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Execution Version AZ Ref: ECHO 10032403 Page 1 of 21 MATERIAL TRANSFER AGREEMENT This Material Transfer Agreement (the “Agreement”) is made effective as of 1 st August, 2016 (the “Effective Date”), by and between ASTRAZENECA UK LIMITED, a company incorporated in England under no. 03674842 whose registered office is at 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge, CB2 0AA, England (“AstraZeneca”) on the one hand; and CHARLES UNIVERSITY IN PRAGUE, with offices at Ovocný trh 3-5, Prague 1, 116 36, Czech Republic (“Recipient”) on the other hand. Recitals WHEREAS, AstraZeneca owns or otherwise controls the Materials (as defined below); and WHEREAS, Recipient desires to obtain samples of the Materials and use such samples for the purpose of conducting the Research (as defined below); and WHEREAS, AstraZeneca is willing to furnish the Materials to Recipient, upon the terms and conditions set forth herein. Agreement NOW, THEREFORE, in consideration of the mutual covenants contained in this Agreement, and other good and valuable consideration, the receipt and sufficiency of which are hereby acknowledged, the Parties, intending to be legally bound, agree as follows: 1. Definitions Unless otherwise specifically provided in this Agreement, the following terms shall have the following meanings: 1.1 Affiliates” means, with respect to a Person, any Person that directly, or indirectly through one or more intermediaries, controls, is controlled by or is under common control with such first Person. Control” and, with correlative meanings, the terms “controlled by” and “under common control with” mean (a) to possess the power to direct the management or policies of a Person, whether through ownership of voting securities or by contract relating to voting rights or corporate governance, resolution, regulation or otherwise, or (b) to own more than fifty percent (50%) of the outstanding voting securities or other ownership interest of such Person. With respect to AstraZeneca, the term Affiliate shall also include, but not be limited to, any business entity that is controlled by or under common control with AstraZeneca PLC. 1.2 AstraZeneca Results” means any Results, whether or not patentable, that are related to the Materials, including their uses and indications, whether as a single agent or in combination with other agents. All AstraZeneca Results shall be considered Confidential Information of AstraZeneca.
Transcript
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MATERIAL TRANSFER AGREEMENT

This Material Transfer Agreement (the “Agreement”) is made effective as of 1st August, 2016

(the “Effective Date”), by and between ASTRAZENECA UK LIMITED, a company

incorporated in England under no. 03674842 whose registered office is at 1 Francis Crick

Avenue, Cambridge Biomedical Campus, Cambridge, CB2 0AA, England (“AstraZeneca”) on

the one hand;

and

CHARLES UNIVERSITY IN PRAGUE, with offices at Ovocný trh 3-5, Prague 1, 116 36,

Czech Republic (“Recipient”) on the other hand.

Recitals

WHEREAS, AstraZeneca owns or otherwise controls the Materials (as defined below);

and

WHEREAS, Recipient desires to obtain samples of the Materials and use such samples

for the purpose of conducting the Research (as defined below); and

WHEREAS, AstraZeneca is willing to furnish the Materials to Recipient, upon the terms

and conditions set forth herein.

Agreement

NOW, THEREFORE, in consideration of the mutual covenants contained in this

Agreement, and other good and valuable consideration, the receipt and sufficiency of which are

hereby acknowledged, the Parties, intending to be legally bound, agree as follows:

1. Definitions

Unless otherwise specifically provided in this Agreement, the following terms shall have

the following meanings:

1.1 “Affiliates” means, with respect to a Person, any Person that directly, or indirectly

through one or more intermediaries, controls, is controlled by or is under common control

with such first Person. “Control” and, with correlative meanings, the terms “controlled

by” and “under common control with” mean (a) to possess the power to direct the

management or policies of a Person, whether through ownership of voting securities or

by contract relating to voting rights or corporate governance, resolution, regulation or

otherwise, or (b) to own more than fifty percent (50%) of the outstanding voting

securities or other ownership interest of such Person. With respect to AstraZeneca, the

term Affiliate shall also include, but not be limited to, any business entity that is

controlled by or under common control with AstraZeneca PLC.

1.2 “AstraZeneca Results” means any Results, whether or not patentable, that are related to

the Materials, including their uses and indications, whether as a single agent or in

combination with other agents. All AstraZeneca Results shall be considered Confidential

Information of AstraZeneca.

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1.3 “Background Intellectual Property” has the meaning given such term in Section 5.1.

1.4 “Confidential Information” means any and all information related to: the terms of this

Agreement; the Research, including the Research Documentation and the Results; any

other information collected, prepared, developed or generated by a Party in the course of

performing this Agreement; and any information disclosed by or on behalf of the

Disclosing Party to the Receiving Party hereunder. Confidential Information may be

disclosed either orally, visually, in writing, or in any other form now known or hereafter

invented.

1.5 “Disclosing Party” means the Party disclosing Confidential Information; provided a

Party owning certain property as provided hereunder shall be considered the Disclosing

Party and the other Party shall be considered the Receiving Party regardless of which

Party discloses such information.

1.6 “Debarred Person” has the meaning given such term in Article 10.

1.7 “Indemnified Party” has the meaning given such term in Section 9.1.

1.8 “Indemnifying Party” has the meaning given such term in Section 9.1.

1.9 “License” has the meaning given such term in Section 5.5(a).

1.10 “Loss” or “Losses” means any and all liabilities, claims, demands, causes of action,

damages, loss and expenses, including interest, penalties, and reasonable lawyers’ fees

and disbursements.

1.11 “Materials” means (a) those materials listed in Schedule 1 hereto, in the aggregate

quantities specified in Schedule 1; (b) any substance or compound that is a derivative or

modification thereof or is replicated therefrom, and any other compositions made using

such substance or compound; and (c) any associated know-how and data that is

transferred to Recipient by AstraZeneca.

1.12 “Negotiation Period” has the meaning given such term in Section 5.5(b).

1.13 “Option” has the meaning given such term in Section 5.5(a).

1.14 “Option Period” has the meaning given such term in Section 5.5(a).

1.15 “Option Notice” has the meaning given such term in Section 5.5(b).

1.16 “Parties” means AstraZeneca and Recipient and “Party” means either of AstraZeneca or

Recipient.

