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`Page 1
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`NEPTUNE GENERICS, LLC, APOTEX INC.,
`
`APOTEX CORP., TEVA PHARMACEUTICALS USA,
`
`INC., and FRESNIUS KABI, USA, LLC,
`
`Case IPR2016-00237
`
`Petitioners,
`
`-v-
`
`ELI LILLY & COMPANY,
`
`Patent Owner
`
`Case IPR2016-00240
`
`Patent 7,772,209
`
`VIDEOTAPED DEPOSITION OF
`
`STEVEN H. ZEISEL, M.D., Ph.D.
`
`Washington, D.C.
`
`Tuesday, November 22, 2016
`
`Reported by:
`
`Gail L. Inghram Verbano,
`
`23
`
`BA, CRR, CLR, RDR, CSR-CA (No. 8635)
`
`Job No. 115462
`
`24
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`25
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`TSG Reporting - Worldwide
`
`877-702-9580
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1086-0001
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`Page 1
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`NEPTUNE GENERICS, LLC, APOTEX INC.,
`
`APOTEX CORP., TEVA PHARMACEUTICALS USA,
`
`INC., and FRESNIUS KABI, USA, LLC,
`
`Case IPR2016-00237
`
`Petitioners,
`
`-v-
`
`ELI LILLY & COMPANY,
`
`Patent Owner
`
`Case IPR2016-00240
`
`Patent 7,772,209
`
`VIDEOTAPED DEPOSITION OF
`
`STEVEN H. ZEISEL, M.D., Ph.D.
`
`Washington, D.C.
`
`Tuesday, November 22, 2016
`
`Reported by:
`
`Gail L. Inghram Verbano,
`
`23
`
`BA, CRR, CLR, RDR, CSR-CA (No. 8635)
`
`Job No. 115462
`
`24
`
`25
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1086-0001
`
`
`
`Page 2
`
`November 22, 2016
`
`8:13 a.m.
`
`Videotaped deposition of STEVEN H.
`
`ZEISEL, M.D., PH.D., held at the offices of
`
`WILLIAMS & CONNOLLY, LLP, 725 Twelfth Street,
`
`N.W., Washington, D.C. 20005-5901, before GAIL
`
`INGHRAM VERBANO, Registered Diplomate Reporter,
`
`Certified Realtime Reporter, Certified
`
`Shorthand Reporter-CA (No. 8635) and Notary
`
`Public in and for the District of Columbia.
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`877-702-9580
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`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1086-0002
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`Page 3
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`A P PEA RAN C E S:
`
`Attorneys for Neptune Generics:
`
`SKIERMONT DERBY
`
`2200 Ross Avenue
`
`Dallas, Texas 75201
`
`BY:
`
`SARAH SPIRES, ESQ.
`
`Attorneys for Sandoz, Inc.:
`
`BRINKS GILSON & LIONE
`
`NBC Tower
`
`455 North Cityfront Plaza Drive
`
`Chicago, Illinois 60611
`
`BY:
`
`LAURA LYDIGSEN, ESQ.
`
`III
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1086-0003
`
`
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`Page 4
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`Attorneys for Mylan:
`
`ALSTON & BIRD
`
`90 Park Avenue
`
`New York, New York 10016
`
`BY:
`
`THOMAS PARKER, ESQ.
`
`Attorneys for Patent Owners:
`
`WILLIAMS & CONNOLLY
`
`725 Twelfth Street, N.W.
`
`Washington, D.C. 20005
`
`BY:
`
`DAVID KRINSKY, ESQ.
`
`DOV GROSSMAN, ESQ.
`
`ADAM PERLMAN, ESQ.
`
`-and-
`
`ELI LILLY AND COMPANY
`
`Lilly Corporate Center
`
`Indianapolis, Indiana 46285
`
`BY:
`
`JAMES LEEDS, ESQ.
`
`25
`
`/ / /
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1086-0004
`
`
`
`Page 5
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`Attorneys for Petitioner Teva:
`
`(Present Telephonically)
`
`CARLSON CASPERS VANDENBURGH LINDQUIST & SCHUMAN
`
`225 South 6th Street
`
`Minneapolis, Minnesotta 55402
`
`BY:
`
`GARY SPEIER, ESQ.
`
`ALSO PRESENT:
`
`JORDAN MUMMERT, Legal Video Specialist
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`TSG Reporting - Worldwide
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`877-702-9580
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`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1086-0005
`
`
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`Page 6
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`STEVEN H. ZEISEL, M.D., Ph.D.
`
`THE VIDEOGRAPHER: This is the start
`
`of the video deposition of Dr. Steven
`
`H. Zeisel in the matter Neptune Generics,
`
`LLC, et ale versus Eli Lilly & Company.
