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` UNITED STATES PATENT AND TRADEMARK OFFICE
`
` BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_______________________________
`
`GENOME & COMPANY, )
`
` Petitioner, )
`
` v. )
`
`THE UNIVERSITY OF CHICAGO, )
`
` Patent Owner. )
`
`_______________________________)
`
` DEPOSITION OF SRIDHAR MANI, M.D.
`
` September 26, 2019
`
` 9:13 a.m.
`
` Deposition of SRIDHAR MANI, M.D.,
`
` taken by Petitioner, at the offices of Mintz,
`
` Levin, Cohn, Ferris, Glovsky and Popeo, P.C.,
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` Chrysler Center, 666 Third Avenue, New York, New
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` York, before Brandon Rainoff, a Federal
`
` Certified Realtime Reporter and Notary Public of
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` the State of New York.
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`GregoryEdwards, LLC | Worldwide Court Reporting
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`A P P E A R A N C E S:
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`MINTZ, LEVIN, COHN, FERRIS, GLOVSKY and POPEO, P.C.
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`Attorneys for Petitioner
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` Chrysler Center
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` 666 Third Avenue
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` New York, New York 10017
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` 212.935.3000
`
`BY: JOHN A. BAUER, ESQ.
`
` 212.692.6795
`
` jabauer@mintz.com
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` ANDREW R. REEVES, Ph.D.
`
` 212.692.6283
`
` arreeves@mintz.com
`
` - and -
`
` One Financial Center
`
` Boston, Massachusetts 02111
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` 617.542.6000
`
`BY: KONGSIK KIM, ESQ.
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` 617.348.3087
`
` kkim@mintz.com
`
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`A P P E A R A N C E S (CONTINUED):
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`COVINGTON & BURLING LLP
`
`Attorneys for Patent Owner
`
` One CityCenter
`
` 850 Tenth Street, NW
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` Washington, DC 20001-4956
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` 202.662.6000
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`BY: SCOTT E. KAMHOLZ, M.D., Ph.D., ESQ.
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` 202.662.5339
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` skamholz@cov.com
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` - and -
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` The New York Times Building
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` 620 Eighth Avenue
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` New York, New York 10018-1405
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` 212.841.1000
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`BY: JENNIFER L. ROBBINS, ESQ.
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` 212.841.1180
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` jrobbins@cov.com
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` I N D E X O F E X A M I N A T I O N
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`Witness:
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`Sridhar Mani, M.D.
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`Examination:
`
`By Mr. Bauer.........................Page 8
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`Index of Exhibits....................Page 4
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`Previously-Marked Exhibit............Page 5
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` *********
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` I N D E X O F E X H I B I T S
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`1041 .........................................37
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`Multipage document entitled: Mechanisms of
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`Resistance to Immune Checkpoint Blockade: Why Does
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`Checkpoint Inhibitor Immunotherapy Not Work for All
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`Patents
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` *********
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`P R E V I O U S L Y - M A R K E D E X H I B I T S
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`2007 .........................................11
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`Declaration of Sridhar Mani, M.D., in Support of
`
`Patent Owner Response
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`1029 .........................................39
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`Multipage document entitled: Mutational landscape
`
`determines sensitivity to PD-1 blockade in non-small
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`cell lung cancer
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`2028 .........................................43
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`Multipage printout from the journal Nature Reviews,
`
`bearing the heading: Tumour immunology &
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`immunotherapy, Cancer
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`2030 .........................................56
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`Multipage printout from the journal Science, bearing
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`the heading: Cancer Immunology and Immunotherapy
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`2037 .........................................34
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`Multipage printout from the journal American
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`Association for Cancer Research, bearing the heading:
`
`Clinical Cancer Research
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`P R E V I O U S L Y - M A R K E D E X H I B I T S
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` ( CONTINUED )
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`2040 .........................................66
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`Multipage printout from the journal Journal of
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`Immunotherapy, September 2013
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`2043 .........................................71
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`Multipage printout from the journal Journal of
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`Clinical Oncology, bearing the heading: 2014 ASCO
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`Annual Meeting Proceedings
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`2048 .........................................73
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`Multipage printout from the journal Journal of
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`Clinical Oncology, bearing the heading: 2015 ASCO
`
`Annual Meeting Proceedings
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`1004 .........................................74
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`Multipage document bearing the heading:
`
`Bifidobacterium longum, a lactic acid-producing
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`intestinal bacterium inhibits colon cancer and
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`modulates the intermediate biomarkers of colon
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`carcinogenesis
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`P R E V I O U S L Y - M A R K E D E X H I B I T S
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` ( CONTINUED )
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`1007 .........................................98
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`Multipage document bearing the heading: Antitumor
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`Effect of Bifidobacterium Infantis in Mice
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`1005 ........................................109
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`Multipage document bearing the heading: Early Human
`
`Development, The role of intestinal bifidobacteria on
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`immune system development in young rats
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`1011 ........................................114
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`Multipage document bearing the heading: BMC Cancer,
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`Anti-proliferative effects of Bifidobacterium
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`adolescentis SPM0212 extract on human colon cancer
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`cell lines
`
`1017 ........................................122
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`United States, Patent Application Publication, No. US
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`2012/0276143 A1
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` * * *
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` P R O C E E D I N G
`
` Thursday, September 26, 2019
`
` New York, New York
`
` 9:13 a.m.