1.17 “Patents” means: (a) all national, regional and international patents and patent

applications, including provisional patent applications; (b) all patent applications filed

either from such patents, patent applications or provisional applications or from an

application claiming priority to any of these, including divisionals, continuations,

continuations-in-part, provisionals, converted provisionals, and continued prosecution

applications; (c) any and all patents that have issued or issue in the future from the

foregoing patent applications ((a) and (b)), including utility and design patents and

certificates of invention; (d) any and all extensions or restorations by existing or future

extension or restoration mechanisms, including revalidations, reissues, re-examinations

and extensions (including any supplementary protection certificates and the like) of the

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foregoing patents or patent applications ((a), (b) and (c)); and (v) any similar rights,

including so-called pipeline protection, or any importation, revalidation, confirmation or

introduction patent or registration patent or patent of additions to any such foregoing

patent applications and patents.

1.18 “Person” means an individual, sole proprietorship, partnership, limited partnership,

limited liability partnership, corporation, limited liability company, business trust, joint

stock company, trust, incorporated association, joint venture or similar entity or

organization, including a government or political subdivision, department or agency of a

government.

1.19 “Receiving Party” means the Party receiving Confidential Information; provided that a

Party owning certain property as provided hereunder shall be considered the Disclosing

Party and the other Party shall be considered the Receiving Party regardless of which

Party discloses such information.

1.20 “Recipient Results” means all Results other than the AstraZeneca Results. Recipient

Results shall be considered Confidential Information of Recipient.

1.21 “Research” means those tests, studies and other activities set forth in Schedule 2 hereto

carried out by Recipient.

1.22 “Research Documentation” means any and all documents, records, accounts, notes,

reports (including, without limitation, the progress reports and the final report prepared

pursuant to Section 4.1) and other data relating to the Research, whether in written,

electronic, video or other tangible form created by, or by a third party on behalf of,

Recipient.

1.23 “Researchers” means all employees or agents of Recipient who are engaged in carrying

out the Research.

1.24 “Results” means any ideas, inventions, discoveries, know-how, data, documentation,

reports, materials, writings, designs, computer software, processes, principles, methods,

techniques and other information, recorded in any form, that are discovered, conceived,

reduced to practice or otherwise generated as a result of or in connection with the

Research or the use of the Materials by, or by a third party on behalf of, Recipient

(whether solely or jointly with others), and any Patent, trade secret, copyright or other

intellectual property rights pertaining to any of the foregoing; provided, however, that

“Results” shall exclude any substance or structure that is a derivative, modification or

replication of the Materials and any other compositions made using the Materials, which

derivatives, modifications, replications and compositions form part of the Materials

pursuant to Section 1.11(b) and are owned by AstraZeneca pursuant to Section 5.6.

1.25 “Retention Period” has the meaning given such term in Section 4.3.

2. Transfer of Materials

2.1 Transfer of Materials. At Recipient’s sole cost and expense, AstraZeneca will provide

the Materials to Recipient, solely to allow Recipient to carry out the Research.

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2.2 DISCLAIMER. ALL MATERIALS PROVIDED BY ASTRAZENECA ARE

PROVIDED “AS IS” AND, TO THE MAXIMUM EXTENT PERMITTED BY

APPLICABLE LAW, ASTRAZENECA HEREBY DISCLAIMS AND EXCLUDES

ANY AND ALL REPRESENTATIONS, WARRANTIES, CONDITIONS OR OTHER

TERMS, WHETHER WRITTEN OR ORAL, EXPRESSED OR IMPLIED, WITH

RESPECT TO THE MATERIALS, INCLUDING ANY REPRESENTATION OR

WARRANTY OF QUALITY, PERFORMANCE, MERCHANTABILITY OR FITNESS

FOR A PARTICULAR USE OR PURPOSE OR THAT THE MATERIALS DO NOT

INFRINGE THE PATENT, COPYRIGHT, TRADEMARK OR OTHER

PROPRIETARY RIGHTS OF A THIRD PARTY.

2.3 NO LIABILITY. TO THE FULLEST EXTENT PERMITTED BY APPLICABLE

LAW, ASTRAZENECA SHALL NOT BE LIABLE TO RECIPIENT, ITS

AFFILIATES, OR ANY OF THEIR RESPECTIVE EMPLOYEES OR AGENTS,

WHETHER FOR BREACH OF CONTRACT, NEGLIGENCE OR OTHERWISE,

WITH REGARD TO THE PROVISION OF MATERIALS TO RECIPIENT.

3. Conditions of Transfer

3.1 Permitted Use of Materials. The Materials transferred pursuant to this Agreement

(a) shall be used by Recipient only for the Research and shall at all times remain solely

under the control of the Recipient; (b) shall not be used by or delivered by Recipient to or

for the benefit of any third party without the prior written consent of AstraZeneca;

(c) shall not be used by Recipient in research or testing involving human subjects; and

(d) shall not be used by Recipient for any commercial purpose, including in any product

for commercial use or distribution, or for the purpose of producing any such product or

providing any such service; and (e) shall not be used in combination with any other

pharmaceutically active agent other than those explicitly set forth in Schedule 2 (whether

commercially available or otherwise). Recipient shall cause each Researcher to comply

with the obligations in this Section 3.1.

3.2 No Sale or Transfer. The transfer of the Materials by AstraZeneca to Recipient shall not

constitute a sale of the Materials or an option or, except to the extent necessary for the

conduct of the Research, a license in or to any rights, title or interest in or to the

Materials.

3.3 Experimental Nature. Recipient acknowledges, and shall inform the Researchers, that not

all of the characteristics of the Materials may be known. Recipient shall use, and shall

cause its Researchers to use, the Materials with prudence and appropriate caution in

performing the Research.

3.4 Compliance with Law. Recipient shall use, and shall cause its Researchers to use, the

Materials in compliance with all applicable laws, rules, regulations, guidelines and

requirements. In accordance with the requirements of the United States law and/or any

other applicable national laws governing the shipment of drugs, Recipient hereby certifies

that (a) it is regularly engaged in conducting tests in vitro or in animals used only for

laboratory research purposes; and (b) the Materials received pursuant to this Agreement

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shall actually be used only for tests in vitro or in animals used only for laboratory

research.

