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` UNITED STATES PATENT AND TRADEMARK OFFICE
` BEFORE THE PATENT TRIAL AND APPEAL BOARD
`* * * * * * * * * * * * *
`Celltrion, Inc., *
` Petitioner, *
`v. * Case No. IPR2017-01121
`Genentech, Inc., * Patent No. 7,846,441
` Patent Owner. *
`* * * * * * * * * * * * *
`
` Videotaped Deposition of ROBERT S. KERBEL, PH.D.
` Wednesday, February 28, 2018
` 10:09 a.m.
` Wilmer Cutler Pickering Hale and Dorr LLP
` 60 State Street - 26th Floor
` Boston, Massachusetts 02109
`
`----------- J. Edward Varallo, RMR, CRR ----------
` Registered Professional Reporter
`
`212-279-9424
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`Veritext Legal Solutions
`www.veritext.com
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`212-490-3430
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` UNITED STATES PATENT AND TRADEMARK OFFICE
` BEFORE THE PATENT TRIAL AND APPEAL BOARD
`* * * * * * * * * * * * *
`Celltrion, Inc., *
` Petitioner, *
`v. * Case No. IPR2017-01121
`Genentech, Inc., * Patent No. 7,846,441
` Patent Owner. *
`* * * * * * * * * * * * *
`
` Videotaped Deposition of ROBERT S. KERBEL, PH.D.
` Wednesday, February 28, 2018
` 10:09 a.m.
` Wilmer Cutler Pickering Hale and Dorr LLP
` 60 State Street - 26th Floor
` Boston, Massachusetts 02109
`
`----------- J. Edward Varallo, RMR, CRR ----------
` Registered Professional Reporter
`
`212-279-9424
`
`Veritext Legal Solutions
`www.veritext.com
`
`212-490-3430
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`Page 2
`Attorneys for Petitioner Celltrion, Inc.:
` Cynthia Lambert Hardman, Esq.
` Goodwin Procter LLP
` The New York Times Building
` 620 Eighth Avenue
` New York, New York 10018-1405
` 212.813.8800 ~ Fax 212.355.3333
` chardman@goodwinlaw.com
`
`Attorneys for Patent Owner Genentech, Inc.:
` Andrew J. Danford, Esq.
` Wilmer Cutler Pickering Hale and Dorr LLP
` 60 State Street - 26th Floor
` Boston, Massachusetts 02109
` 617.526.6000 ~ Fax 617.526.5000
` andrew.danford@wilmerhale.com
`
`Videographer:
` Cedar Bushong, CLVS, Legal Video Specialist
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`Page 3
`
` I N D E X
`
`----------------------------------------------------
`DEPONENT PAGE
`----------------------------------------------------
`Robert S. Kerbel, Ph.D.
` by Ms. Hardman............................... 5
` by Mr. Danford............................... 73
`
`----------------------------------------------------
`CELLTRION EXHIBITS FOR IDENTIFICATION PAGE
`----------------------------------------------------
`Exhibit 1100 34
`Patent application filed January 28, 2000,
`for U.S. Provisional Application No.
`60/178791, Therapeutic Method for Reducing
`Angiogenesis
`
` ORIGINAL EXHIBITS RETAINED BY THE COURT REPORTER
` AND RETURNED TO ATTORNEY CYNTHIA HARDMAN
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`Page 4
`----------------------------------------------------
` MORNING SESSION
` 10:09 a.m.
`----------------------------------------------------
` THE VIDEOGRAPHER: We are on the record.
`The time is 10:08 a.m. on February 28, 2018.
` Please note that microphones are
`sensitive and may pick up whispering and private
`conversations and cellular interference. Please
`turn off all cell phones and place them away from
`the microphones as they can interfere with
`deposition audio.
` Audio and video recording will continue
`to take place unless all parties agree to go off the
`record.
` This is media unit 1 of the video-
`recorded deposition of Dr. Robert Kerbel taken by
`counsel for the petitioner in the matter of
`Celltrion, Inc. versus Genentech, Inc., filed in the
`United States Patent and Trademark Office before the
`Patent Trial and Appeal Board. This deposition is
`being held at WilmerHale, located at 60 State
`Street, Boston, Massachusetts.