`
` * * *
`
`SRIDHAR MANI, M.D.,
`
` having been duly sworn, was examined
`
` and testified as follows:
`
`EXAMINATION
`
`BY MR. BAUER:
`
` Q. Good morning, I'm John Bauer. I
`
` represent Genome & Company for the petitioner.
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` How are you today, Dr. Mani?
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` A. I'm fine, thank you.
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` Q. Are you under any medication that
`
` would prevent you from giving truthful answers?
`
` A. No.
`
` Q. Or that would prevent you from fully
`
` understanding any question?
`
` A. No.
`
` Q. Have you ever had your deposition
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` taken before?
`
` A. No.
`
` Q. Have you ever been involved in any
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` patent-related work, not as an inventor but as a
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` consultant?
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` A. Not that I recall.
`
` Q. You've never been hired in the
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` capacity as an expert in a patent case?
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` A. Not that I recall.
`
` Q. How did your first contact with the
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` law firm of Covington & Burling take place?
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` A. I received an e-mail from a company,
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` the name slips me, asking if I would be
`
` interested in this particular issue. And I
`
` looked at it and my expertise to pass a comment
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` on the issue and that's how it proceeded. I
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` said yes. They asked me for my CV and --
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` Q. So this company that you mention, was
`
` that Covington & Burling or were you working
`
` with a company that represents experts that
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` offer their expertise in certain fields?
`
` A. Correct, that I was working with a
`
` company that offered expertise.
`
` Q. Do you recall approximately when you
`
` received this first e-mail from this company
`
` that hires experts?
`
` A. Approximately May, I can't be sure
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` exactly of the date.
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` Q. May --
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` A. 2019.
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` Q. Do you recall when you first were
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` contacted by anyone from Covington & Burling?
`
` A. It was, I believe, shortly after the
`
` first contact with the company.
`
` Q. Do you recall who that was?
`
` A. It was Scott and Jennifer.
`
` Q. So that would be Scott Kamholz --
`
` A. Scott Kamholz and Jennifer.
`
` Q. Okay. All right, Jennifer. I think
`
` that will be good enough.
`
` Unless you would like to put your last
`
` name on the record?
`
` Why don't you put your last name on
`
` the record. Excuse me, for not recalling your
`
` last name.
`
` MS. ROBBINS: Robbins.
`
`BY MR. BAUER:
`
` Q. Would it have been Jennifer Robbins?
`
` A. Yes.
`
` Q. Basically what happened next in terms
`
` of your relationship and developing what
`
` ultimately became this report that was filed in
`
` this case?
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` A. I was questioned about my expertise,
`
` and I was asked to meet with Scott and Jennifer
`
` and I was presented materials pertinent to the
`
` case, in particular Dr. Braun's declaration.
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` And I was asked to scientifically, in my
`
` scientific capacity as an expert, review the
`
` evidence therein.
`
` Q. In terms of a draft of your expert
`
` report, who prepared the first draft?
`
` A. I did.
`
` Q. Were there multiple changes that went
`
` back and forth with your attorneys?
`
` A. Yes. There was some assistance but it
`
` was largely my draft, my writing, yeah.
`
` Q. When you say assistance, what do you
`
` mean by that?