3.5 Prohibition on Structure Determination. Recipient agrees that neither it nor any of its

Researchers shall attempt to determine the structure of the Materials (e.g., chemical

structure, amino acid sequence or nucleotide sequence) or otherwise characterize the

Materials without the prior written consent of AstraZeneca.

3.6 Animal Care. Recipient agrees that, insofar as the Research involves the use of animals,

the Research shall be conducted in accordance with the AstraZeneca Global Policy on

Bioethics on “Using Animals in Research Studies,” as the same may be amended from

time to time and made available on the website of AstraZeneca and its Affiliates (see

http://www.astrazeneca.com/Sustainability/responsible-research).

4. Disclosures and Reports

4.1 Reports. Recipient shall keep AstraZeneca informed of all uses that Recipient makes of

the Materials. During the term of this Agreement, Recipient shall, and shall require the

Researchers to, prepare and submit written progress reports to AstraZeneca within thirty

(30) days of the end of each calendar quarter. Such report(s) shall include all Results

achieved during the relevant period including, for the avoidance of doubt, all raw data

resulting from studies conducted in the course of the Research. Recipient shall, and shall

require the Researchers to, prepare and submit a final written report to AstraZeneca

within thirty (30) days of the expiration or earlier termination of this Agreement, which

report shall include a comprehensive summary of the Research undertaken, all Results,

and any other accomplishments achieved in connection with such Research. All reports

submitted under this Section 4.1 shall be prepared in accordance with the requirements

specified in Section 4.2 and any other instructions provided by AstraZeneca.

4.2 Recordkeeping. All Research Documentation shall be complete, current, accurate,

organized and legible, and shall be prepared and maintained in a manner acceptable for

the collection of data for submission to, or review by, regulatory authorities and in full

compliance with all applicable laws. The Recipient shall cause each Researcher to

maintain the Research Documentation separate from all other records kept by each such

Researcher. Without limiting the generality of the foregoing, such Research

Documentation shall provide at least the level of detail necessary to support the filing and

prosecution of patent applications for any inventions discovered, created, conceived or

reduced to practice in the conduct of the Research.

4.3 Retention of Records. Recipient shall retain, or cause to be retained, all Research

Documentation (including, where appropriate, copies of the reports specified under

Section 4.1) during the term of this Agreement and thereafter until (a) the third (3rd)

anniversary of the date that this Agreement expires or terminates; or (b) until such later

date as may be required by applicable law (the “Retention Period”). Recipient shall

make all Research Documentation available upon request for review, copying and audit

pursuant to Section 4.4 at all times during the Retention Period.

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4.4 Audits. AstraZeneca or its authorized representatives shall have the right, during regular

business hours and with reasonable notice, to: (a) inspect the facilities used in the

performance of the Research; (b) monitor the conduct of the Research; and (c) review,

copy and audit during the Retention Period all Research Documentation and any other

books, records, and data relating to the Research. Recipient shall, and shall cause the

Researchers to, cooperate with any such activities and shall ensure timely access to

requested facilities and documentation.

5. Ownership of Results and Licenses

5.1 Background Intellectual Property. For the avoidance of doubt, all intellectual property

and know-how existing as of the Effective Date, or developed or acquired outside of the

scope of this Agreement (“Background Intellectual Property”), that is used in

connection with the Research shall remain the property of the Party introducing the same.

Nothing in this Agreement shall transfer any rights in such Background Intellectual

Property to the other Party. In the event that a license to certain Background Intellectual

Property owned by Recipient is necessary for AstraZeneca to develop or exploit

commercially any AstraZeneca Results, and if Recipient has the right to grant

AstraZeneca rights in such Background Intellectual Property, Recipient shall use

reasonable efforts to grant to AstraZeneca an exclusive or non-exclusive license, on

commercially reasonable terms, to the applicable intellectual property rights in such

Background Intellectual Property.

5.2 Ownership of Results; Cooperation

(a) The Parties agree that: (i) AstraZeneca (or its designee) shall own all right, title

and interest in and to all AstraZeneca Results and all intellectual property and

proprietary rights associated therewith; and (ii) Recipient shall own all right, title

and interest in and to all Recipient Results and all intellectual property and

proprietary rights associated therewith.

(b) At the request and expense of AstraZeneca (or its designee), Recipient shall, and

shall cause the Researchers to, apply or join with AstraZeneca (or its designee) in

executing and delivering any and all instruments necessary or useful to enable

AstraZeneca (or its designee) to apply for, procure, maintain and enforce

intellectual property rights, including Patents, in AstraZeneca Results anywhere in

the world as AstraZeneca (or its designee) may in its sole discretion determine,

including providing powers of attorney and all assignments necessary or useful to

vest all right, title and interest in and to such intellectual property rights in

AstraZeneca (or its designee). Recipient shall cause its employees and agents,

including the Researchers, to execute, or cause to be executed, all papers

necessary to effect the foregoing without additional consideration. In no event

shall Recipient file any patent relating to the Results. The AstraZeneca

contracting Party may transfer any and all intellectual property rights to any of its

Affiliates.

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(c) Each Party shall be responsible for all costs associated with the application,

prosecution, maintenance and enforcement of intellectual property rights in

Results owned by such Party pursuant to Section 5.2(a).

5.3 Consultation on Patent Filings. The Parties agree to consult with each other prior to the

filing of any patent application(s) arising from the Research and to co-operate with one

another with respect to the preparation, filing, prosecution and maintenance of such

patent applications and patents.

5.4 License to Recipient Results. Recipient hereby grants to AstraZeneca and its Affiliates a

perpetual, non-exclusive, royalty-free, fully paid-up, irrevocable, world-wide license,

with the right to sublicense without limitation, to make, have made, use, have used, sell,

have sold, offer for sale, import, export and otherwise use the Recipient Results for all

purposes.

5.5 Option to an Exclusive License in Recipient Results

(a) Recipient hereby grants to AstraZeneca and its Affiliates an exclusive option (the

“Option”) to take an exclusive, worldwide, perpetual and sublicenseable license

upon commercially reasonable terms (the “License”) to any Patent arising from

the Recipient Results; provided, however, that Recipient shall have a retained

right, subject to the requirements of Article 6, to use any such Patent for the sole

purpose of academic and educational research, but Recipient may not use any

such Recipient Results for any activities for or on behalf of any third party other

than a nonprofit, not for profit or governmental organization. The Option shall

commence and will extend for a period of twelve (12) months from the date of

filing of the patent application in respect of the Recipient Results (the “Option

Period”). During the Option Period, Recipient shall not negotiate with or grant

any rights to such Patent to any third party for the use or commercial exploitation

of the same.