` My name is Cedar Bushong from the firm
`Veritext Legal Solutions and I am the videographer.
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`Page 5
`The court reporter is Edward Varallo from the firm
`Veritext Legal Solutions. I am not authorized to
`administer an oath. I am not related to any party
`in this action, nor am I financially interested in
`the outcome.
` Counsel and all parties present remotely
`will now state their appearances for the record.
` MS. HARDMAN: Cynthia Hardman of Goodwin
`Procter for petitioner Celltrion.
` MR. DANFORD: Andrew Danford for patent
`owner Genentech and the witness.
` THE VIDEOGRAPHER: Perfect. Will the
`court reporter please swear in the witness and we
`can proceed.
` ROBERT S. KERBEL, PH.D.,
` having been first duly sworn on oath,
` was examined and testified as follows:
` EXAMINATION
`BY MS. HARDMAN:
` Q. Good morning, Dr. Kerbel. Would you
`please state your full name for the record?
` A. Robert Stephen, with a p-h, Kerbel.
` Q. And you've had your deposition taken
`before?
` A. I had a deposition yesterday.
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`Page 6
` Q. Okay. If I ask any questions today that
`are unclear, would you please let me know so that I
`could try to rephrase?
` A. Yes.
` Q. Did you do anything to prepare for
`today's deposition?
` A. Yes.
` Q. What did you do?
` A. I had consultations with the lawyers
`that I'm dealing with here at WilmerHale. I did
`quite a bit of reading mainly of literature,
`relevant literature, prior most of it to 1997, the
`filing of the patent; and I had some phone
`conversations with the lawyers, a few; and then when
`I was preparing my declaration, there was some back-
`and-forth with the lawyers.
` Q. When you were preparing your
`declaration, which lawyers were you working with?
` A. Primarily with Nora -- How do you
`pronounce her last name?
` MR. DANFORD: Passamaneck.
` A. Passamaneck. To some extent with Andrew
`Danford here. Andrew was on paternity leave for a
`while, so I was dealing while he was away with Nora.
` Q. And besides Nora and Andrew, did you
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`Page 7
`
`work with any other lawyers?
` A. No.
` Q. And in terms of your preparation for
`deposition, you mentioned you met with lawyers.
`Right?
` A. Yes.
` Q. And which lawyers were those?
` A. I met once in Boston for a very brief
`time, maybe an hour and a half, here at WilmerHale
`in September, I believe. Physically that was the
`only time other than now for this deposition.
` Q. In connection with this deposition,
`which lawyers did you meet to prepare for the
`deposition?
` A. At the time that I met in September, I
`met Andrew in person and Nora through a video.
` Q. Did you have any in-person meetings with
`the lawyers specifically to prepare for this
`deposition?
` A. I'm not sure what you mean by that, if
`you could repeat it.
` Q. Sure. In the days leading up to this
`deposition, did you have any in-person meetings with
`the lawyers?
` A. On Monday, yes.
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`Page 8
` Q. Okay. And who did you meet with on
`Monday?
` A. I met with the two lawyers in question.
` Q. Meaning Nora and Andrew?
` A. Nora and Andrew.
` Q. And how long did you meet with them on
`Monday?
` A. Oh, for about six hours, seven hours,
`something like that.
` Q. In preparing your -- Well, let me ask:
`In connection with your work on this case, have you
`spoken with anybody who is employed by Genentech?
` A. No.
` Q. When were you first retained to work on
`this matter?
` A. Around mid-August.
` Q. Of 2017?
` A. Yes.
` Q. And what was your understanding of what
`your role would be?
` A. That I would be an expert who would
`submit a declaration in relationship to the claims
`of the '441 and '549 patents.
` Q. Prior to this engagement on these, the
`'441 and '549 patents, had you done any prior work
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`
`for Genentech?
` A. I was involved as an expert outside, an
`outside expert, where I wrote a declaration on
`behalf of Genentech in relationship to a European
`Patent Office filing, a patent that had to deal with
`another Genentech drug called Avastin, an anti-
`angiogenic drug. That took place in Munich. I
`can't remember exactly when, but more than fifteen
`years ago.
` Q. And did you provide oral testimony in
`connection with that engagement?
` A. No.