`
` A. There were a number of legal terms --
`
` I'm not a legal expert -- that Dr. Braun used,
`
` actually, that was formatted in a sense. It's
`
` my content, but just put in the right place,
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` formatting, as I said, and -- for copies and
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` that kind of --
`
` Q. Okay.
`
` MR. BAUER: So I'll hand to you what
`
` has already been marked as Exhibit 2007. You'll
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`Sridhar Mani, M.D., - September 26, 2019
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` see that we originally copied all in black and
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` white. To the extent there are some color
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` pages, I have put them on the top just in case
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` we get -- in case we need to see them in color.
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` (Exhibit 2007, Declaration of Sridhar
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` Mani, M.D., in Support of Patent Owner Response,
`
` previously marked for identification)
`
`BY MR. BAUER:
`
` Q. Now, in preparing this declaration,
`
` what documents did you review?
`
` A. I reviewed Dr. Braun's declaration, I
`
` reviewed briefly the '302 patent, I reviewed the
`
` papers relevant to Dr. Braun's declaration, and
`
` I researched the topic.
`
` Q. When you say the papers relevant to
`
` Dr. Braun's declaration, can you be more
`
` specific?
`
` A. Papers he referenced in his
`
` declaration.
`
` Q. I see. You said you briefly reviewed
`
` the '302 patent.
`
` Did you also review the file history
`
` for the '302 patent?
`
` A. Briefly reviewed the file history.
`
` Q. About how long do you think you took
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` to go through that?
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` A. I really don't recall. It was -- I
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` really don't recall.
`
` Q. An hour? Two hours? A half hour?
`
` A. Perhaps.
`
` Q. Perhaps a half hour?
`
` A. No, perhaps an hour.
`
` Q. Okay. Since you haven't had your
`
` deposition taken before, I want to just fill you
`
` in on the roles as we move forward to help you.
`
` A. Yes.
`
` Q. As you can see, I ask the questions,
`
` you provide the answers. To the extent that you
`
` can understand the question, you have to answer
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` or provide an answer. However, from time to
`
` time your attorney may object or he may instruct
`
` you not to answer. If the attorney says, "I
`
` object," that's a legal issue between the
`
` lawyers, but you still have to answer the
`
` question if you can understand it.
`
` A. Yes.
`
` Q. If the lawyer says, "I object on the
`
` basis of attorney-client privilege and I
`
` instruct you not to answer," you are not
`
` required to answer the question.
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` A. Yes.
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` Q. If you don't understand a question
`
` today, will you let me know that you don't
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` understand it?
`
` A. Yes, I will.
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` Q. And if you don't ask me to rephrase
`
` it, can I assume that you understood the
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` question?
`
` A. Yes.
`
` Q. In terms of the rules, I'll read to
`
` you what your attorney read to Dr. Braun when
`
` his deposition was taken.
`
` A. Yes.
`
` Q. You may not talk with counsel for
`
` patent owner concerning the substance of your
`
` testimony until the deposition is entirely over
`
` at the end of the day.
`
` Is that understood?
`
` A. Yes, I understand.
`
` Q. So throughout the entire day you
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` cannot talk to your lawyer or lawyers about
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` your -- the substance of your testimony.
`
` A. Yes, I understand.
`
` Q. Did you meet with your lawyers prior
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` to coming here today to have your deposition
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` taken?
`
` A. Yes.
`
` Q. About how long?
`
` A. From the beginning?
`
` Q. Sure.
`
` A. Over 200 hours. I didn't meet with
`
` them for 200 hours --
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` Q. Right.
`
` A. -- I -- that's the amount of time I
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` took to prepare my materials --
`
` Q. Right.
`
` A. -- and my declaration.
`
` Q. Okay.
`
` A. I can't say how many hours of that I
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` met with my lawyers.
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` Q. Okay. The question I asked was --
`
` thank you for your answer -- the question I
`
` asked was: In order to prepare for today, did
`
` you meet with your lawyers yesterday?
`
` A. Yes, I did.
`
` Q. So where do you -- I guess where do
`
` you reside?
`
` A. I met twice this week and twice last
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` week, yeah.
`
` Q. To prepare for your deposition?
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` A. To prepare for my deposition.
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` Q. If you would add up those amount of
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` hours, approximately how long was that just for
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` the deposition prep?