(b) AstraZeneca or any of its Affiliates may elect to exercise the Option at any time

during the Option Period by giving Recipient written notice thereof (“Option

Notice”). Following Recipient’s receipt of an Option Notice within the Option

Period, Recipient shall enter into good faith negotiations for a period of no less

than six (6) months (the “Negotiation Period”) with AstraZeneca or its Affiliates

with a view to granting AstraZeneca or such Affiliate the License. The terms of

the License shall include such payment to Recipient as may in all the

circumstances be reasonable, taking into account the relevant contributions of

each Party to the generation of the relevant Recipient Results.

(c) If, after good faith negotiations, the Recipient and AstraZeneca or its Affiliate fail

to reach agreement on the terms of a license agreement for the License within the

Negotiation Period, then Recipient shall have the right to negotiate with third

parties with respect to any rights under the relevant Patent directed to Recipient

Results; provided, however, that for a period of six (6) months following the

expiry of the Negotiation Period, Recipient may not offer to any third party any

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rights in or to such Patent on more favorable terms (including payments) to such

third party than last offered to AstraZeneca or its Affiliate in writing. If Recipient

should grant, or agree (orally or in writing) to grant, to any third party any rights

in or to the relevant Patent during a period of six (6) months following the expiry

of the Negotiation Period, then, upon AstraZeneca’s request, Recipient shall

certify to AstraZeneca that the terms (including payments) of such transaction are

not more favorable to the third party than the terms last offered to AstraZeneca or

its Affiliate in writing.

(d) If (i) during the Option Period AstraZeneca notifies Recipient in writing that it

and its Affiliates do not wish to take a License; or (ii) AstraZeneca or any of its

Affiliates has not on or prior to the end of the Option Period furnished Recipient

with an Option Notice, then the Option in respect of the relevant Patent shall

terminate and Recipient shall be free to license and commercialize the relevant

Patent without any requirement to account to AstraZeneca.

5.6 Ownership of Materials. AstraZeneca shall own and retain all right, title and interest in

and to the Materials. Recipient acknowledges that the Materials may be the subject of

issued patents and pending applications covering inter alia the Materials, salts thereof,

pharmaceutical compositions thereof, processes for the preparation of the Materials,

methods of treatment using the Materials, and uses of the Materials. In the event that

Recipient creates, discovers, reduces to practice or otherwise develops any of the

Materials described in Section 1.11(b), Recipient shall, and shall cause the Researchers,

to (a) transfer such Materials to AstraZeneca upon completion of the Research or the

earlier termination of this Agreement; and (b) execute, or cause to be executed, all papers

necessary or useful to vest all right, title and interest in and to such Materials, and any

intellectual property rights associated therewith, in AstraZeneca without additional

consideration.

5.7 No Other Rights. Nothing in this Agreement is intended to grant either Party any rights

by the other Party, except those rights expressly set forth herein.

6. Confidentiality and Non-Disclosure

6.1 Confidentiality Obligations. At all times during the term of this Agreement and for a

period of five (5) years following termination or expiration of this Agreement, the

Receiving Party shall (a) use the Disclosing Party’s Confidential Information solely for

the Research or as otherwise expressly permitted under the Agreement and for no other

purpose, and (b) keep confidential and not publish (except as permitted in Article 7),

make available or otherwise disclose any of the Disclosing Party’s Confidential

Information, except to its directors, officers, employees, agents or representatives

(collectively “Representatives”) who reasonably require access to such Confidential

Information in connection with the Research and who are bound by confidentiality and

non-use obligations with respect to such Confidential Information that are no less onerous

than those set forth in this Agreement. The Receiving Party shall notify the Disclosing

Party promptly upon the Receiving Party’s discovery of any disclosure or use of

Confidential Information of the Disclosing Party by the Receiving Party or its

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Representatives in breach of the terms hereof, and the Receiving Party at its expense,

shall cooperate with the Disclosing Party at the Disclosing Party’s reasonable request to

mitigate such unauthorized disclosure or use and prevent any further breach hereof.

The Parties recognize the desire to share certain information with a key collaborator on

the Research. Recipient is hereby permitted to share Confidential Information relating to

the Research and Results under this Agreement with of

Westfälische Wilhelms-Universität Münster under terms no less protective of

AstraZeneca’s interest in the Materials, Confidential Information and Results than this

Agreement

6.2 Exceptions. The Receiving Party’s obligations in Section 6.1 shall not extend to any

Confidential Information to the extent that the Receiving Party can demonstrate that such

Confidential Information (a) is or hereafter becomes generally available to the public by

use, publication, general knowledge or the like other than by breach by the Receiving

Party or any of its Representatives of the terms hereof, (b) is received from a third party,

other than a Representative of, or any other Person that disclosed Confidential

Information on behalf of, Disclosing Party, that is lawfully in possession of such

information and is not in violation of any contractual or legal obligation of confidentiality

between such third party and Disclosing Party or any of its Representatives with respect

to such information, (c) was already in the possession of the Receiving Party or any of its

Representatives prior to receipt from Disclosing Party or any of its Representatives as

shown in the written records of the Receiving Party or its Representatives or by other

competent evidence, (d) is or was independently developed by the Receiving Party or any

of its Representatives without use or reference to Confidential Information, as shown in

the written records of the Receiving Party or its Representatives or by other competent

evidence, or (e) is or was generally made available to third parties by or on behalf of

Disclosing Party, or its Affiliates, without restriction on disclosure.

Information disclosed or made available to the Receiving Party by or on behalf of

Disclosing Party shall be presumed to be Confidential Information subject to this

Agreement and the burden of establishing that such information comes within the

foregoing exceptions to the Receiving Party’s obligations of confidentiality shall rest

with the Receiving Party. Confidential Information disclosed to the Receiving Party

hereunder shall not be deemed by the Receiving Party to fall within the above exceptions

merely because it is embraced by more general information that falls within such

exceptions.