` Q. And aside from this proceeding and the
`Avastin work that you just mentioned, have you done
`any other work for Genentech?
` A. I have interacted with Genentech in a
`number of ways. I have served as an ad hoc
`scientific advisory board member on a number of
`occasions over the last fifteen years. I don't
`recall the exact number but it would probably be in
`the range of about a half a dozen such meetings.
`Secondly, I have used Genentech research materials
`which I requested through their Genentech website.
`I was provided with those materials. The materials
`in question were primarily antibodies, primarily
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`Page 10
`antibodies that were designed to be so-called
`anti-angiogenic drugs. And finally most recently I
`have initiated a sponsored research agreement with
`Genentech to help evaluate one of their
`immunotherapeutic agents, an antibody against an
`entity called PD-L1. I'm not receiving any
`consulting fees for that, but there is a small
`amount of money to facilitate the research project
`which they're interested in supporting.
` Q. So that sponsored research agreement
`concerning the PD-L1 antibody is currently ongoing?
` A. It hasn't started yet. It's taken, as
`is often the case with these things, many months for
`the university, the hospital where I work, and
`Genentech, the technology transfer offices and
`lawyers, to finalize the agreement.
` Q. And when did your discussions with
`Genentech on that particular sponsored research
`agreement begin?
` A. Yes, they arose at the beginning of
`August as a result of the fact that I attended
`what's known as a Gordon Research Conference on the
`topic of partly angiogenesis and blood vessels and
`tumors. There I met a researcher who works at
`Genentech named Dr. Weilan Li and I discussed an
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`Page 11
`idea with her based on her presentation, and she
`liked the idea and we decided then to initiate this
`collaboration.
` Q. And that discussion you had with Ms. Li
`was in August 2017?
` A. Yes.
` Q. And that was also the same time that you
`began work on this or that you were approached for
`this matter?
` A. No. We had that conversation before.
`That was at the beginning of August and I did not
`receive a call from WilmerHale until sometime later
`in August.
` Q. Do you have any understanding of why
`WilmerHale reached out to you on this particular
`engagement?
` A. No.
` Q. Do you know petitioner's expert
`Dr. Robert Earhart?
` A. No.
` Q. Had you heard his name before this
`proceeding?
` A. I had not.
` Q. I'll hand you what's been previously
`marked as Celltrion Exhibit 1002 in IPR2017-01121.
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`Page 12
`I'm sorry. Can I have that back? I actually gave
`you the wrong -- That's not what I intended to give
`you.
` A. Sure.
` Q. Thank you. (Pause)
` Okay, so instead of that exhibit that I
`just took back, I will instead hand you what's been
`marked as Genentech Exhibit 2061 in IPR2017-01121.
`And I'll also hand you what's been marked as
`Genentech Exhibit 2061 in IPR2017-01122.
` Andrew, I'm sorry, I don't have a copy
`of the second one for you, but....
` Why don't we start with the thicker
`version which has the appendices to your
`declaration. Would you look in there? Would you
`turn, please, to page 38 of that declaration. And
`is that your signature there?
` A. It is.
` Q. Now, we have the second declaration in
`front of you in the 1122 proceeding. Are the two
`declarations substantively the same in terms of the
`opinions that you're expressing in those documents?
` A. Yes, I recall so. They're pretty much
`the same.
` Q. Okay. So just to make this easy, why
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`Page 13
`don't we just focus on the declaration in the 1121
`proceeding.
` A. Sure.
` Q. Who actually drafted this declaration?
` A. I drafted it, the majority of it, the
`vast majority of it.
` Q. Did you start with a first draft from
`the attorneys?
` A. My recollection is that I provided a
`number of my arguments and thoughts particularly
`about Baselga '94 and we went back and forth. So
`some of the more legal aspect, legalese, they would
`provide and my input was to give my scientific
`opinions of Baselga '94 and some other information
`but mainly Baselga '94.
` Q. And now besides counsel, did anyone else
`assist you in preparing this declaration?
` A. Other than my secretary? No.
` Q. Let's turn, please, to paragraph 51 of
`your declaration. And that's on page 22. And in
`this paragraph you set forth what you had been asked
`to render your expert opinion on. Is that correct?
` A. That is correct.
` Q. And does this paragraph provide an
`accurate summary of your assignment in this case?
