOS’s undertaking of

indemnity and hold harmless.

2.8          Notwithstanding

the above, ICOS shall be at liberty to use SGI Information as it sees fit in

providing the Services subject to nondisclosure pursuant to Section 7.

2.9          The

obligations of each party under this Section 2 shall survive the termination of

this Agreement for whatever reason.

3.             Provision of the Services

3.1          ICOS

shall diligently perform the Services as provided in Appendix A and shall use

all reasonable commercial efforts to achieve the estimated schedules,

specifications and amounts of Product.  Furthermore,

ICOS shall keep SGI regularly informed of any changes to the estimated

schedules for performance of the Services  and provide a monthly report, in a

form agreed by the parties.

3.2          With

respect to all services provided by ICOS from time to time that are agreed upon

by the Parties but are outside the scope of the Services ("Additional

Services"), SGI shall pay to ICOS [*]. 

ICOS will invoice SGI monthly for all Additional Services performed, with

each such invoice containing a reference to the services performed and the

personnel used.  All such invoices will

be payable under the terms described in Section 5.

[*] Confidential Treatment Requested

3.3          Due to

the unpredictable nature of the biological processes involved in the Services,

the schedules set down for the performance of the Services (including, without

limitation, the dates for production and delivery of Product) set out in

Appendix D are estimates only.

3.4          In the event that ICOS is unable to,

or notifies SGI, in writing, that it is unable, for any reason, except events

of Force Majeure where Clause 9.1 of this Agreement shall be applicable, to

supply one cGMP clinical production run of Product by [*]; and a second cGMP

clinical production run of Product by [*], SGI may at its discretion, seek to

manufacture or have manufactured by a third party designated by SGI that

quantity of the Products required by SGI that ICOS is unable to supply.  Provided however, that prior to manufacture

of Product by a third party, SGI and ICOS negotiate in good faith the supply of

undelivered Product by ICOS to SGI at a future date agreed upon by the

parties.  If the parties cannot agree on

a time period for delivery of Product and SGI determines to manufacture or have

manufactured by a third party such Products, ICOS will supply SGI and/or any

such third party all reasonably available information and data, and a

non-exclusive, royalty free license to all ICOS Know-How, if any, required to

manufacture the Product in accordance with the Manufacturing Specifications,

which license shall be for the sole purpose of permitting SGI or its designee

to manufacture the Product.

[*] Confidential Treatment Requested

3.5          Delivery

of Product shall be FAS ICOS's premises. 

Risk in and title to Product shall pass on delivery.  Transportation of Product, whether or not

under any arrangements made by ICOS on behalf of SGI, shall be made at the sole

risk and expense of SGI.  In the case

where SGI accepts ICOS Product tests (QC Release Tests) and shipment is to be

made to a third party, “delivery” for the purposes of risk in and title to

Product, shall occur upon the signed acceptance of ICOS Product tests(QC

Release Tests) by SGI but which shall occur no later than ICOS's delivery of

the Product FAS ICOS's premises.  Unless

otherwise agreed between the parties in writing, ICOS will tender delivery to

SGI upon completion of all QA and QC tests approximately six (6) to eight (8)

weeks following completion of manufacture.

3.6          Unless

otherwise agreed, ICOS shall package and label Product for FAS delivery in

accordance with its standard operating procedures.  It shall be the responsibility of SGI to provide prior written

notice to ICOS of any special packaging and labeling requirements for Product.  All additional costs and expenses (including

reasonable profit) of whatever nature incurred by ICOS in complying with such

special requirements shall be charged to SGI in addition to the Price.

3.7          Upon

completion of the Services, or as soon thereafter as can be mutually agreed,

ICOS will deliver to SGI a cell bank, generated by ICOS, comprised of the Cell

Line and used to provide the Services herein.

3.8          Joint

Communication on Manufacturing:  ICOS

and SGI shall communicate and cooperate on a regular basis during the provision

of Services herein and in the event that the parties observe the need for a

regular and active committee, such body shall be established and meet regularly

to discuss and communicate the progress of the Services.

3.9          As soon as practicable after execution of

this Agreement, the parties will develop and agree upon a Quality Understanding

document, the format and content of which is to be agreed upon by the parties

from time to time during the term of this Agreement.  The agreed upon Quality Understanding will be attached as

Appendix F to this Agreement.

4.             SGI

Tests and Return Procedures

4.1          Except

where SGI has accepted ICOS Product testsand provided written notice to ICOS of

such acceptance, promptly following delivery of Product, SGI shall carry out

SGI Tests.  If SGI Tests show that the

Product fails to meet Product Specifications due to ICOS failing to meet its

obligations hereunder, SGI shall give ICOS written notice thereof as soon as

practicable but in no case later than [*] days from the date SGI takes delivery

of the Product and shall return such Product to ICOS's premises for further

testing.  In the absence of such written

notice Product shall be deemed to have been accepted by SGI as meeting Product

Specifications.  If ICOS agrees that

Product returned to ICOS fails to meet Product Specifications, and such failure

is not due (in whole or in part) to acts or omissions of SGI or any third party

after delivery of such Product to SGI, ICOS shall at SGI's discretion replace

such Product at its own cost and expense. 

ICOS shall be entitled to consider its other obligations and its

commercial commitments to third parties in the timing of such replacement.  SGI acknowledges that there may, therefore,

be a delay in the timing of the replacement of such Product; provided, however,

that such delay shall not exceed [*] from date of return to ICOS.

[*] Confidential Treatment Requested

FOR THE AVOIDANCE

OF DOUBT, WHERE THE SPECIFICATION HAS NOT BEEN AGREED BY THE PARTIES HERETO

ICOS SHALL BE OBLIGED ONLY TO USE ITS REASONABLE ENDEAVOURS TO PRODUCE PRODUCT

THAT MEETS DRAFT PRODUCT SPECIFICATIONS.

4.2          If

there is any dispute concerning whether Product returned to ICOS fails to meet

Product Specifications or whether such failure is due (in whole or in part) to

acts or omissions of SGI or any third party after delivery of such Product to

SGI, such dispute shall be referred for decision to an independent expert

(acting as an expert and not as an arbitrator) to be appointed by agreement

between ICOS and SGI.

The costs of such

independent expert shall be borne by the parties equally; provided that the

party that is determined to be incorrect in the dispute shall be responsible

for all such costs and shall indemnify the correct party for its share of the

costs incurred.  The decision of such

independent expert shall be in writing and shall be binding on both ICOS and

SGI.

4.3          In the

event that the parties hereto agree that a shipment or batch of Product fails

to meet Product Specifications as a result of ICOS failing to meet its

obligations hereunder, the entire shipment or batch of Product that failed to

meet Product Specifications shall either be returned to ICOS or destroyed, at

ICOS’s option.

4.4          The

provisions of Clauses 4.1 and 4.2 shall be the sole remedies available to SGI

in respect of Product that fails to meet Product Specifications.

5.             Price

and Terms of Payment

5.1          SGI

shall pay the Price in accordance with the Terms of Payment all as specified in

Appendix E.

5.2          Unless

otherwise indicated in writing by ICOS, all prices and charges are exclusive of

State Sales Tax or of any other applicable taxes, levies, duties and fees of

whatever nature imposed by or under the authority of any government or public

authority, which shall be paid by SGI (other than taxes on ICOS's income).  All invoices are strictly net and payment

must be made within thirty (30) days of date of invoice.  Payment shall be made without deduction,

deferment, set-off, lien or counterclaim of any nature.

5.3          In

default of payment on due date interest shall accrue on a day to day basis with

effect from the date which is [*] after the due date for payment on any amount

overdue at the lower of [*] or the maximum rate allowable under Washington law.