6.3 Compliance with Laws. This Agreement shall not be deemed to restrict the Receiving

Party or its Representatives from complying with a lawfully issued governmental order or

other legal requirement to produce or disclose Confidential Information; provided,

however, that the Receiving Party shall promptly notify Disclosing Party upon learning

of such order or other requirement, to enable Disclosing Party to oppose such order or

requirement, as the case may be, or obtain a protective order, and the Receiving Party

shall, and shall cause any applicable Representative to, reasonably cooperate with

Disclosing Party in objecting to such order or requirement and in any related

proceedings; and provided, further, that if such order or requirement is not quashed or a

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protective order is not obtained, any Confidential Information disclosed in response to

such order or requirement shall be limited to information that is legally required to be

disclosed in such response to such order or requirement, and the Receiving Party shall,

and shall cause any applicable Representative to, cooperate with Disclosing Party to

obtain confidential treatment, to the extent reasonably possible, with respect to any

Confidential Information so disclosed.

6.4 Press Releases and Use of Name. Each Party shall keep the existence of, the terms of and

the transactions covered by this Agreement confidential and shall not disclose such

information to any other Person through a press release or otherwise, or mention or

otherwise use the name, insignia, symbol, trademark, trade name or logotype of the other

Party or its Affiliates in any manner without the prior written consent of the other Party in

each instance (which shall not be unreasonably withheld). The restrictions imposed by

this Section 6.4 will not prohibit any Party from making any disclosure identifying the

other Party that is required by applicable law, rule or regulation or the requirements of a

national securities exchange or another similar regulatory body, in which event such

Party (a) may disclose only that portion of such information that is legally required to be

disclosed and shall exercise its reasonable best efforts to obtain a protective order or other

reliable assurance that confidential treatment will be accorded to the information so

disclosed; and (b) shall notify the other Party prior to making such disclosure.

Notwithstanding anything to the contrary in this Section 6.4, to the extent any

information relating to this Agreement or the transactions covered by it is publicly

disclosed with the consent of the Parties, a Party may thereafter disclose such information

without the prior written approval of the other Party.

7. Publication

7.1 Publication. Notwithstanding Article 6, Recipient shall have the right, subject to this

Section 7.1, to publish in scientific or other journals, or to present at professional

conferences or other meetings, the Results. At least thirty (30) days prior to submission

of any material for publication or presentation, Recipient shall provide AstraZeneca with

a copy of such material for its review. If requested in writing by AstraZeneca, Recipient

shall (a) withhold material from submission for publication or presentation for an

additional ninety (90) days from the date of AstraZeneca’s request to allow for the filing

of a patent application and the taking of such measures as AstraZeneca deems appropriate

to establish and preserve its proprietary rights in the information contained in the material

being submitted for publication or presentation, and (b) remove any information

determined at AstraZeneca’s sole discretion to be Confidential Information from such

publication or presentation. Any permitted publication resulting from work using the

Materials shall, subject to Section 6.4, acknowledge AstraZeneca in a manner consistent

with the usual conventions in the field of research involved.

7.2 AstraZeneca Rights. Recipient agrees that if it publishes the Results pursuant to

Section 7.1 and retains any rights to such publication, AstraZeneca and its Affiliates are

hereby granted an irrevocable, perpetual and royalty-free license to make and distribute

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copies of such publication under any copyright privileges that Recipient may have.

AstraZeneca and its Affiliates also shall have the right to publish independently the

Results with appropriate acknowledgement of Recipient’s contribution to the publication.

8. Termination

8.1 Term and Termination. This Agreement shall commence upon the Effective Date and

shall continue until the Research is completed, unless earlier terminated in accordance

with this Section 8.1. AstraZeneca may terminate this Agreement at any time with or

without cause upon providing thirty (30) days’ prior written notice to Recipient.

8.2 Effect of Termination. Upon termination of this Agreement, Recipient shall promptly

cease performing the Research. The expiration or termination of this Agreement shall be

without prejudice to any rights or obligations of the Parties that may have accrued prior

to the termination and, except as otherwise expressly provided herein, shall not limit any

rights or remedies which may be available by law or otherwise. Upon termination or

expiration of this Agreement, Recipient shall promptly (a) at AstraZeneca’s option, either

destroy or return to AstraZeneca all Materials; provided that in the case of the destruction

of the Materials, Recipient shall certify in writing to AstraZeneca that such Materials

have been destroyed; (b) deliver to AstraZeneca copies of all Research Documentation in

accordance with Section 4.3; (c) at AstraZeneca’s option, either destroy or return to

AstraZeneca all Confidential Information received from AstraZeneca; provided, however,

that Recipient shall be permitted to retain one copy of such Confidential Information for

archival purposes; and (d) provide AstraZeneca with a final written report in accordance

with Section 4.1.

8.3 Survival. The provisions of Articles 1, 5, 6, 7, 9 and 10, and Sections 2.2, 2.3, 3.5, 4.1,

4.2, 4.3, 4.4, 8.2, 11.2, 11.3, 11.4, 11.6 and this Section 8.3 shall survive the expiration or

termination of this Agreement for any reason according to their respective terms.

9. Indemnification

9.1 Indemnification. In addition to any other remedy available to the Parties, each Party (the

“Indemnifying Party”) shall defend, indemnify and hold harmless the other Party, its

Affiliates and its and their respective officers, directors, partners, shareholders,

employees and agents (each an “Indemnified Party”) from and against any and all

Losses incurred by the Indemnified Party to the extent resulting from, arising out of, or in

connection with, (a) any material breach of any obligation in this Agreement by the

Indemnifying Party; (b) the material inaccuracy or breach of any representation or

warranty made by the Indemnifying Party in this Agreement; or (c) the enforcement of

the Indemnified Party's rights under this Section 9.1, except, in each case, to the extent

such Losses arise as a result of the gross negligence, fraud, willful misconduct or

wrongful act of any of the Indemnified Parties.

9.2 Indemnification Procedure. Upon receipt of a notice of claim or action for any Loss for

which a Party may be entitled to indemnification under Section 9.1, the Party receiving

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such notice shall promptly notify the other Party. Each Party shall cooperate with the

other Party in the defense of such claim or action.