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`Page 14
` A. If you'd just give me a moment. (Pause)
`Yes.
` Q. And in this paragraph you say that you
`were asked to render an expert opinion as to whether
`preclinical human tumor xenograft animal data
`provides any predictive value. Is that right?
` A. Correct.
` Q. And in your declaration you did not
`offer an opinion as to whether any human clinical
`data for trastuzumab or paclitaxel has any
`predictive value in humans. Is that correct?
` A. That's correct. My major focus was on
`the preclinical data.
` Q. So in your declaration you do not
`provide an opinion on how a clinician would view the
`combination of the preclinical data together with
`human clinical data. Is that correct?
` MR. DANFORD: Objection to form.
` A. My major focus was how a clinician, one
`skilled in -- an ordinary person skilled in the art,
`a medical oncologist with some research experience,
`would view Baselga '94.
` Q. And Baselga '94 is limited to
`preclinical data. Is that correct?
` A. Completely, yes.
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` Q. And is it correct -- Well, let me start
`over. Your declaration does not set forth an
`opinion on how a person of skill in the art would
`view the Baselga preclinical data in light of human
`clinical data for the combination of drugs.
`Correct?
` A. It primarily focused on the preclinical
`data.
` Q. Did it present any opinion at all as to
`how one would view the preclinical data in view of
`existing human clinical data for the combination of
`drugs in Baselga?
` MR. DANFORD: Objection to form.
` A. Once again, my assessment mainly was
`confined to how a clinician would view Baselga '94.
` Q. I'm not sure that answers my specific
`question.
` A. Okay.
` Q. So you didn't give an opinion about how
`a clinician would view Baselga '94 in combination
`with human clinical work on trastuzumab and
`paclitaxel. Correct?
` A. In my declaration there was little
`mention of that, as I recall.
` Q. Your declaration does not provide any
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`Page 16
`opinion on the validity of the '441 or '549 patents.
`Correct?
` A. I didn't comment on that.
` Q. Now, you have a Ph.D. in microbiology
`and immunology?
` A. To be more specific, immunology.
` Q. And you do not have an M.D. Correct?
` A. That is correct.
` Q. Is it fair to say that much of your
`career has focused on preclinical studies?
` A. Yes.
` Q. And is it fair to say that part of the
`calculus as to whether to put a combination of
`anti-cancer drugs into humans is a consideration of
`the safety and efficacy, is a consideration of
`safety and efficacy data that's generated in
`preclinical studies?
` MR. DANFORD: Objection to form.
` A. The decision to undertake that type of
`combination would be in part dependent on the
`requisite associated preclinical data.
` Q. Is it fair to say that before putting a
`drug combination in humans, one of skill in the art
`would need a reasonable expectation that that
`combination would be safe and effective?
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`Page 17
` MR. DANFORD: Objection to form.
` A. I can't really speculate on that.
`There's a hope, that might be a better word, there
`is a hope that it would be safe and effective.
`Expectation I think would be a stretch.
` Q. Conversely, a person of skill in the art
`would not put a drug combination into a human if
`they had an expectation that it would be unsafe.
`Correct?
` MR. DANFORD: Objection to form.
` A. Right. Yes, I would agree with that.
` Q. Have you ever had personal
`responsibility for deciding whether sufficient
`evidence, preclinical evidence, existed to advance
`to a human clinical?
` A. Could you rephrase that or -- ? Sorry.
`Could you repeat that question?
` Q. Sure. Have you ever had personal
`responsibility for deciding whether sufficient
`preclinical evidence existed to advance a drug to a
`human clinical trial?
` A. I have been involved in preclinical
`studies assessing various therapies which looked
`promising and which appeared safe and which I
`discussed with medical oncology colleagues to
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`Page 18
`solicit their opinion of the work and also to
`determine whether they might be interested in
`carrying out a clinical trial or a pilot study of
`that type of combination.
` Q. Is it correct that the medical
`oncologist would have the ultimate decision as to
`whether to carry out a clinical trial or pilot
`study?
` MR. DANFORD: Objection to form.
` A. Mostly but not entirely. For example,
`even if the medical oncologist agreed that this was
`a good idea and that he or she was interested in
`pursuing a clinical study, that study would have to
`be approved by for example a review board in a
`hospital; for example, the ethics review board. And
`sometimes approval might not be given.