[*] Confidential Treatment Requested

6.             Warranty

and Limitation of Liability

6.1          ICOS

warrants that:

6.1.1       the

Services shall be performed in accordance with Clause 3.1; and

6.1.2       the

Product shall meet Product Specifications, except where the Product

Specifications has not been agreed between the parties hereto in which case ICOS

shall be obliged only to use its reasonable commercial efforts to produce

Product that meets draft Product Specifications.

6.1.3       the

Product delivered to SGI pursuant to this Agreement shall conform to the

Product Specifications and that such Product shall (i) be free from defects in

material and workmanship, (ii) be manufactured in accordance with cGMP and

(iii) be manufactured in accordance with Appendix C hereof.

6.2          Clause

6.1 is in lieu of all conditions, warranties and statements in respect of the

Services and/or the Product whether expressed or implied by statute, custom of

the trade or otherwise (including but without limitation any such condition,

warranty or statement relating to the description or quality of the Product,

its fitness for a particular purpose or use under any conditions whether or not

known to ICOS) and any such condition, warranty or statement is hereby

excluded.  ICOS MAKES NO OTHER

WARRANTIES, EXPRESS OR IMPLIED, WITH RESPECT TO THE PRODUCT.  ALL OTHER WARRANTIES, EXPRESS OR IMPLIED,

INCLUDING WITHOUT LIMITATION, THE IMPLIED WARRANTIES OF MERCHANTABILITY AND

FITNESS FOR A PARTICULAR PURPOSE ARE HEREBY DISCLAIMED BY ICOS.  IN NO EVENT SHALL ICOS BE LIABLE FOR

INDIRECT, INCIDENTAL OR CONSEQUENTIAL DAMAGES.

6.3          Without

prejudice or modification to the terms of Clauses 6.1 and 6.2 the liability of

ICOS to SGI, its permitted assigns and successors in interest, for any loss

suffered by SGI or its permitted assigns and successors in interest, arising as

a direct result of a breach of this Agreement, or of any other liability,

including without limitation, misrepresentation and negligence (whether active,

passive or imputed), arising out of this Agreement and Services provided

thereunder, including without limitation the production and/or supply of the

Product, shall be limited to the payment of damages which shall not exceed in

US Dollars THE PRICE FOR SERVICES PAID BY SGI UNDER THE AGREEMENT; provided,

however, if and to the extent such damages are caused by ICOS's willful or

intentional breach of this Agreement or willful or intentional misconduct in

the performance of the Services, then the damage limitation in this Clause 6.3

shall not apply.

6.4          ICOS

shall in no event be liable for the following loss or damage howsoever caused

(even if foreseeable or in the contemplation of ICOS or SGI):

6.4.1       loss of

profits, business or revenue suffered by SGI or any other person who may be

subrogated to, or assigned rights in the loss or damage; or

6.4.2       special,

indirect or consequential loss, whether suffered by SGI or any other person.

6.5          SGI

shall indemnify, defend and hold harmless and maintain ICOS indemnified and

held harmless against all Damages in respect of:

6.5.1       any

product liability in respect of Product, except for ICOS's obligations to

indemnify in Clause 2.7 above; and

6.5.2       any

negligent (active, passive or imputed), gross negligence or intentional act or

omission of SGI in relation to the use, processing, storage or sale of the

Product.

6.6          SGI

represents and warrants that unless already expressly agreed in a written and

executed document immediately prior to the initiation of the first cGMP

manufacturing run, SGI will adopt the initial Manufacturing Specifications as

its own specification.  Any changes or

additions to the Manufacturing Specifications shall be made with the written

approval of SGI.

6.7          The

obligations of SGI under this Section 6 shall survive the termination for

whatever reason of this Agreement.

7.             Confidentiality

7.1          Each

party agrees to keep the other party's Confidential Information (as defined in

Clause 7.3) strictly confidential and to respect the other's proprietary rights

therein and not at any time for any reason whatsoever to disclose or use the

other party's Confidential Information for any purpose other than as expressly

provided herein.

7.2          SGI and

ICOS shall each ensure that all their respective employees, consultants and

contractors having access to confidential ICOS Know-How or confidential SGI

Information, SGI Know-How, SGI Materials, or SGI Technology shall be subject to

the same obligations of confidence as the principals pursuant to Clause 7.1 and

shall be subject to written confidentiality agreements in support of such

obligations.

7.3          For

purposes of this Agreement, "Confidential Information" means any business or technical information, trade

secrets, know-how, techniques, data or other information, disclosed by the

disclosing party to the receiving party in writing or that is disclosed orally

and confirmed in writing as confidential within forty-five (45) days following

such disclosure. The parties agree that SGI 's Confidential Information

includes, without limitation, the SGI Information, SGI Materials, SGI

Trade-Secrets and SGI Technology.  The

parties further agree that ICOS's Confidential Information includes, without

limitation, ICOS Know-How.

7.4          The

obligations of confidence referred to in this Section 7 shall not extend to any

Confidential Information that:

7.4.1       is or

becomes generally available to the public otherwise than by reason of a breach

by the recipient party of the provisions of this Section 7;

7.4.2       is

lawfully known to the recipient party prior to its receipt from the other;

7.4.3       is

subsequently disclosed to the recipient party without being made subject to an

obligation of confidence by a third party that does not have a prior obligation

of confidence to SGI or ICOS, as the case may be; or

7.4.4       which may

be required to be disclosed under any statutory, regulatory or similar

legislative requirement, subject to the imposition of obligations of

confidentiality to the extent allowed and provided further that each party

shall, unless prohibited by law, use reasonable efforts to notify the other

party of such compelled disclosure prior to such disclosure in order to seek

injunctive or any other relief provided in law or equity; or

7.4.5       is

independently developed by the recipient party without reliance on the

Confidential Information of the disclosing party as shown by its written

records.

7.5          SGI

acknowledges that:

7.5.1       ICOS

Know-How is vested in ICOS; and

7.5.2       Except as

provided herein, SGI shall not at any time have any right, title, license or

interest in or to ICOS Know-How or any other intellectual property rights

relating to the Process which are vested in ICOS or to which ICOS is otherwise

entitled.

7.6          ICOS

acknowledges that:

7.6.1       SGI

Information, SGI Materials, SGI Technology, SGI Know-How and SGI-Patent Rights

are vested in SGI; and

7.6.2       except as

provided herein ICOS shall not at any time have any right, title, license or

interest in or to SGI Technology or any other intellectual property rights

vested in SGI or to which SGI is entitled.

7.7          The

obligations of ICOS and SGI under this Section 7 shall survive the termination

of this Agreement for whatever reason.

8.             Termination

8.1          If, on

or before [*], it becomes apparent to ICOS that after using its commercially

reasonable efforts (or such higher standard as may be required under this

Agreement), it will be unable to meet the Product Specifications, ICOS may

immediately terminate this Agreement upon written notice to SGI (which written

notice will be delivered to SGI promptly upon ICOS determining that it will be

unable to meet the Product Specification, but in no event later than [*]).  Upon such termination, SGI shall pay to ICOS

a termination sum calculated by reference to all the Services performed by ICOS

(as demonstrated by signed timesheets in so far as they are applicable) and all

expenses reasonably incurred by ICOS in giving effect to such termination,

including the costs of terminating any commitments entered into under this

Agreement such termination sum not to exceed [*], and SGI shall have the right

to third party manufacture as set forth in Section 3.4 and 8.5.3.  Provided, however, that if the termination

sum is less than the amount of any advance payments made by SGI against the

performance of the Services a payment in sum equal to the residue of such

advance payments shall be made to SGI

[*] Confidential Treatment Requested

8.2          Except

as provided for in Section 8.1, if it becomes apparent to either ICOS or SGI at

any stage in the provision of the Services that it will not be possible to

complete the Services for scientific or technical reasons, a sixty (60) day

period shall be allowed for discussion to resolve such problems.