10. Representations, Warranties and Covenants

Recipient represents, warrants and covenants to AstraZeneca that (a) it has full power and

authority, and has taken all necessary actions and has obtained all necessary

authorizations, licenses, consents and approvals required, to execute and perform its

obligations under this Agreement; (b) it shall, prior to initiation of the Research, obtain

from each of its Researchers and other employees and agents who have access to any

Confidential Information of AstraZeneca, rights to any and all information and inventions

that relate to the Research, such that AstraZeneca and its Affiliates shall receive from

Recipient the rights granted to AstraZeneca and its Affiliates hereunder without

additional consideration; (c) neither it nor any of its Researchers are, or during the term

of this Agreement shall become, a party to any agreement, arrangement, joint venture,

collaboration, competitive project or other dealing whatsoever with any other Person or

body that would or might affect, conflict with or prejudice this Agreement or the rights of

AstraZeneca under it, or that would or might prejudice the general objectives of the

Research; (d) it will not offer, pay, request or accept any bribe, inducement, kickback or

facilitation payment, and will not make or cause another to make any offer or payment to

any individual or entity for the purpose of influencing a decision for the benefit of

AstraZeneca; and (e) neither it nor any Researcher has been debarred or is subject to

debarment or has otherwise been disqualified or suspended from performing scientific or

clinical investigations or otherwise subjected to any restrictions or sanctions by the FDA

or any other governmental or regulatory authority or professional body with respect to the

performance of scientific or clinical investigations (a “Debarred Person”), and Recipient

shall not use in any capacity, in connection with the Research, any Debarred Person.

11. Miscellaneous

11.1 Assignment. This Agreement may not be assigned by either Party in whole or in part

without the prior written consent of the other Party, except that AstraZeneca without such

consent may assign this Agreement and its rights and obligations hereunder to any of its

Affiliates or any successor in interest (whether by merger, acquisition, asset purchase or

otherwise) to all or substantially all of the business to which this Agreement relates.

AstraZeneca shall always have the right to perform any or all of its obligations and

exercise any or all of its rights under this Agreement through any of its Affiliates.

11.2 Governing Law. The interpretation and construction of this Agreement shall be governed

by the laws of England, excluding any conflicts or choice of law rule or principle that

might otherwise refer construction or interpretation of this Agreement to the substantive

law of another jurisdiction.

11.3 Jurisdiction. Subject to Section 11.6, the Parties hereby irrevocably and unconditionally

consent to the exclusive jurisdiction of the courts of England and Wales (other than

appeals therefrom) for any action, suit or proceeding arising out of or relating to this

Agreement, and agree not to commence any action, suit or proceeding (other than appeals

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therefrom) related thereto except in such courts. The Parties irrevocably and

unconditionally waive their right to a jury trial.

11.4 Notices. Any notice, request, or other communication permitted or required under this

Agreement shall be in writing, shall refer specifically to this Agreement, and shall be

deemed given only if hand delivered or sent by an internationally recognized overnight

delivery service, costs prepaid, or by facsimile (with transmission confirmed) or

electronic mail, to the Party to whom notice is to be given at the address set forth in the

preamble to this Agreement or at such other address such Party may have provided to the

other Party in accordance with this Section 11.4. Such notice, shall be deemed to have

been given as of the date delivered by hand or transmitted by facsimile (with transmission

confirmed) or electronic mail, or on the second business day (at the place of delivery)

after deposit with an internationally recognized overnight delivery service, whichever is

the earlier.

11.5 Relationship of the Parties. The status of a Party under this Agreement shall be that of an

independent contractor. Nothing contained in this Agreement shall be construed as

creating a partnership, joint venture or agency relationship between the Parties or, except

as otherwise expressly provided in this Agreement, as granting either Party the authority

to bind or contract any obligation in the name of or on the account of the other Party or to

make any statements, representations, warranties or commitments on behalf of the other

Party.

11.6 Equitable Relief. A breach by either Party of Sections 3.1, 3.4 or 3.5 or Articles 5, 6 or 7

may cause irreparable damage and the non-breaching Party will not be adequately

compensated by monetary damages. In the event of a breach, or threatened breach, of

Sections 3.1, 3.4 or 3.5 or Articles 5, 6 or 7, the non-breaching Party shall be entitled to

seek equitable relief, whether preliminary or permanent, without the need to show

irreparable harm or the inadequacy of monetary damages as a remedy and without the

requirement of having to post a bond or other security. Nothing in this Section 11.6 is

intended, or shall be construed, to limit the Parties’ rights to equitable relief or any other

remedy for a breach of any provision of this Agreement.

11.7 Waiver. A Party's failure to enforce, at any time or for any period of time, any provision

of this Agreement, or to exercise any right or remedy shall not constitute a waiver of that

provision, right or remedy or prevent such Party from enforcing any or all provisions of

this Agreement and exercising any rights or remedies. To be effective any waiver must

be in writing. All rights and remedies are cumulative and do not exclude any other right

or remedy provided by law or otherwise available.

11.8 Severability. If any provision of this Agreement is held to be invalid, illegal or

unenforceable, in any respect, then, to the fullest extent permitted by applicable law and

if the rights and obligations of any Party will not be materially and adversely affected:

(a) such provision will be given no effect by the Parties and shall not form part of this

Agreement; (b) all other provisions of this Agreement shall remain in full force and

effect; and (c) the Parties shall use their best efforts to negotiate a provision in

replacement of the provision held invalid, illegal or unenforceable that is consistent with

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applicable law and achieves, as nearly as possible, the original intention of the Parties.

To the fullest extent permitted by applicable law, the Parties waive any provision of law

that would render any provision in this Agreement invalid, illegal or unenforceable in any

respect.

11.9 Entire Agreement. This Agreement constitutes the entire agreement between the Parties

with respect to the subject matter of the Agreement. This Agreement supersedes all prior

agreements, whether written or oral, with respect to the subject matter of the Agreement.

Each Party confirms that it is not relying on any statements, representations, warranties or

covenants of any person (whether a Party to this Agreement or not) except as specifically

set out in this Agreement. Nothing in this Agreement is intended to limit or exclude any

liability for fraud. All Schedules referred to in this Agreement are intended to be and are

hereby specifically incorporated into and made a part of this Agreement. No

modification will be effective unless in writing and signed by authorized representatives

of both Parties.