` Q. Have you ever personally been part of
`the initiation of a clinical trial or pilot study of
`a drug in a human?
` MR. DANFORD: Objection, form.
` A. Are you asking whether the work that I
`did led to a clinical trial?
` Q. No. If you have attempted to initiate a
`clinical trial in humans.
` MR. DANFORD: Objection.
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`Page 19
` A. Oh, I can't do that. I can only do
`clinical trials in mice.
` Q. Why is that?
` A. I'm not a clinician. I can suggest to
`clinicians, medical oncologists, either through
`personal interaction or by being a member of a
`scientific advisory board in a company or by giving,
`for example, lectures at cancer treatment centers
`that perhaps a particular drug or combination of
`drugs or a particular concept might be considered
`for a clinical trial based on the data and the ideas
`that I present and possibly on the data obtained by
`others.
` Q. And have you in fact made such
`suggestions in the past?
` A. Oh, yes, many times.
` Q. Now, in 1997 did the USFDA require
`in vivo preclinical studies as part of an
`application for a new drug?
` A. As far as I know, in general that would
`be required. At least the patents that I saw at
`that time, and I can't say that I saw a great
`number, had animal data.
` Q. In terms of the FDA, though, for
`approval or for an application to market a new drug,
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`Page 20
`do you know whether the FDA required preclinical
`data?
` A. I can't say with complete certainty.
` Q. Is it your best understanding that the
`FDA does in fact require preclinical data?
` MR. DANFORD: Objection, asked and
`answered.
` A. Again, I would be guessing, so I'd
`prefer to stay away from that.
` Q. Are in vivo preclinical studies
`typically used before a drug is dosed in humans?
` MR. DANFORD: Objection.
` A. Yes.
` Q. And in 1997 were xenograft studies
`common in the development of drugs for use in cancer
`treatment?
` A. They were.
` Q. Is it fair to say that in 1997 xenograft
`studies were universally used in the development for
`anti-cancer drugs?
` MR. DANFORD: Objection to form.
` A. No. There were other models that were
`used.
` Q. What other in vivo animal models were
`commonly used in cancer drug development in 1997?
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`Page 21
` A. There were two types, at least with
`respect to mice, which was the common species that
`was used. The first would be the continuation of
`the use of mouse tumors grown in immunocompetent
`mice, especially if one was undertaking analysis of
`a drug designed to stimulate the tumor, the immune
`system to fight the disease. And the second
`approach, which was beginning to become increasingly
`popular, was the use of what are called genetically
`engineered mouse models of cancer, so-called GEMMs,
`G-E-M-M-S. So these are mice which have been
`genetically manipulated so that they spontaneously
`develop certain types of cancers and do so in a way
`that more faithfully recapitulates the development
`of that type of tumor -- that was the theory, at
`least -- in humans.
` Q. Was the use of the mouse tumor model
`common in 1997?
` A. The genetically engineered mouse model?
` Q. No, the first option you mentioned, the
`tumor --
` A. It was still being used quite a bit in
`the mid 1990s, yes, along with human tumor
`xenografts and genetically engineered mouse models
`of cancer.
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`Page 22
` Q. So the GEMMs were also in common use in
`1997?
` A. They were beginning to be in common use,
`yes.
` Q. Are both of those types of models still
`used today?
` A. They are. Interestingly, there was a
`period where the use of transplantable mouse tumors
`grown in immunocompetent mice was falling by the
`wayside compared to some of these other models, but
`there has been over the last five years a really
`very strong resurrection of the use of those models
`because of the remarkable ascendancy and interest in
`immunotherapeutics.
` And the other development that has taken
`hold, and this began about ten years ago, is the use
`of what are called PDXs, P-D-X, PDXs, patient-
`derived xenografts. So these involve taking a
`biopsy specimen, removing a bit of tumor from a
`patient, and putting it into an immune-suppressed
`mouse. That technology has greatly improved from
`when it was first developed in the late 19 -- or
`1970s and 1980s. And this was used primarily for
`personalized medicine oncology decision-making.
` Q. Stepping back to the 1997 time frame,
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`Page 23
`once there was xenograft data in hand, was it common
`to then perform additional in vivo tests in other
`types of animal models?