If such problems

are not resolved at the end of such sixty (60) day period, ICOS and SGI shall

each have the right to terminate this Agreement.  In the event of such termination, SGI shall pay to ICOS a

termination sum calculated by reference to all the Services performed by ICOS

prior to such termination (including a pro rata proportion (as demonstrated by

signed timesheets in so far as they are applicable) of the Price for any stage

of the Services which is in process at the date of termination) and all

expenses reasonably incurred by ICOS in giving effect to such termination,

including the costs of terminating any commitments entered into under this

Agreement, such termination sum not to exceed the Price. Provided however, that

if the termination sum is less than the amount of any advance payments made by

SGI against the performance of the Services a payment in sum equal to the

residue of such advance payments shall be made to SGI.

8.3          SGI

shall be entitled to terminate this Agreement at any time for any reason

by  [*] 

days' notice to ICOS in writing providing that the termination sum set

forth in Clause 8.3.1 or 8.3.2, as applicable, has been paid.

[*] Confidential Treatment Requested

In the event SGI

serves written notice to terminate this Agreement, which notice is expressly to

be given pursuant to this Clause 8.3, SGI shall:

8.3.1       pay to

ICOS a termination sum calculated by reference to all the Services performed by

ICOS prior to such termination (including a pro rata proportion (as demonstrated

by signed timesheets in so far as they are applicable) of the Price for any

stage of the Services which is in process at the date of termination) and all

expenses reasonably incurred by ICOS in giving effect to such termination,

including the costs of terminating any commitments entered into under this

Agreement such termination sum not to exceed the Price plus any changes.  Provided however, that if the termination

sum is less than the amount of any advance payments made by SGI against the

performance of the Services a payment in sum equal to the residue of such

advance payments shall be made to SGI; and

8.3.2       pay to

ICOS a sum equal to the full Price less all amounts already paid to ICOS for

the Services.

8.4          ICOS

and SGI may each terminate this Agreement by notice in writing to the other

upon the occurrence of any of the following events:

8.4.1       if the

other commits a breach of this Agreement which (in the case of a breach capable

of remedy) is not remedied within sixty (60) days of the receipt by the other

of written notice identifying the breach with specificity and requiring its

remedy; provided, however, if the breach is as a result of nonpayment of any

amounts owing, the breaching party must remedy the breach within [*] days after

receiving such written notice; or

[*] Confidential Treatment Requested

8.4.2       if the

other ceases for any reason to carry on business or convenes a meeting of its

creditors or has a receiver or manager appointed in respect of all or any part

of its assets or is the subject of an application for an administration order

or of any proposal for a voluntary arrangement or enters into liquidation

(whether compulsorily or voluntarily) or undergoes any analogous act or

proceedings under foreign law; provided, however, either party may merge with

or into another equity pursuant to which the obligations of this Agreement will

be assumed or effect the sale of all its assets or substantially all of its

assets pursuant to which the acquiring party will assume such party’s obligations

under this Agreement without notice to or waiver by the other party.

8.5          Upon

the termination of this Agreement for whatever reason:

8.5.1       ICOS shall

promptly return all SGI Information to SGI and shall dispose of or return to

SGI, SGI Materials and any materials therefrom, as directed by SGI;

8.5.2       SGI shall

promptly return to ICOS all ICOS Know-How it has received from ICOS;

8.5.3       SGI shall not thereafter use or exploit the ICOS Know-How in

any way whatsoever for production by SGI, or production by a third-party.  If SGI determines to manufacture or have manufactured by a third

party such Products, ICOS will give SGI and/or any such Third Party all

reasonably necessary information and cooperation, and a non-exclusive, royalty free license to all

ICOS Know-How, if any, required to manufacture the Product

in accordance with the Manufacturing Specifications, for the sole purpose of enabling SGI

or such third party to manufacture the Products in connection with the

Manufacturing Specifications.

8.5.4       ICOS may

thereafter use or exploit the ICOS Know-How in any way whatsoever without

restriction; and

8.5.5       ICOS and

SGI shall do all such acts and things and shall sign and execute all such deeds

and documents as the other may reasonably require to evidence compliance with

this Clause 8.5.

8.6          Termination

of this Agreement for whatever reason shall not affect the accrued rights of

either ICOS or SGI arising under or out of this Agreement and Sections 2, 6, 7,

and 8 and any definitions in Section 1 required to interpret such surviving

provisions, and all provisions which are expressly to survive this Agreement or

have a continuing obligation shall remain in full force and effect.

9.             Force

Majeure

Neither ICOS nor

SGI shall be deemed to be in default nor be liable for loss, damage, or delay

in performance, when and to the extent due to causes beyond its reasonable

control or from fire, strike, labor difficulties, insurrection or riot,

embargo, or inability to obtain materials from usual sources, or any other

unforeseeable cause or causes beyond the reasonable control and without the

fault or negligence of the party so affected, or from defects or delays in the

performance of its suppliers or subcontractors due to any of the foregoing

enumerated causes.  If ICOS is prevented

or delayed in the performance of any of its obligations under this Agreement by

Force Majeure and shall give written notice thereof to SGI specifying the

matters constituting Force Majeure together with such evidence as ICOS

reasonably can give and specifying the period for which it is estimated that

such prevention or delay will continue, ICOS shall be excused from the

performance or the punctual performance of such obligations as the case may be

from the date of such notice for so long as such cause of prevention or delay

shall continue, provided that within [*] from the date of such notice, ICOS

shall provide SGI with written notice of the anticipated date of resumption of

performance.  In the event that the anticipated

date of such resumption is greater than [*] months from the date of the

original notice, SGI may invoke the remedy of third party manufacture provided

in Clause 3.3 herein or terminate this Agreement.

[*] Confidential Treatment Requested

10.           Governing

Law, Jurisdiction and Enforceability

10.1        This

Agreement shall be governed and interpreted, and all rights and obligations of

the parties shall be determined, in accordance with the laws of the State of

Washington and the United States of Americawithout regards to principles of conflicts

of law.

10.2        No

failure or delay on the part of either ICOS or SGI to exercise or enforce any

rights conferred on it by this Agreement shall be construed or operate as a

waiver thereof nor shall any single or partial exercise of any right, power or

privilege or further exercise thereof operate so as to bar the exercise or

enforcement thereof at any time or times thereafter  of any other right.

10.3        The illegality or invalidity of any

provision (or any part thereof) of this Agreement shall not affect the legality,

validity or enforceability of the remainder of its provisions or the other

parts of such provision as the case may be and this Agreement shall continue in

full force and effect without such provision.

 

11.          Miscellaneous

11.1        Neither party shall be entitled to

assign, or in any way transfer the benefit and/or the duties of this Agreement

without the prior written consent of the other which consent shall not be

unreasonably withheld or delayed, except that either party shall be entitled

without the prior written consent of the other to assign transfer, charge,

subcontract, deal with or in any other manner make over the benefit and/or

burden of this Agreement to an Affiliate, or to any limited liability partner

or to any [*] company of which the party in question is the beneficial owner of  [*]

of the issued share capital thereof or to any company with which the party in

question may merge or to any company to which that party may transfer its

assets and undertakings.