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` Just approximate, just approximate.
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` A. Approximately 20, 30 hours.
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` Q. That's good.
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` A. Without having the numbers --
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` Q. That's fine, that's fine.
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` You are the author of a number of
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` peer-reviewed journals, aren't you?
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` A. Yes, I am.
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` Q. What's your understanding of the peer
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` review process?
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` A. I did not really opine on that in my
`
` declaration. It's a broad process and I didn't
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` really opine on that in my declaration as I was
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` commenting or rebutting Dr. Braun's declaration.
`
` Q. Okay. Thank you for your answer, but
`
` I'm going to ask you again.
`
` What is your understanding of the peer
`
` review process?
`
` A. As I mentioned, I wasn't prepared
`
` because I didn't opine on that in my declaration
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` of peer-reviewed papers, so I don't -- I can't
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` really comment on that with an opinion.
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` Q. So you have no opinion on what the
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` peer review process is?
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` A. It's a very broad term, and for me to
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` opine on that I need to be specific, and as
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` specific as I can get is what I opined on in
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` terms of Dr. Braun's declaration and his papers
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` in my declaration.
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` Q. So from time to time I'm going to ask
`
` you questions that may or may not be squarely
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` addressed in your declaration.
`
` A. Yes.
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` Q. Unless your attorney instructs you not
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` to answer, you are required to answer those to
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` the best of your ability, is that understood?
`
` A. Yes.
`
` Q. So in terms of peer review, would you
`
` agree that when you submit an article that is a
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` peer-reviewed -- the journals -- a group of
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` scientists completes a study -- well, let's put
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` it this way.
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` In the process -- you've had your --
`
` you've had a number of papers that are
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` published?
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` A. Yes.
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` Q. Right? Generally what's the peer
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` review process for those papers generally, what
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` are the steps?
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` A. Scientist submits a paper, there is a
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` review of that, scientific review of that.
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` Q. Who reviews that, which -- what kind
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` of person, an expert in the field?
`
` A. Not necessarily. It's distributed
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` to -- there are a lot of factors that go -- who
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` is available. It doesn't have to be with
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` expertise in that field, it can be an editorial
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` decision depending on which journal it is.
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` It's such a broad term, that's why I
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` mentioned I did not opine on the peer review
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` process in my -- in my declaration in reviewing
`
` Dr. Braun's peer review papers.
`
` Q. In your declaration you discuss
`
` anything about checkpoint inhibitors, correct?
`
` A. I discuss checkpoint inhibitors as it
`
` relates to Dr. Braun's declaration, my rebuttal
`
` to it, yes.
`
` Q. Now, you have -- in applying your
`
` analysis to the term "checkpoint inhibitor," did
`
` you include any antigen binding fragments that
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` bind to and inhibit an immune checkpoint
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` protein, did you include that embodiment within
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` your analysis in your report?
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` A. Would you repeat that question?
`
` Q. Sure.
`
` A. It's a long question, I want to
`
` understand it.
`
` Q. In your report, when you were
`
` discussing an ailment of immune checkpoint
`
` inhibitors, did you also include that immune
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` checkpoint inhibitor to include an antigen
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` binding fragment that bound to and inhibit an
`
` immune checkpoint protein?
`
` A. I do not recall using those exact
`
` phrases in my declaration.
`
` Q. Your declaration does not address
`
` antibody fragments acting as immune checkpoint
`
` inhibitors, does it?
`
` A. It talks about inhibitors, checkpoint
`
` inhibitors.
`
` Q. Right. It does not talk about
`
` fragments that act as checkpoint inhibitors,
`
` correct?
`
` A. I don't use those specific terms
`
` verbatim, but checkpoint inhibitors implies an
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` inhibitor of a checkpoint.
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` Q. Right, but nowhere in your declaration
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` do you discuss an embodiment in which an
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` antibody fragment can be used as a checkpoint
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` inhibitor, do you?
`
` A. I don't understand the term
`
` "embodiment."
`
` Q. Nowhere in your declaration do you
`
` discuss an example in which an antibody fragment
`
` can be used as a checkpoint inhibitor, do you?
`
` A. In paragraph 33 of my declaration I
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` can take you and read this -- excuse me, if I
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` can take you to the sentence.
`
` Q. Sure.