`
`This deposition is taking place at
`
`725 12th Street Northwest, Washington,
`
`D.C. on November 22nd, 2016, at
`
`approximately 8:13 a.m.
`
`My name is Jordan Mummert from TSG
`
`Reporting, Inc.
`
`I am the legal video
`
`specialist. The court reporter is Gail
`
`Verbano in association with TSG Reporting.
`
`Will the counsel please introduce
`
`yourselves.
`
`MR. KRINSKY: David Krinsky from
`
`Williams & Connolly, LLP, on behalf of the
`
`patent owner, Eli Lilly & Company. With
`
`me are Dov Grossman and Adam Perlman, also
`
`of Williams & Connolly; and James Leeds of
`
`Eli Lilly & Co.
`
`MS. SPIRES: Sarah Spires of
`
`Skiermont Derby, LLP, representing Neptune
`
`Generics.
`
`MR. PARKER:
`
`Thomas Parker,
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1086-0006
`
`
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`Page 7
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`STEVEN H. ZEISEL, M.D., Ph.D.
`
`P-A-R-K-E-R, Alston & Bird, for Mylan.
`
`MS. LYDIGSEN: Laura Lydigsen of
`
`Brinks Gilson & Lione for Sandoz, Inc.
`
`THE VIDEOGRAPHER: And on the phone?
`
`MS. SPIRES:
`
`I believe we'll have
`
`some people on the phone at some point but
`
`we haven't been able to dial in yet.
`
`THE VIDEOGRAPHER:
`
`The court
`
`reporter may swear in the witness.
`
`STEVEN H. ZEISEL, M.D., PH.D.
`
`called as a witness, having been duly sworn by
`
`a Notary Public, was examined and testified as
`
`follows:
`
`EXAMINATION
`
`BY MS. SPIRES:
`
`Q
`
`A
`
`Q
`
`Good morning, Dr. Zeisel.
`
`Morning.
`
`Could you start by describing your
`
`experience working with cancer drugs up to
`
`1999.
`
`A
`
`Sure.
`
`I am a professor at the
`
`University of North Carolina, Chapel Hill.
`
`Prior to that I was trained in medicine, and I
`
`have a Ph.D. in neurochemistry and nutrition.
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1086-0007
`
`
`
`Page 8
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`STEVEN H. ZEISEL, M.D., Ph.D.
`
`And during my work as a professor,
`
`I've conducted research in nutrition and in
`
`nutrition as it relates to cancer; and have
`
`worked with studies on -- funded by the
`
`National Cancer Institute; and agents like
`
`genistein, a Phase 1 study, would be an
`
`example.
`
`Q
`
`Prior to this case, have you ever
`
`done in any work for Eli Lilly?
`
`A
`
`I was an expert witness in a case
`
`approximately two years ago in Indiana District
`
`Court.
`
`Q
`
`In your work as a nutritionist, do
`
`you ever work with oncologists?
`
`A
`
`I do.
`
`I've collaborated on a number
`
`of research studies, and I'm a member of the
`
`Lineberger Cancer Research Institute, an
`
`NIH-funded center focusing on cancer, the
`
`treatment and causes of cancer and its
`
`prevention.
`
`Q
`
`Do you ever work with oncologists in
`
`conjunction with patient care?
`
`A
`
`Again, I worked with oncologists in
`
`conjunction with patient care as part of
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1086-0008
`
`
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`Page 9
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`STEVEN H. ZEISEL, M.D., Ph.D.
`
`research studies.
`
`Q
`
`Have you ever worked with
`
`oncologists in conjunction with patient care
`
`outside of the context of research studies?
`
`A
`
`Once I finished my residency in
`
`pediatrics, I've solely seen patients as part
`
`of research thereafter.
`
`Let me correct that.
`
`I was a Fellow
`
`at Children's Hospital in Boston for a couple
`
`of years where I saw patients as well. But
`
`after that period of time, since 1982 or so,
`
`I've mainly done -- only done research and seen
`
`patients in the context of them being subjects
`
`in a clinical trial.
`
`Q
`
`So you don't have experience working
`
`with oncologists in conjunction with routine
`
`patient care?
`
`A
`
`So again, patients in a clinical
`
`trial get routine patient care; but we are
`
`collecting information and data to develop new
`
`knowledge during that.
`
`So it's a research study, and I
`
`don't get paid.
`
`I don't charge patients for
`
`the care. They're covered because they're part
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1086-0009
`
`
`
`Page 10
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`STEVEN H. ZEISEL, M.D., Ph.D.