[*] Confidential Treatment Requested

11.2        The text of any press release or other

communication to be published by or in the media concerning the subject matter

of this Agreement shall require the prior written approval of ICOS and SGI.

11.3        Notices.  All notices, requests, demands, waivers,

consents, approval or other communications to any party hereunder shall be in

writing and shall be deemed to have been duly given if delivered personally to

such party or sent to such party by recorded electronic transmission

(facsimile) or by registered or certified mail, postage prepaid, to its address

as shown below:

 

	

   

  	

  SGI:

  	

  Seattle Genetics, Inc.

  
	

   

  	

   

  	

  22215 26th Avenue S.E., Suite 3000

  
	

   

  	

   

  	

  Bothell, WA 

  98021

  
	

   

  	

   

  	

  Attention: 

  H. Perry Fell

  
	

   

  	

   

  	

   

  
	

   

  	

  ICOS:

  	

  ICOS

  Corporation

  
	

   

  	

   

  	

  22021

  20th Avenue S.E.

  
	

   

  	

   

  	

  Bothell,

  WA  98021

  
	

   

  	

   

  	

  Attention: 

  Legal Department

  

 

or to such other address as the addressee may have

specified in a notice duly given to the sender as provided herein.  Such notice, request, demand, waiver,

consent, approval or other communications will be deemed to have been given as

of the date so delivered, telegraphed, telexed, or five (5) days after so

mailed.

11.4        Independent Contractor.  Each party shall be and shall act as the

independent contractor of the other party. 

Neither party shall be the legal agent of the other for any purpose

whatsoever and therefore has no right or authority to make or underwrite any

promise, warranty or representation, to execute any contract or otherwise to

assume any obligation or responsibility in the name of or on behalf of the

other party, except to the extent specifically authorized in writing by the

other party.  Neither of the parties

hereto shall be bound by or liable to any third persons for any act or for any

obligation or debt incurred by the other toward such third party, except to the

extent specifically agreed to in writing by the party so to be bound.

11.5        Headings.  All section headings and numbering contained

in this Agreement are for convenience of reference only, do not form a part of

this Agreement and shall not affect in any way the meaning or interpretation of

this Agreement.

11.6        Entire Agreement.  The Agreement, and the attached appendixes,

embodies the entire understanding of ICOS and SGI and there are no promises,

terms, conditions or obligations, oral or written, expressed on implied, other

than those contained in this Agreement, and the attached appendixes.  The terms of this Agreement shall supersede

all previous agreements (if any) which may exist or have existed between ICOS

and SGI relating to the Services.

11.7        Modifications.  Any and all modifications or amendments to

this Agreement, or any Appendix hereto, shall be binding only if made in

writing and signed by both parties.

11.8        Counterparts.  This Agreement may be executed

simultaneously in any number of counterparts, each of which shall be deemed an

original and all of which together shall constitute one in the same agreement.

IN WITNESS WHEREOF,

the parties hereto have executed this Agreement as of the date first above

written.

 

	

  ICOS

  CORPORATION

  	

   

  	

  SEATTLE GENETICS, INC.

  
	

   

  	

   

  	

   

  
	

  By:  /s/Gary

  Wilcox

  	

   

  	

  By:  /s/H.

  Perry Fell

  
	

   

  	

   

  	

   

  
	

  Name:  Gary

  Wilcox

  	

   

  	

  Name:  H.

  Perry Fell

  
	

   

  	

   

  	

   

  
	

  Title:  EVP,

  Operations

  	

   

  	

  Title: 

  C.E.O.

  

APPENDIX A

Scope of Services

 

 

Assumptions

 

1.       ICOS will make a go-no go decision on [*] with regard to the

ability to meet agreed upon Product Specifications.

[*] Confidential Treatment Requested

2.       Seattle Genetics will provide the raw materials, protocols,

and data as described in Appendix B.

3.       ICOS will transfer the Seattle Genetics cell culture process

as-is and only make modifications as necessary to facilitate process transfer

to the ICOS Manufacturing facility.

4.       ICOS will use historical process data provided by Seattle

Genetics to guide development of the BR96 purification process.

5.       At least [*] at-scale development lot and [*] cGMP clinical

lots will be manufactured that are suitable for regulatory filings and human

clinical trials.

[*] Confidential Treatment Requested

6.       ICOS will provide documentation summarizing development and manufacturing

activities that are sufficient to support the generation of CMC sections

necessary for IND filings for Phase II/III material.

7.       The costs listed for process development,

the development runs, and cGMP lots do not include the purchase of chromatography

resins, special or non-standard cell culture media components, or storage.  ICOS reserves the right to invoice Seattle

Genetics for these costs, including (but not limited to):

-        Basal media (e.g. HSFM, CD Hybridoma,

eRDF)

-        Yeastolate

-        Defined lipids

-        Storage of liquid media

-        Chromatography resins

 

1.      Development

 

Objectives

•      Transfer the cell culture process, purification

process, and product specific analytical methods from Seattle Genetics to ICOS

•      Evaluate the

cell culture and purification process at bench-scale.

•      Adapt the

process in order to make the process suitable for transfer and scale-up in the

ICOS Manufacturing Plant

 

1.1.    Cell Culture Process Development

1.1.1.       Transfer raw materials and protocols from

Seattle Genetics to ICOS

•      Transfer of

process documentation from Seattle Genetics to ICOS Corporation

-        Data on mycoplasma and sterility tests

for the cell bank

-        Process protocols and in-process

specifications (media preparation, thaw, expansion, production, and harvest)

-        Raw material specifications (including

vendors and catalog numbers)

-        Historical process data (e.g. bioreactor

data, cell-line stability)

•      Transfer a

sufficient quantity of material to support experiments until such time that

materials can be ordered and received by ICOS

•      Transfer [*]

vials each of [*] BR96 cell lines

[*] Confidential Treatment Requested

 

1.1.2.       Preparation of prebanks

•      Prepare

prebanks of the primary and back-up cell line; store in two places

•      Test the

primary cell line pre-bank: mycoplasma, sterility, in vitro viral, MVM

•      Transfer the

primary cell line pre-bank to cGMP liquid nitrogen storage

1.1.3.       Order raw materials

1.1.4.       Evaluation of expansion media

•      Evaluate

growth of cells in HSFM (Bovine Transferrin) and CD Hybridoma.

•      On basis of

growth, productivity, regulatory impact of components in medium, and cost,

Seattle Genetics and ICOS will make a joint decision on an expansion medium.

1.1.5.       Establish expansion process

•      Define cell

growth rates and viability in chosen medium

•      Establish

upper and lower cell density limits

•      Establish

expansion process through a  [*]  spinner

•      Demonstrate

that the expansion process through a 

[*]  spinner is reproducible.

[*] Confidential Treatment Requested

 

1.1.6.       Establish a baseline production process

in bioreactors

•      Generate a

preliminary process development protocol incorporating changes to the Seattle

Genetics process such that the process is suitable for the ICOS process

development lab.

•      Evaluate

production process in  [*] bioreactor with automated DO, pH and temperature control.

•      Assess

suitability of the process for scale-up in the ICOS Manufacturing Plant.

•      Evaluate feed

media (preliminary work in shake flasks.)

•      Verification

of reproducibility of the process: at least [*] consecutive bioreactor runs

that both ICOS and Seattle Genetics agree are reasonably consistent with

respect to the cell growth profile, process chemistries and product titers.

[*] Confidential Treatment Requested

 

1.1.7.       Harvest material provided for

purification process development

1.1.8.       Modifications made to the cell culture

process as needed in order to optimize the process and make it suitable for

transfer to the ICOS Manufacturing Plant. 