`
` A. Examples of preclinical studies
`
` illustrating the field's interest and pursuit of
`
` different checkpoint inhibitors included Romagné
`
` Exhibit 2009 and Kohrt Exhibit 2011, both
`
` anti-KIR antibodies; Woo, Exhibit 2012;
`
` anti-LAG3 antibody, alone and in combination
`
` with PD-1 antibody, Brignone Exhibit 2013;
`
` LAG-3Ig, which is an immunoglobulin --
`
` Q. Correct.
`
` A. -- Le Mercier Exhibit 2014 anti-VISTA
`
` antibody --
`
` Q. Right.
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` A. -- Sakuishi anti-TIM-3, alone and in
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` combination with PD-1 antibody; Beavis, Exhibit
`
` 2016 A2A antagonist.
`
` Q. Right.
`
` A. So while I don't use the term, that
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` specific term that you just quoted, it is
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` understood that the checkpoint inhibitor,
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` whether an antibody or a fragment or an
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` antagonist, could also serve the same purpose.
`
` Q. Those references don't deal with
`
` fragments of antibodies, they deal with complete
`
` antibodies, correct?
`
` A. I'd have to look in depth. I know I
`
` referred to them, but I believe -- I believe
`
` some do.
`
` Q. You are guessing?
`
` A. I'm -- I need to look at the paper.
`
` Q. Is there a discussion of the epitope
`
` which these antibodies bind to in terms of which
`
` fragment they are using?
`
` A. An epitope -- well, it discussed the
`
` checkpoint KIR, LAG-3, LAG, VISTA, TIM-3, A2A.
`
` These are all checkpoints.
`
` Q. They are checkpoints, they are
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` complete antibodies with the complete -- the
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` chain, the variable constant, and the variable
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` region. There is no discussion in your
`
` declaration of a fragment that actually
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` functions as a checkpoint inhibitor, is there,
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` as your declaration is drafted right there?
`
` A. Yes, I have not used those words.
`
` Q. I'm not asking if you have used words.
`
` I'm asking you from the substance --
`
` A. Yes.
`
` Q. -- do you discuss an example of using
`
` an antibody fragment as a checkpoint inhibitor
`
` in that paragraph, do you?
`
` DR. KAMHOLZ: Objection, asked and
`
` answered.
`
` A. As I stated before, there are a number
`
` of examples here of checkpoint inhibitors.
`
` Q. Right.
`
` A. So you could inhibit a checkpoint with
`
` different molecules. Those are all checkpoint
`
` inhibitors, and I list -- as I just listed them
`
` here.
`
` Q. What is your understanding of the
`
` difference between an antibody and a fragment of
`
` an antibody?
`
` A. If an antibody is an inhibitor of a
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` target and the same -- a fragment of that
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` antibody is also an inhibitor of the target,
`
` then both are inhibitors of the target.
`
` Q. What's the difference between a
`
` complete antibody and a fragment of an antibody?
`
` DR. KAMHOLZ: Objection, asked and
`
` answered.
`
` A. I just answered that but I'll repeat
`
` it.
`
` If an antibody inhibits a target, and
`
` a fragment of that antibody, whatever that
`
` fragment is, inhibits the target, then both are
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` checkpoint inhibitors.
`
` Q. But would you agree with me that the
`
` way -- just on the page in front of you there is
`
` not a description of a fragment of an antibody
`
` acting as a checkpoint inhibitor in that
`
` paragraph?
`
` DR. KAMHOLZ: Objection, asked and
`
` answered.
`
` A. I will repeat the statement again:
`
` Examples of preclinical studies illustrating the
`
` field's interest in different checkpoint
`
` inhibitors -- checkpoint inhibitors -- include
`
` Romagné and Kohrt, both anti-KIR antibody -- I
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` could read the whole paragraph --
`
` Q. But they don't say fragments of those
`
` antibodies, do they, that paragraph -- let me
`
` ask the question.
`
` In the paragraph you just cited, you
`
` are talking about a description of an antibody,
`
` not a fragment of an antibody, correct?
`
` A. I'm just -- in this paragraph I'm
`
` stating that there are different checkpoint
`
` inhibitors. Some are antibodies, some are
`
` antibody-like immunoglobulins, some are
`
` antagonist, and it's listed here and I can go
`
` over that again.