`
`of the research program.
`
`So they get routine care, but
`
`they're a part of a research study.
`
`I do not
`
`see patients where I'm seeing them, billing
`
`them for my services.
`
`Q
`
`As part of your work in the research
`
`studies, do you work with oncologists to
`
`develop a protocol for patient cancer
`
`treatment?
`
`MR. KRINSKY: Objection to the form
`
`of the question.
`
`THE WITNESS: Could you repeat that
`
`again.
`
`BY MS. SPIRES:
`
`Q
`
`I'll ask a better question.
`
`Do you work -- do you ever work with
`
`oncologists in developing a protocol for
`
`patient care for cancer treatment?
`
`A
`
`So as part of these research
`
`studies, we have to put together a protocol
`
`that we will follow with each of the patients
`
`being studied.
`
`So, for instance, let's take the
`
`genistein study. We would have -- I would have
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1086-0010
`
`
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`Page 11
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`STEVEN H. ZEISEL, M.D., Ph.D.
`
`sat down with oncologists, and we would have
`
`discussed the dosing, the timing, the
`
`measurements we would make, and we would submit
`
`a protocol to a board called the Institutional
`
`Review Board together. And that would have
`
`been approved, and that's what we would have
`
`proceeded in the study.
`
`So, yes, I would have worked with
`
`them for the research study clinical care
`
`design and the exact protocol that would be
`
`followed with every subject in the study.
`
`MR. KRINSKY: Could we go off the
`
`record for a moment?
`
`MS. SPIRES: Sure.
`
`THE VIDEOGRAPHER:
`
`Time is 8:19.
`
`We're off the record.
`
`(Discussion off the record.)
`
`THE VIDEOGRAPHER:
`
`Time is 8:24.
`
`We're on the record.
`
`BY MS. SPIRES:
`
`Q
`
`So I understand you have experience
`
`developing protocols for research studies.
`
`A
`
`Q
`
`I do.
`
`Do you have experience developing a
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1086-0011
`
`
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`Page 12
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`STEVEN H. ZEISEL, M.D., Ph.D.
`
`treatment protocol for a patient outside of a
`
`research study? A cancer patient?
`
`A
`
`Q
`
`A
`
`Q
`
`Not since I finished my residency.
`
`You said that was in around 1992?
`
`I finished my residency in '77.
`
`In 1999, it was not uncommon for an
`
`oncologist to consult with a nutritionist
`
`regarding the nutrition of a cancer patient;
`
`correct?
`
`A
`
`No. When a nutritional issue carne
`
`up with a cancer patient, an oncologist would
`
`consult; and normally that consultation was
`
`about the patient was losing weight for a
`
`treatment, et cetera.
`
`MR. PERLMAN: Could we just go off
`
`the record for a second?
`
`THE WITNESS:
`
`Time is 8:25. Off the
`
`record.
`
`(Discussion off the record.)
`
`THE VIDEOGRAPHER:
`
`Time is 8:27.
`
`We're on the record.
`
`BY MS. SPIRES:
`
`Q
`
`In 1999, a typical oncologist would
`
`have had limited knowledge in the field of
`
`TSG Reporting - Worldwide
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`877-702-9580
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1086-0012
`
`
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`Page 13
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`STEVEN H. ZEISEL, M.D., Ph.D.
`
`nutrition; correct?
`
`A
`
`I think it depends on the training
`
`of the oncologist.
`
`In certain areas, the
`
`oncologist would have had a deeper
`
`understanding because the interventions they're
`
`performing involved some aspect of metabolism
`
`or nutrition.
`
`In other areas, they might have
`
`not been as well up-to-date.
`
`But I think it's very hard to say
`
`what any individual oncologist's nutrition
`
`background might have been outside of the areas
`
`that directly impact on their oncology
`
`services.
`
`Q
`
`When is the last time you treated
`
`patients with vitamin deficiencies?
`
`A
`
`Again, as part of research studies,
`
`probably a year or two ago, maybe this year.
`
`Depends on the research protocol.
`
`Q
`
`As part of these research studies,
`
`would you know from the outset that a patient
`
`had vitamin deficiencies?
`
`A
`
`Q
`
`I'm sorry. Could you repeat that.
`
`Would you know from the outset of
`
`the research protocols that the patients had
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1086-0013
`
`
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`Page 14
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`STEVEN H. ZEISEL, M.D., Ph.D.
`
`vitamin deficiencies?
`
`A
`
`You would have had a set of
`
`laboratory studies that you would have
`
`interpreted, along with physical exam studies,
`
`that you would have drawn the conclusion that
`
`they have a health problem or an organ
`
`dysfunction problem relating to having too
`
`little of a nutrient; and you then would have
`
`treated that for some of the studies.