11.10 Counterparts. This Agreement may be executed in any number of counterparts, each of

which shall be deemed an original and all of which taken together shall be deemed to

constitute one and the same Agreement. The Parties agree that execution of this

Agreement by industry standard electronic signature software and/or by exchanging

executed signature pages by facsimile transmission (with transmission confirmed) or in

.pdf format via e-mail shall have the same legal force and effect as the exchange of

original signatures, and that in any proceeding arising under or related to this Agreement,

each Party hereby waives any right to raise any defence or waiver based upon execution

of this Agreement by means of such electronic signatures or maintenance of the executed

Agreement electronically.

[Signature Page Follows]

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Execution

THIS AGREEMENT IS EXECUTED by the authorized representatives of the Parties as of the

date first written above.

ASTRAZENECA UK LIMITED

By: ASig1

Name: AName1

Title: ATitle1

CHARLES UNIVERSITY IN PRAGUE

By: ASig1

Name: AName1

Prof. MUDr. Aleksi Šedo, DrSc.

Title: ATitle1

Dean of First faculty of Medicine

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Schedule 1 - Materials

AZD8835 5 g

AZD5363 5 g

AZD8186 5 g

Delivery address for Charles University

Ustav patologicke fyziologie 1.LF UK

U Nemocnice 5

12853, Praha 2

Czech Republic

Tel

Email: @gmail.com

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Schedule 2 - Research

1. Preclinical Research Proposal Title :

Investigation of AZD8835, AZD8186 and AZD5363 efficacy in DLBCL PDX mouse models

2. Hypothesis: Statement of the hypothesis for the compound and biological target in human disease.

Brief evidence why this biological pathway may be important in the disease area under investigation. AZD8835 is working as specific PI3K inhibitor targeting only the α and δ subunit whereas AZD8186 is a PI3K inhibitor targeting the β and δ subunit. AZD5363 is inhibiting AKT [1; 2; 3]. Since the PI3K/AKT signaling pathway that is targeted by all three compounds is highly activated in the two major DLBCL subclasses, ABC and GCB DLBCL, it seems reasonable to test efficacy of these compounds in this malignant lymphoma subtype [4; 5; 6].

3. Outline of Research Plan

• Specific aims including scientific rationale

The efficacy of PI3K inhibition could already be shown for PTEN deficient GCB DLBCL in vitro models that where highly sensitive to the pan-PI3K inhibitor Ly294002 [6]. The more specific and also clinically more suitable PI3K inhibitors AZD8835 and AZD8186 as well as the AKT inhibitor AZD5363 shall now be investigated in DLBCL models. Sensitivity to these inhibitors was already detected in different DLBCL in vitro models and should now be confirmed in patient derived xenograft (PDX) mouse models. Due to this more patient-related setting the experiments should enable to make conclusions about potential therapeutic effect of the inhibitors in clinical trials.

• Overview of the experimental plans including rationale for choice of in vitro cell/tissue assay

and/or animal model with a clear study design and details of endpoints being measured. For in vitro cell assays, provide details on any cell lines that will be used. For in vivo studies justify choice of species, animal numbers and group size (e.g. using statistics/power analysis for primary endpoints). For studies using transgenic mouse, tissue or cells include details of the genetic background with appropriate published references. To have a more patient-related setting PDX mouse models are used to test the inhibitors. For this reason patient derived lymphoma cell lines from at least one ABC and one GCB DLBCL patient are engrafted in mice. For each model and each treatment a cohort of 8 mice will be used.

• Include approximate timelines for completing this work

The experiments for the PDX mouse models will be completed in 2-3 month.

• Anticipated outcome of results and describe the impact of the results (e.g. progressing this compound as a therapy or increasing understanding of mechanisms in disease) Relating to the in vitro results it is expected that ABC DLBCL PDX models shows sensitivity to the PI3K inhibitor AZD8835 and to AZD8186. For the GCB DLBCL PDX model sensitivity to AZD5363 is expected at least if the model is PTEN deficient. Furthermore sensitivity to AZD8186 would be possible. Sensitivity to the compounds is reflected by reduced tumor growth compared to vehicle treated mice.

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If patient derived PDX models respond to the inhibitors the same way in vitro models do the compound can probably be used in clinical trials.

4. Operational feasibility What has been done before? By you or members of your team? What

hasn’t? [Note: Innovative, ‘never tried before’ approaches are welcome] Thus far only efficacy of 8186, 8835, and 5363 has only been tested by us in various models of DLBCL in vitro.

5. References: List of key publications used in your proposal

[1] Hudson K, Hancox UJ, Trigwell C, McEwen R, Polanska UM, Nikolaou M, et al. Intermittent High-

Dose Scheduling of AZD8835, a Novel Selective Inhibitor of PI3Kalpha and PI3Kdelta, Demonstrates Treatment Strategies for PIK3CA-Dependent Breast Cancers. Molecular cancer therapeutics 2016 May; 15(5): 877-889.

[2] Hancox U, Cosulich S, Hanson L, Trigwell C, Lenaghan C, Ellston R, et al. Inhibition of PI3Kbeta

signaling with AZD8186 inhibits growth of PTEN-deficient breast and prostate tumors alone and in combination with docetaxel. Molecular cancer therapeutics 2015 Jan; 14(1): 48-58.

[3] Davies BR, Greenwood H, Dudley P, Crafter C, Yu DH, Zhang J, et al. Preclinical pharmacology

of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background. Molecular cancer therapeutics 2012 Apr; 11(4): 873-887.

[4] Young RM, Staudt LM. Targeting pathological B cell receptor signalling in lymphoid malignancies.

Nature reviews Drug discovery 2013 Mar; 12(3): 229-243. [5] Dal Porto JM, Gauld SB, Merrell KT, Mills D, Pugh-Bernard AE, Cambier J. B cell antigen

receptor signaling 101. Molecular immunology 2004 Jul; 41(6-7): 599-613. [6] Pfeifer M, Grau M, Lenze D, Wenzel SS, Wolf A, Wollert-Wulf B, et al. PTEN loss defines a

PI3K/AKT pathway-dependent germinal center subtype of diffuse large B-cell lymphoma. Proc Natl Acad Sci U S A 2013 Jul 9.

6. Project Decision Tree or Scheme of Work Flow Plan: Including estimated timelines

Subcutaneuos injection of PDX cell lines in mice

Wait for development of visible tumor

Subsequent treatment of the cells with inhibitors (AZD8835: 25 mg/kg BID; AZD8186 50 mg/kg BID;

AZD5363 150 mg/kg BID) or vehicle

Measurment of tumor size twice weekly

Euthaniziation of mice when tumor reaches size of 2 cm in the largest diameter

*Outside of remit: Stand alone experiments which only look at pharmacokinetic or safety parameters, screening assays using multiple compounds and clinical studies should not be included in these preclinical research proposals.