`
` Q. Are any of those entities that you
`
` just mentioned a fragment of an antibody?
`
` DR. KAMHOLZ: Objection, asked and
`
` answered.
`
` A. As I have stated in my declaration,
`
` Romagné and Kohrt both describe anti-KIR
`
` antibodies, Brignone describes a LAG-3Ig, and
`
` Beavis describes an A2A antagonist. Different
`
` checkpoint inhibitors.
`
` Q. Are they fragments, are any of them
`
` fragments or are any of them not fragments?
`
` A. I did not opine on those words in my
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` declaration.
`
` Q. Now, in your declaration, when you
`
` were taking about an ailment of immune
`
` checkpoint inhibitors, did you also include an
`
` ailment of an immune checkpoint inhibitor that
`
` is an interfering nucleic acid molecule?
`
` A. Could you repeat that question? You
`
` used a term "an ailment."
`
` Sorry, could you repeat the question?
`
` Q. In your declaration when you were
`
` discussing checkpoint inhibitors, did you
`
` include the term "checkpoint inhibitor" to
`
` include an interfering nucleic acid molecule?
`
` A. I don't see that I used the specific
`
` terms as you've mentioned verbatim in my
`
` declaration, but I allude to checkpoint
`
` inhibitors.
`
` Q. Proteins?
`
` A. Checkpoint inhibitors.
`
` Q. You are talking about proteins, aren't
`
` you?
`
` A. I'm talking about any strategy that
`
` inhibits checkpoints.
`
` Q. Nowhere in that declaration do you
`
` reference an interfering nucleic molecule
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` functioning as an immune checkpoint inhibitor,
`
` do you?
`
` A. In my declaration I've not referenced
`
` that specifically.
`
` Q. Nowhere in your declaration do you
`
` reference an immune checkpoint inhibitor as
`
` including an antisense RNA molecule, do you?
`
` A. I don't see a specific reference to
`
` that.
`
` Q. You see a general reference to it?
`
` A. As I mentioned, and I stated
`
` previously, that -- and I'm talking about
`
` inhibitors of checkpoints, any inhibitor of
`
` checkpoint.
`
` Q. Any?
`
` A. Any inhibitor, inhibitors of
`
` checkpoints, checkpoint inhibitors.
`
` Q. Nowhere in your declaration do you
`
` reference as an immune checkpoint inhibitor an
`
` SI RNA molecule, correct?
`
` A. If I can understand, that was the
`
` previous question?
`
` Q. No, that was not the previous
`
` question.
`
` A. Can you repeat that again? SI is --
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` Q. Do you understand what an SI RNA
`
` molecule is?
`
` A. Yes, I do.
`
` Q. What is it?
`
` A. Short interfering.
`
` Q. Okay.
`
` A. Your previous question was antisense
`
` RNA.
`
` Q. Right.
`
` A. The outcome is the same.
`
` Q. The antisense RNA doesn't deal with
`
` the length, does it?
`
` It's more generic, correct?
`
` A. No. You had asked me a question
`
` whether antisense RNA reflected -- whether I
`
` mentioned it in relationship to a checkpoint.
`
` Q. Right.
`
` A. But antisense is to the message of a
`
` checkpoint.
`
` Q. RNA molecule, correct?
`
` A. It's an RNA molecule, so is SI RNA,
`
` short interfering.
`
` Q. Nowhere in your declaration do you
`
` mention RNA molecules specifically or generally
`
` as functioning as immune checkpoint inhibitors,
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` do you?
`
` DR. KAMHOLZ: Objection, compound.
`
` A. Can you break that question up?
`
` Q. Sure. Nowhere in your declaration do
`
` you mention RNA molecules functioning as immune
`
` checkpoint inhibitors, correct?
`
` A. I don't use the term RNA molecules as
`
` checkpoint inhibitors. However, as I stated
`
` before, they are all checkpoint inhibitors.
`
` Q. What is the word "all" that you are
`
` referring to, "they are all"?
`
` A. Any -- any strategy that inhibits
`
` checkpoints.
`
` Q. So I'm asking you a specific question.
`
` A. Yes.
`
` Q. I'm talking about -- I'm trying to
`
` find out what is in your declaration --
`
` A. Yes.
`
` Q. -- and what is not in your
`
` declaration.
`
` A. Yes.
`
` Q. That's thi