Possible modifications may include, but are not limited to:

•      process parameter

setpoints (e.g. DO, pH, agitation)

•      methods of DO

and pH control

•      change of the

feed schedules

•      substitution

of vendors and/or raw materials

1.1.9.       Generate process description suitable for

use in preparation of Manufacturing Batch Records

1.1.10.     Genetic characterization of EOP and MCB

cells following cGMP production runs to confirm genetic stability (assuming

that methods are relatively simple to implement at ICOS as determined by ICOS).

•      Southern

blots

•      Sequencing of

antibody-encoding bulk RT-PCR

1.1.11.     Prepare report describing key experimental

results generated during the establishment of the cell culture production

process at ICOS

1.2.    Purification process development

1.2.1.       Harvest hold time stability

•      Assess

harvest fluid stability.  Testing to

include, titer (by Protein A), SDS-PAGE and HPLC-SEC.

•      Target

maximum harvest hold time in production to be five days.

1.2.2.       Protein A chromatography (ProSep A).

•      Evaluate

standard load and wash procedures.

•      Determine

resins capacity

•      Evaluate low

pH.  Evaluate salt concentration as

needed to minimize aggregation and precipitation.

1.2.3.       Protein A eluate stability.

•      Determine

stability against aggregation with respect to pH (3.0-4.0) and time (0-3 h) and

concentration.

•      Define pH

inactivation protocol with the above data. 

Target pH range of < 3.7 to get robust viral clearance.

1.2.4.       Ion exchange chromatography.

•      Determine

antibody pI.

•      Evaluate

relative retention Ion-Exchange resins (S-Sepharose, and DEAE-Sepharose for

example) as a function of pH and NaCI concentration.  For example, S-Sepharose from pH 5-7 and DEAE Sepharose from pH

7-8.5.

•      Optimize

binding and elution conditions.

•      Determine

resin capacity

1.2.5.       Hydrophobic interaction chromatography

(Phenyl Sepharose)

•      Evaluate capacity

and retention as a function of ammonium sulfate concentration.

•      Optimize

elution conditions for aggregate removal.

1.2.6.       Evaluate stability for all in-process

eluate hold times with respect to time, temperature and concentration.  Testing to include HPLC-SEC, SDS-PAGE and

concentration (A280)

1.2.7.       Develop UF concentration/buffer exchange.

1.2.8.       Evaluate viral removal filter for product

passage.

1.2.9.       Purification process qualification

(verify reproducibility).

•      Demonstrate

process reproducibility by purifying cell culture process development batches

•      Monitor

process performance with respect to yield, product purity, and quality.  SEC and SDS PAGE will be used to monitor

process eluates.  Yield will be

determined by absorbance measurements on process eluates.

1.2.10.     Analytical characterization of the antibody

as described in Section 4.

1.2.11.     Generate process description and report on

Purification Development.

1.2.12.     Evaluate process for viral inactivation

using one virus.

1.3.    Formulation Process Development

1.3.1.       Evaluate the current buffer provided by

Seattle Genetics in a -70°C freeze-thaw cycle study

1.3.2.       Evaluate the current buffer provided by

Seattle Genetics in an accelerated stability study at one temperature for two

weeks

1.3.3.       If necessary, evaluate two additional

buffers in a freeze-thaw study to identify a back-up

1.3.4.       Evaluate antibody using HPLC-SEC,

SDS-PAGE and concentration (A280).

1.3.5.       Generate report on the results of the

study

1.4     Analytical and Quality Control

1.4.1.          Transfer raw materials, protocols, and

data from Seattle Genetics to ICOS

•      Binding

assay

•      Transferrin

assay (if necessary)

•      Murine

Heavy Chain ELISA

•      Seattle

Genetics and S2.14.19 reference standard

1.4.2.          Qualify standard test methods for

process and product characterization with the BR96 Antibody and modify if

necessary.

 

2.             Process

Transfer and Scale-Up

 

Objectives

•      Manufacture

Master Cell Bank

•      Transfer the

cell culture process and antibody purification process into  Manufacturing Plant.

•      Evaluate

process parameters at intermediate and production scale to confirm they are

comparable to results generated in the bench-scale process.

•      Perform

analytical tests on in-process samples and drug substance to confirm that the

production process has been successfully scaled up.

 

2.1.    Intermediate Scale Development Run

2.1.1.       Evaluate the cell culture process:

•      Perform at

least one bioreactor run at an intermediate scale.

•      Assess

process performance in terms of specific growth rate, maximum cell density,

process chemistries, and antibody expression.

•      Compare

results obtained in the intermediate scale bioreactor to those generated at the

15L scale to determine whether scale-up of the process was successful.

2.1.2.       Evaluate the harvest process:

•      Harvest of

cell culture fluid generated in the previous step.

•      Characterize

the harvest fluid for antibody titer and other tests as specified in Section 4.

•      Determine

filter capacity required for production scale bioreactor.

2.1.3.       Evaluate the purification process:

•      Purify

product from the harvest fluid

•      Analyze

in-process samples and the end product

•      Compare data

obtained at the intermediate scale to those obtained in process development

 

2.2.    Production Scale Development Run

2.2.1.       Evaluate cell culture process at

production scale:

•      Perform at

least [*] bioreactor run

[*] Confidential Treatment Requested

 

•      Assess

process performance in terms of specific growth rate, maximum cell density,

process chemistries and antibody expression.

•      Compare

results obtained in the at-scale bioreactor to those generated at the

intermediate scale to determine whether scale-up of the process was successful.

2.2.2.       Evaluate the harvest process at-scale:

•      Harvest of

cell culture fluid generated in the previous step.

•      Characterize

the harvest fluid for antibody titer.

2.2.3.       Evaluate the purification process

at-scale:

•      Purify

product from the harvest fluid

•      Analyze

in-process samples

•      Comparison of

data obtained at the at-scale to those obtained in the intermediate scale to

determine whether scale-up of the process was successful.

2.2.4.       Evaluations will be performed using draft

MBRs, SOPS, and TMs

2.2.5.       The process intermediates and drug

substance will be tested by the methods listed in Section 4 to demonstrate the

process has been successfully transferred and to characterize the product for

regulatory submissions.

2.2.6.       Raw materials will be released following

ICOS Raw Material Quality Assurance procedures.

2.2.7.       Data obtained in the production scale run

will be reviewed to asses the suitability of the process for clinical

manufacturing, and to make modifications to the process, if necessary, for

preparation of the final drafts of the master documents

2.2.8.       An interim reference standard will be

made from production scale development run. 

This standard will be qualified and used as the reference standard for

release testing of the clinical GMP lots

 

3.      Clinical Manufacturing

 

Objectives

•      Perform

clinical production runs.

•      Perform

in-process and drug substance testing to confirm that the process is in control

and that the product from each lot meets pre-defined standards

 

3.1.    All clinical (cGMP) operations will be

performed according to the Quality Understanding.

3.2.    A [*] (approximate) Master Cell Bank (MCB)

will be created from a pre-bank vial that is released for manufacturing

use.  The MCB will be tested according

to ICH guidelines.  Vials from the bank

will be stored in two locations.

[*] Confidential Treatment Requested

 

3.3.    Following the MBR which was finalized in

Section 2.2, manufacture and purify [*] lots of bulk drug substance.

[*] Confidential Treatment Requested

3.4.    Manufacturing processes and testing will be

performed according to approved, written procedures.  Master documents will be reviewed and approved by ICOS and

Seattle Genetics according to the Quality understanding.

3.5.    Every effort should be made to store the

harvest fluid for as minimal a time as possible.  Ideally, the storage period will be at [*] for a target period of

[*] days.