` A. I would say that would be an exception
`more than the rule. More common would be to repeat
`that type of experiment in another xenograft rather
`than, say, trying to repeat it in a so-called
`genetically engineered mouse model of cancer.
` Q. Is one purpose of in vivo preclinical
`testing to help decide whether to move a drug
`candidate into humans?
` A. Yes.
` Q. Is another purpose of in vivo
`preclinical testing to help decide whether to
`propose modifications to existing dose regimens of
`drugs that are already in humans?
` A. That can happen. It's much more -- It's
`much less common.
` Q. Is another purpose of in vivo
`preclinical testing to help decide whether to
`propose combining administration of two drugs that
`are already used in humans?
` A. Yes.
` Q. I'll hand you what has been pre-marked
`as Genentech Exhibit 2080 in the 1121 IPR. Is this
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`Page 24
`
`a paper on which you are a co-author?
` A. It is.
` Q. And was this published in 2009?
` A. Correct.
` Q. And the title of this paper is
`Comparative Impact of Trastuzumab and
`Cyclophosphamide on HER2-Positive Human Breast
`Cancer Xenografts. Correct?
` A. That's right.
` Q. And you worked with trastuzumab in this,
`in the experiments described in this paper.
`Correct?
` A. Yes. This was one of a number of
`studies. Not a large number but I did work in the
`past on trastuzumab.
` Q. And the trastuzumab used in these
`studies was a generous gift from Genentech.
`Correct?
` A. That's right, as I recall.
` Q. If you'd look on the front page here,
`6358, do you see under Grant Support, do you see
`that reference there --
` A. Yes.
` Q. -- to a gift from Genentech?
` A. Yes. Yes.
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`Page 25
` Q. And was this a preclinical study of
`trastuzumab and cyclophosphamide using either a
`conventional maximum tolerated dose regimen or a
`continuous low-dose metronomic dosing regimen?
` MR. DANFORD: Objection, form.
` A. Well, the major focus of the study was
`to evaluate whether this unconventional dosing and
`scheduling regimen of cyclophosphamide, often
`referred to as metronomic chemotherapy, might be an
`ideal partner for a biologic agent which in this
`case was trastuzumab.
` Q. If you could turn, please, to page 6359.
` A. Mm-hmm.
` Q. And under the box there in the first
`full paragraph, the paragraph starts "Given the
`development."
` A. Which page are we on? Oh, 59? Okay.
` Q. Correct.
` A. Yes.
` Q. You report there that the results
`illustrate the possible benefits of using
`trastuzumab in combination with metronomic
`chemotherapy for metastatic breast cancer. Right?
` A. Yes.
` Q. Now, above that paragraph is a box that
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`Page 26
`is titled Translational Relevance. What does
`translational relevance mean?
` A. Translational relevance generally and in
`this particular case specifically was referring to
`the notion that perhaps this regimen might be
`effective in patients or at least should be or could
`be considered as a possible therapeutic strategy to
`assess in patients.
` Q. And more generally what does the term
`translational mean in the context of research?
` A. That a basic research finding has some
`degree of chance of being relevant and translated
`into human beings.
` Q. One thing that you point out in this box
`on translational relevance is that the combination
`involving metronomic chemotherapy did not exhibit
`the severe toxicity associated with the maximum
`tolerated dose regimen. Correct?
` A. That's correct.
` Q. And that finding on toxicity, that was
`generated in a xenograft study?
` A. Yes.
` Q. And is it correct that in this paper the
`only original research results that you present are
`based on preclinical models?
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`Page 27
`
` A. Yes.
` Q. And was it in fact only xenograft models
`or were there other types of preclinical models used
`here as well?
` A. Only xenograft.
` Q. If we could turn, please, to page 6363.
`In the left column, the last paragraph, you refer to
`a fundamental aspect of your study. What was that
`referring to, the fundamental aspect of the study?
` MR. DANFORD: Just help me. Where are
`you looking?
` MS. HARDMAN: Sure. Left column, the
`heading is Discussion but I'm looking all the way
`down at the last paragraph. It begins "We have used
`the met2 model."
` MR. DANFORD: Right, thanks.
` A. Yes.
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