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Note: Only non-confidential information should be included in the Preclinical Research Proposal. If confidential data exists that would strengthen the rationale or other aspects of the proposal, the author can/should emphasize that a statement is supported by confidential information the author is able to share, but only under a Confidential Disclosure Agreement (CDA). If AstraZeneca finds the non-confidential Concept Proposal sufficiently intriguing, execution of a CDA so that information can be considered will be discussed. During the submission process, additional details regarding the use of human tissue and/or animals will be requested as with respect to the proposal. 7. Animal Use Risk Assessment for non-AZ funded external animal studies: please complete if

your research proposal includes the use of animals. Put a check (X) in each category that most accurately represents the animal model in the proposal.

Species ___ Invertebrates, fish, birds, fetal/larval forms, reptiles

X Mice, rats, hamsters

___ Guinea pigs, rabbits, ferrets, mini pigs, genetically altered animals, other species

___ Farm animals, equines, dogs, cats, harmful mutants, surgically prepared animals (any species)

___ Non human primates (NHPs)

Sensitivity X Ex vivo studies, terminal studies, or studies on conscious animals with appropriate mitigation of pain/distress,

but do not involve any of the criteria in sensitivity selections below ___ Studies use not humanely established or unconventional methods of euthanasia

___ Models involve: major surgery and/or repeated surgery, prolonged restraint, juvenile or neonatal animals

___ Models of: public concern, smoking, brain surgery/instrumentation, drug dependency in NHPs, unalleviated pain,

or with death required as an endpoint

Potential for pain and distress ___ Ex vivo or terminal studies

X Studies involve: no more than minor or transient discomfort or stress (routine dosing/sampling) or which have the

potential to cause prolonged pain or distress, but the use of anesthetics/analgesics provides appropriate mitigation ___ Studies involve: some pain or distress but with appropriate mitigation (most toxicity tests, surgery) or the potential

to cause high degrees of pain or distress, but procedures are terminated before pain or distress occurs ___ Studies involve potential for significant pain or distress which cannot be alleviated, but are scientifically justified,

(acute tox studies with significant morbidity or death as an endpoint, pain models)

Degree of Engagement ___ AZ and the external facility have had previous agreements over the last 5 years

X AZ and the external facility have had no previous agreements in the last 5 years

Name and Location* of external facility:

___________________________________________________________________________

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Reputation of Facility ___ Facility has external regulatory oversight and AAALAC accreditation or equivalent , no history of security /media

issues in last 3 yrs ___ Facility has no external regulatory oversight and has AAALAC accreditation, no history of security /media issues

in last 3 yrs X Facility has no external regulatory oversight, no AAALAC accreditation, no history of security /media issues in

last 3 yrs ___ Facility has no external regulatory oversight, no AAALAC accreditation and/or has a history of security / media

issues in last 3 yrs ___________________________________________________________________________

Please note the questions below. You will be required to provide responses to these questions in the online form.

Can your institute assure AstraZeneca that any in vivo studies using animals, conducted under this proposal, will be performed in a manner consistent with the principles of AstraZeneca's Bioethics policy? Yes

List and justify the choice of species, animal numbers and group size (e.g. using statistics/power analysis for primary endpoints). Please include details on dose route, volume, frequency and duration: six to eight week old female NOD.Cg-Prkdc severe combined immunodeficiency Il2rgtm1Wjl/SzJ (NSG; Jackson Laboratory) mice will be used. The mice are held in individually ventilated cages under sterile and standardized environmental conditions (25 ± 2°C room temperature, 50 ± 10% relative humidity, 12 hours light–dark-rhythm). The mice received autoclaved food and bedding and acidified drinking water ad libitum. Mice will be dosed twice daily orally (100uL, 20-40mg/kg, AZ compounds solubilized in HPMC/Tween of Phosal-G/PEG400). For therapy initation and termination, see below.

For studies using transgenic mouse, tissue or cells include details of the genetic background with appropriate published references: not part of the proposal

Please give details of the specific procedures the animals will undergo e.g. surgery, imaging sample collection and measurements: Mice will be subcutaneously (s.c.) injected with diffuse large B-cell lymphoma (DLBCL) cell lines (K422, WSU-DLCL, OCI-LY10) or intravenously (i.v.) injected with DLBCL patient-derived xenograft (PDX) cells established in our laboratory. S.c. lymphoma-bearing mice will be observed daily and when half of the experimental animals will develop visible tumors, the mice will be stratified into treatment cohorts (10 animals each cohort) and the therapy with AZ compounds will be initiated until s.c. tumors will reach 2cm in any diameter. In case of the i.v.-injected animals the treatment will be initiated at estimated half of the overall survival of untreated mice (differs for particular PDX model). The mice will be euthanized if they develop signs of advanced lymphoma including: weight loss > 20%, generalized inability to thrive, hint-leg paralysis, or other signs of dyscomfort as a result of lymphoma.

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Please indicate if this is a terminal procedure under anaesthetic, and if so, the anaesthetic used: The mice will be euthanized by cervical dislocation. No anaesthesia is part of the proposal.

List anaesthetic and analgesic agents used as part of the study and describe how and when they will be used: Not part of the proposal.

If surgery is involved, please include details of the procedure: No surgery is involved.

Will the animals be imaged as part of the procedure? Please indicate frequency and length of each procedure. How will the animal be monitored? No imaging will be part of the procedure.

What criteria will be used to assess pain and distress to ensure that appropriate action is taken to minimise pain and distress? Mice will be daily observed and will be euthanized in case they show sings of pain or distress (see above).

Does your institute have an ethical welfare body eg IACUC/ERP? If so, please give brief details on remit, membership and meeting frequency: dr. Klener is board-examined for animal handling (certificate number CZ02632). Experimental therapy of lymphoma-bearing animals were approved by the institutional Animal Care and Use Committee, as well as by the Research and Higher Education section of the Ministry of Education, Youth and Sports of the Czech Republic under the number 592/15 (MSMT-11255/2015-4)


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