[*] Confidential Treatment Requested

 

3.6.    Solutions, process intermediates, and

formulated bulk product (Drug Substance) will be stored in controlled access

locations under appropriate conditions as specified in the Material

Specifications.

3.7.    Each lot of Drug Substance will be tested by

the methods described in Section 4 and as specified in the Material

Specification.

3.8.    Batch Disposition will be performed

according to the Quality Understanding.

3.8.1.       ICOS QA will review all MBRs and QC Data

Sheets for completeness and accuracy.

3.8.2.       ICOS QA will verify that materials used

in the production process were released within expiration.

3.8.3.       Deviations from ICOS procedures, MBRs, or

Materials Specifications will be recorded and justified.  Product impact will be assessed for all

deviations and non-conforming materials.

3.8.4.       ICOS will issue a Certificate of Analysis

that includes all ICOS release testing results and a notice of disposition from

ICOS Quality Assurance.

 

4.      Test Methods

 

The test methods in the

table below will be performed at the indicated process stages.  The development or performance of any other

assays is out-of-scope work.

 

	

   

  	

   

  	

  Process Development/Transfer

  	

   

  	

  Production Scale (Development and

  Clinical)

  	

   

  
	

  Method

  	

   

  	

  Process Characterization

  	

   

  	

  Product Characterization

  	

   

  	

  Cell Culture 

  In-Process

  	

   

  	

  Purification 

  In-Process

  	

   

  	

  Drug 

  Substance

  	

   

  
	

  Mycoplasma1

  	

   

  	

   

  	

   

  	

   

  	

   

  	

  ü(EOP)3

  	

   

  	

   

  	

   

  	

   

  	

   

  
	

  Sterility1

  	

   

  	

   

  	

   

  	

   

  	

   

  	

  ü(EOP)3

  	

   

  	

   

  	

   

  	

   

  	

   

  
	

  MMV1

  	

   

  	

   

  	

   

  	

   

  	

   

  	

  ü(EOP)3

  	

   

  	

   

  	

   

  	

   

  	

   

  
	

  In-vitro Viral1

  	

   

  	

   

  	

   

  	

   

  	

   

  	

  ü(EOP)3

  	

   

  	

   

  	

   

  	

   

  	

   

  
	

  BR96 Titer

  (Protein A)

  	

   

  	

  ü

  	

   

  	

   

  	

   

  	

  ü(Harvest)

  	

   

  	

   

  	

   

  	

   

  	

   

  
	

  Bioburden

  	

   

  	

  ü

  	

   

  	

   

  	

   

  	

  ü(Harvest)

  	

   

  	

   

  	

   

  	

  ü

  	

   

  
	

  Endotoxin

  	

   

  	

  ü

  	

   

  	

   

  	

   

  	

  ü(Harvest)

  	

   

  	

  ü

  	

   

  	

  ü

  	

   

  
	

  BR96

  concentration (A280)

  	

   

  	

  ü

  	

   

  	

   

  	

   

  	

   

  	

   

  	

  ü

  	

   

  	

  ü

  	

   

  
	

  Size Exclusion

  HPLC

  	

   

  	

  ü

  	

   

  	

  ü

  	

   

  	

   

  	

   

  	

  ü

  	

   

  	

  ü

  	

   

  
	

  SDS-PAGE,

  unreduced

  	

   

  	

  ü

  	

   

  	

  ü

  	

   

  	

   

  	

   

  	

  ü

  	

   

  	

  ü

  	

   

  
	

  SDS-PAGE,

  reduced

  	

   

  	

  ü

  	

   

  	

  ü

  	

   

  	

   

  	

   

  	

  ü

  	

   

  	

  ü

  	

   

  
	

  Isoelectric

  Focusing

  	

   

  	

   

  	

   

  	

  ü

  	

   

  	

   

  	

   

  	

   

  	

   

  	

  ü

  	

   

  
	

  MALDI-MS

  	

   

  	

   

  	

   

  	

  ü

  	

   

  	

   

  	

   

  	

   

  	

   

  	

   

  	

   

  
	

  Silver stain,

  unreduced

  	

   

  	

   

  	

   

  	

  ü

  	

   

  	

   

  	

   

  	

   

  	

   

  	

  ü

  	

   

  
	

  Silver stain,

  reduced

  	

   

  	

   

  	

   

  	

  ü

  	

   

  	

   

  	

   

  	

   

  	

   

  	

  ü

  	

   

  
	

  Appearance

  	

   

  	

   

  	

   

  	

   

  	

   

  	

   

  	

   

  	

   

  	

   

  	

  ü

  	

   

  
	

  Osmolality

  	

   

  	

   

  	

   

  	

   

  	

   

  	

   

  	

   

  	

   

  	

   

  	

  ü

  	

   

  
	

  PH

  	

   

  	

   

  	

   

  	

   

  	

   

  	

   

  	

   

  	

   

  	

   

  	

  ü

  	

   

  
	

  Insulin

  	

   

  	

   

  	

   

  	

  ü

  	

   

  	

   

  	

   

  	

   

  	

   

  	

  ü

  	

   

  
	

  Residual Protein

  A EIA

  	

   

  	

   

  	

   

  	

  ü

  	

   

  	

   

  	

   

  	

   

  	

   

  	

  ü

  	

   

  
	

  Residual Host

  Cell DNA Content

  	

   

  	

   

  	

   

  	

  ü

  	

   

  	

   

  	

   

  	

   

  	

   

  	

  ü

  	

   

  
	

  Binding assay2

  	

   

  	

   

  	

   

  	

  ü

  	

   

  	

   

  	

   

  	

   

  	

   

  	

  ü

  	

   

  
	

  Bovine

  transferrin 2,4

  	

   

  	

   

  	

   

  	

  ü

  	

   

  	

   

  	

   

  	

   

  	

   

  	

  ü

  	

   

  
	

  Murine IgG heavy

  chain2

  	

   

  	

   

  	

   

  	

  ü

  	

   

  	

   

  	

   

  	

   

  	

   

  	

  ü

  	

   

  
													

 

1Contracted

to an outside vendor

2Protocol

and necessary reagents to be transferred from Seattle Genetics to ICOS

3Clinical

lots only

4This

test may be omitted if bovine transferrin is not in the process

 

5.      Deliverables

 

The following items will

be delivered from ICOS Corporation to Seattle Genetics

 

5.1.    Samples from various development stages for

sample retention and comparability studies. 

Sample requests must be made in writing at least [*] in advance of the

execution of the process step.

[*] Confidential Treatment Requested

5.2.    [*] lots of bulk drug substance manufactured

from [*] clinical productions runs in the ICOS [*] bioreactor.

[*] Confidential Treatment Requested

5.3.    ICOS will issue a Certificate of Analysis

that includes all ICOS release testing results and a notice of disposition from

ICOS Quality Assurance

5.4.    Documentation as described in the Quality

Agreement

5.5.    The pre-bank and Master Cell Bank1

5.6.    Summary reports and data describing the work

completed in Sections 1, 2, and 3.

5.7.    Qualified Interim Reference Standard

 

1If desired,

ICOS will retain a umber of vials in the event that at some future date Seattle

Genetics would like to request additional clinical production runs

APPENDIX B

Materials to be Transferred

 

1.      Cell

Culture

 

1.1.    [*] vials of the primary and back-up cell

line which produce the BR96 antibody

[*] Confidential Treatment Requested

1.2.    List of raw materials and specifications

(e.g. vendor, catalog number)

1.3.    Process protocols (e.g. media formulations,

thaw and expansion protocol, final production tank protocol)

1.4.    Historical process data (e.g. thaw and

expansion data, in-process data from final production tank)

1.5.    Cell-line stability data (as it becomes

available)

 

2.      Purification

 

2.1.    List of raw materials and specifications

(e.g. resin identification, column loads)

2.2.    Process Protocols for the current

purification process (e.g. buffer recipes, cleaning protocols)

2.3.    Historical process data (e.g. yields,

reproducibility, clearance of contaminants, product aggregate)

2.4.    Data on product stability, especially at

intermediate hold points

2.5.    Reference Antibody1 for assay

development and comparability studies

 

3.      Quality

Control

 

3.1.    Reagents and protocols for the

antigen/antibody binding assay

3.2.    Reagents and protocols for Murine IgG Heavy

Chain Assay

3.3.    Reagents and protocols for a bovine

transferrin assay- if transferrin is used in the cell culture media.

3.4.    Reference Antibody1 for assay

development and comparability studies

 

4.      Formulation

 

4.1     List of raw materials and specifications

for the final antibody formulation

4.2     Historical stability data (e.g. freeze/thaw

data, stability data)

4.3     Reference Antibody1 for

comparability studies

 

1Reference

Antibody should be derived from the same cell line and process being

transferred to ICOS.

 

APPENDIX C

Acceptance Criteria / Internal

Release Specs – Drug Substance

"Product Specifications"

 

Unless otherwise stated, ICOS test methods will be

used.

 

	

   

  	

   

  	

   

  	

   

  	

   

  
	

   

  	

   

  	

  Test

  	

   

  	

  Acceptance

  Criteria ("Product Specifications")

  
	

  Quality

  	

   

  	

  Appearance (color and clarity)

  	

   

  	

  Colorless, clear to slightly opalescent

  
	

   

  	

   

  	

  Appearance (particulates)

  	

   

  	

  Report

  
	

   

  	

   

  	

   

  	

   

  	

   

  
	

  Identity

  	

   

  	

  IEF

  	

   

  	

  pI range consistent with reference

  
	

   

  	

   

  	

  SEC HPLC

  	

   

  	

  Main peak retention time consistent with reference

  
	

   

  	

   

  	

  SDS-PAGE (unreduced, Coomassie)

  	

   

  	

  IgG band molecular weights consistent with reference

  
	

   

  	

   

  	

  SDS-PAGE (reduced, Coomassie)

  	

   

  	

  IgG band molecular weights consistent with reference

  
	

   

  	

   

  	

   

  	

   

  	

   

  
	

  Purity

  	

   

  	

  SEC HPLC

  	

   

  	

  3

  97.0 % main peak, No single impurity > 2.0%

  
	

   

  	

   

  	

  SDS-PAGE (unreduced, Coomassie)

  	

   

  	

  Impurity profile consistent with reference

  
	

   

  	

   

  	

  SDS-PAGE

  (reduced, Coomassie)

  	

   

  	

  Impurity profile consistent with reference

  
	

   

  	

   

  	

  DNA Content

  	

   

  	

  Report (pg DNA/mg protein)

  
	

   

  	

   

  	

  Murine IgG Heavy Chain1

  	

   

  	

  Report (%)

  
	

   

  	

   

  	

  Protein A EIA

  	

   

  	

  < 100 ppm (w/w)

  
	

   

  	

   

  	

  Bovine Transferrin1, 2

  	

   

  	

  Report (ppm)

  
	

   

  	

   

  	

  Insulin

  	

   

  	

  Report (ppm)

  
	

   

  	

   

  	

   

  	

   

  	

   

  
	

  Potency

  	

   

  	

  Protein Concentration (A280)3

  	

   

  	

  10 ±

  1 mg/mL

  
	

   

  	

   

  	

  Binding Assay3

  	

   

  	

  100 ±

  30% of reference

  
	

   

  	

   

  	

   

  	

   

  	

   

  
	

  Safety

  	

   

  	

  Endotoxin (LAL)4

  	

   

  	

  < 0.33 EU/mg

  
	

   

  	

   

  	

   

  	

   

  	

   

  
	

   

  	

   

  	

  Microbial Limit

  (Bioburden)

  	

   

  	

  < 1 (CFU/mL)

  
	

   

  	

   

  	

   

  	

   

  	

   

  
	

  Excipient/Chemical

  Composition

  	

   

  	

  PH

  	

   

  	

  5.5  ±

  0.3

  
	

   

  	

   

  	

  Osmolality5

  	

   

  	

  Value5 + 50 mOsm

  
	

   

  	

   

  	

   

  	

   

  	

   

  
	

  Other Tests (For

  information only)

  	

   

  	

  SDS-PAGE (unreduced, Silver)

  	

   

  	

  Report

  
	

   

  	

   

  	

  SDS-PAGE

  (reduced, Silver)

  	

   

  	

  Report

  
	

   

  	

   

  	

   

  	

   

  	

   

  

 

1  SGI Test to be

transferred to ICOS

2  This test may be omitted if bovine

transferrin is not in the process.

3  Extinction coefficient = 1.44.

4  Based on a maximum human

dose of [*] by parenteral administration.
   [*] Confidential Treatment Requested

 

5  Osmolality acceptance criteria needs to be

established.

 

 

 

 

 

 

 

APPENDIX D

Estimate of Manufacturing Schedules

 

[*]

[*]

Confidential Treatment Requested

 

 

APPENDIX E

Price and Payment Terms 

 

	

  Stage

  	

   

  	

  Terms1

  	

   

  	

  Estimated

  Date

  of Payment2

  	

  Total

  Price

  for Stage

  	

   

  
	

  Technology

  Transfer, and 

  Process Development.

  	

   

  	

  $[*] upon signing of the agreement3; 

  	

   

  	

  [*]

  	

  $[*

  	

  ]

  
	

   

  	

   

  	

  $[*] at initiation of purification process

  development; .

  	

   

  	

  [*]

  	

   

  	

   

  
	

   

  	

   

  	

  $[*] upon ICOS

  decision to proceed based on “research specifications”4

  	

   

  	

  [*]

  	

   

  	

   

  
	

  Manufacturing

  Campaign (Including Mfg. Transfer and Scale-up; 

  	

   

  	

  $[*] at

  initiation of  Process Transfer to

  Manufacturing and Scale-up stage as described in Appendix A, Section 2;

  	

   

  	

  [*]

  	

  $[*

  	

  ]

  
	

  Development run

  and two cGMP clinical production runs)5

  	

   

  	

   

  	

   

  	

   

  	

   

  	

   

  
	

   

  	

   

  	

  $[*] at initiation of Development Run;

  	

   

  	

  [*]

  	

   

  	

   

  
	

   

  	

   

  	

  $[*] at initiation of first GMP run;

  	

   

  	

   

  	

   

  	

   

  
	

   

  	

   

  	

  $[*] at initiation of second GMP run;

  	

   

  	

  [*]

  	

   

  	

   

  
	

   

  	

   

  	

  $[*] at stage completion.

  	

   

  	

  [*]

  	

   

  	

   

  
	

  Total

  	

   

  	

   

  	

   

  	

   

  	

  [*

  	

  ]

  
	

  Option for [*]

  years from  

  	

   

  	

  [*] reservation fee8;

  	

   

  	

   

  	

  [*] per

  	

   

  
	

  [*] for up to [*] additional 

  cGMP clinical production runs6,7.

  	

   

  	

  [*] of the cost

  of the campaign at the start of the campaign;

  	

   

  	

   

  	

  cGMP 

  run9,10.

  	

   

  
	

   

  	

   

  	

  [*] of the cost

  of the campaign at the  completion of

  the campaign.

  	

   

  	

   

  	

   

  	

   

  

[*] Confidential

Treatment Requested

1.     Seattle

Genetics and ICOS will mutually commit to the manufacturing campaign upon

signing the agreement.  As stated in

Section 8.1 of the Agreement, the Agreement will terminate on [*]  with no further obligation to either party if

ICOS determines it is unable to meet the Product Specifications.

[*] Confidential Treatment Requested

2.     The dates

listed are estimates only.  The actual

payment date is the date on which the applicable event occurs as stated in the

“Terms” column.

3.     Includes

[*] non-refundable payment made in connection with the Letter of Agreement of

[*].

[*] Confidential Treatment Requested

4.     Decision

to proceed to cGMP production will be based on ICOS meeting certain “research

specifications”.

5.     Seattle

Genetics will bear the cost of the resins and “special or non-standard” media

components (including, without limitation, storage and stocking fees) needed

for the process.  The cost for the

“special or non-standard” basal media components (listed in Assumption 7 of

Appendix A) will be less any standard ICOS basal media components removed from

the process.

6.     Additional

production runs will be at Seattle Genetics’ option.  ICOS will have [*] months to start the additional cGMP campaign

after payment of a reservation fee from Seattle Genetics.  For ICOS planning purposes Seattle Genetics

will provide a non-binding forecast on the first working day of each quarter.

[*] Confidential Treatment Requested

7.     All terms and conditions as stated in the

Agreement and Appendices will apply to the additional cGMP clinical production

runs.

8.     The

reservation fee applies to the total cost of the reserved campaign.

9.     Fee for

additional cGMP clinical production runs increases to $[*]  per run if not reserved by the end of the

Development run or the end of [*], whichever is later.  The “end of the Development run” is defined

as the completion of the purification process at scale as described in Appendix

A, Section 2.2.4.

[*] Confidential Treatment Requested

10.   If at the

end of the second cGMP clinical production run the combined yield from the [*]

cGMP clinical production runs is less than [*] grams, then Seattle Genetics may

have [*]  working days following the

completion of the following tests to reserve [*] of the [*] optional cGMP

clinical production runs at a fee of $[*]: SEC HPLC, IEF, Protein

concentration, the Binding Assay, and Endotoxin.  The fee will be paid in two installments: [*] reservation fee;

and [*] at the start of the optional cGMP clinical production run.  The “end of the second cGMP clinical

production run” is defined as the completion of the purification process at

scale as described in Appendix A, Section 3.3.

[*] Confidential Treatment Requested

APPENDIX F

Quality Understanding

 

[*]

[*] Confidential Treatment RequestedPrepared by MERRILL CORPORATION

 

 

SEATTLE GENETICS, INC.

 

2001 Executive Performance Plan

 

Objective

 

The objective of this program is to reward and recognize members of the

Company’s management team for the successful attainment of corporate goals and

objectives and individual performance toward meeting those goals and objectives

for 2001.

 

Eligibility

 

Employees at the

Associate Director level and above are eligible to participate in this program.

Eligibility of other positions is subject to approval in the sole discretion of

the Company’s Compensation Committee of the Board of Directors.  (See "Conditions" set forth

below.)

 

Employees must be employed in an eligible position through December 1,

2001 in order to participate in the program for 2001.  Employees hired or promoted into an eligible position after

January 1, 2001, but prior to December 1, 2001 will be eligible to earn a

pro-rated bonus payment based on their period of participation from their date

of hire or eligibility through December 1, 2001.  Eligible employees who change management positions during the

year will be eligible to earn a pro-rated bonus payment based on time served in

each eligible position. Participants must be considered an active employee on

the date of bonus payout in order to be eligible for payout under the plan

guidelines.

 

Eligible employees at the level below Vice President may also receive

the Company's periodic milestone awards, which may be paid to specific

departments or the Company at large in recognition for the successful

accomplishment of a milestone event. 

All employees at the level of Vice President and above are not eligible

to receive periodic milestone awards.

 

Program Criteria

 

The Board of Directors or its Compensation Committee will establish the

corporate goals and objectives for the year based on recommendations from the

Chief Executive Officer and President. 

Upon approval, these corporate goals and objectives will be communicated

to all eligible program participants. 

Seventy-five percent (75%) of the participant's annual performance bonus

will be based on the attainment of these corporate goals and objectives.  Twenty-five percent (25%) of the annual

performance bonus will be based on individual performance toward meeting these

corporate goals and objectives.

 

Toward the close of the calendar year the Board of Directors will

evaluate, measure and determine the success of the Company’s management teams

efforts toward the attainment of the corporate goals and objectives.   Based on this assessment, the Compensation

Committee of the Board will set the percentage of bonus that will be awarded

for the corporate portion of the program.

 

The Chief Executive Officer and President will evaluate the

contribution of each eligible participant (other than themselves) towards the

attainment of the approved corporate goals and objectives for the calendar

year.  (The Board of Directors or the

Compensation Committee will evaluate the contribution of the Chief Executive

Officer and President.) Recommendations will be provided to the Compensation

Committee of the Board of Directors for consideration in their determination of

the individual portion of the total bonus payment to be earned by each

participant based on their individual performance toward meeting the corporate

goals and objectives.

Participants will need to successfully achieve at least half (50%) of

their expected individual contributions toward corporate goals and objectives

in order to be eligible to receive any payment under this program.

 

Bonus Payments

 

Payments will be processed in the next practical payroll cycle

following the date of approval by the Board of Directors or its Compensation

Committee.

 

Bonus payments will be based on the base pay rate of an eligible

participant as of December 1, 2001. 

Payments will be made minus all applicable payroll deductions.

 

Participants whose employment terminates for any reason prior to the

bonus payouts will not be eligible to receive a bonus payment

 

Leave

of Absence

 

Employees on an approved leave of absence of longer than 30 days will

be eligible to receive a pro-rated payout based on the number of months they

were an active employee.  If an employee

is on an approved leave of absence on the date bonus payout is made, the

employee will be eligible to receive payout, if any, upon return from the leave

of absence.

 

Target Awards

 

The target awards for successful achievement of the 2001 corporate

goals and objectives shall be determined by the Board, such target awards to

range from 3% to 30% of base salary depending on the level of management responsibility.

 

Conditions

 

This program may be amended, modified or terminated at any time, for

any reason within the sole discretion of the Compensation Committee of the

Board of Directors or by the Board of Directors itself.  This may be done with or without notice to

the participants. These changes may be retroactive or prospective, as

determined in the sole discretion of the Compensation Committee or the Board.

Additionally, this program may not be modified by any oral statement; it may

only be modified in writing in a form authorized by the Compensation Committee

or the Board.  Also, the Compensation

Committee or the Board of Directors expressly reserves the right to decide that

this program should not apply due to individual circumstances.  Such decision(s) will be made in the sole

discretion of the Compensation Committee or the Board.  Accordingly, no one should rely on this

statement as a firm commitment and no one should rely on any oral statements

made about any change to the program.

 

As a reminder, your employment with the Company is on an “at will”

basis, meaning that either you or the Company may terminate your employment at

any time for any reason, with or without cause or advance notice.  This program sets forth the terms of the

Executive Performance Plan with the Company and supersedes any prior

representations or agreements, whether written or oral.

Source: [{"source": "alea-institute/alea-institute/kl3m-data-edgar-agreements/train-00031-of-00352.parquet"}, [{"source": "alea-institute/alea-institute/kl3m-data-edgar-agreements/train-00031-of-00352.parquet"}]]