`
`We were specifically studying people
`
`who had a problem and asking whether giving the
`
`vitamin or nutrient back made that problem go
`
`away.
`
`Q
`
`Was it part of the research
`
`protocols to do this testing, this lab work
`
`that you mentioned prior to patients entering
`
`the clinical trials?
`
`A
`
`So that -- you're asking me was it
`
`part of the protocol to do all of the tests?
`
`It was a part of the protocol to do
`
`a set of tests to describe the patient and
`
`determine whether they were, quote, normal or
`
`not. And then you would do additional tests as
`
`indicated by the results of the first test that
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`STEVEN H. ZEISEL, M.D., Ph.D.
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`were part of the protocol.
`
`All tests are part of the protocol,
`
`but there might have been some extra ones that
`
`had to follow-up tests after you got the first
`
`results back.
`
`Q
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`Are you aware of whether similar
`
`testing is done outside of the research
`
`context?
`
`MR. KRINSKY: Objection; scope.
`
`THE WITNESS:
`
`So your question is,
`
`is
`
`would a physician be doing tests
`
`like this when they're seeing their
`
`patients?
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`And some of the tests are fairly
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`standard tests that you would do on a
`
`patient at their yearly physical, and
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`other tests you would do because you had
`
`some specific symptom or sign in the
`
`patient that told you you should follow up
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`with more testing to figure out what is
`
`the cause or what's going on in the
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`patient.
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`BY MS. SPIRES:
`
`Q
`
`Is testing for vitamin deficiencies
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`STEVEN H. ZEISEL, M.D., Ph.D.
`
`a standard part of these tests?
`
`MR. KRINSKY: Object to the form;
`
`scope.
`
`THE WITNESS:
`
`So, again, would a
`
`physician test for vitamin deficiencies in
`
`every patient? No. But some of the tests
`
`that they would normally do on a yearly
`
`physical might be the first clue that
`
`there was a vitamin deficiency, and then
`
`they would follow up to look at that.
`
`BY MS. SPIRES:
`
`Q
`
`And would a physician, as of 1999,
`
`be conducting these tests?
`
`A
`
`Yes, a physician in 1999 would be
`
`doing laboratory tests on patients and
`
`following up with more tests if the first test
`
`gave them indications to do so.
`
`Q
`
`You state in your declaration that
`
`antifolates interfere with the natural action
`
`of folates; correct?
`
`A
`
`Q
`
`Yes.
`
`How do antifolates interfere with
`
`the natural action of folates?
`
`A
`
`So there is a variety of drugs
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`STEVEN H. ZEISEL, M.D., Ph.D.
`
`called antifolates. Most of them act by
`
`competing with folate, reduced folate, for
`
`folates in general, for binding to some
`
`enzyme -- an enzyme being the protein that
`
`helps folate progress through the steps in
`
`metabolism that have to occur to make DNA or to
`
`be used in other ways.
`
`And the different antifolates bind
`
`differently to different enzymes depending on
`
`their structure and properties. But in
`
`general, they are called an anti folate because
`
`they compete with folate, at least one of these
`
`important enzymes that normally folate would be
`
`published through metabolism by.
`
`Q
`
`I think you mentioned that
`
`antifolates compete with reduced folate for
`
`binding to enzymes; is that correct?
`
`A
`
`Q
`
`I'm sorry.
`
`I think you mentioned
`
`trying to
`
`go without realtime here -- that
`
`I think you
`
`mentioned that antifolates compete with reduced
`
`folate for binding to enzymes; is that correct?
`
`A
`
`I should correct that. They compete
`
`with folate because -- dihydrofolate reductase,
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`STEVEN H. ZEISEL, M.D., Ph.D.
`
`they would be competing with a nonreduced
`
`folate, a folic acid for binding to the
`
`dihydrofolate reductase.
`
`So be more accurate, they compete
`
`with folate at some step for binding to an
`
`enzyme, whether it's reduced or not reduced.
`
`Q
`
`So if the anti folate is competing
`
`with the folate for DHFR,
`
`then the anti folate
`
`is competing with nonreduced folate; correct?
`
`A
`
`Q
`
`A
`
`I'm sorry. With--
`
`With nonreduced folate.
`
`So when folic acid comes into it,
`
`it's not in a form that could be used in folate
`
`15 metabolism and has to be converted. And so at
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`that point, a drug like methotrexate is binding
`
`and preventing the folic acid completely or
`
`partially from being converted to the form,
`
`reduced form that it can be used in.
`
`Q
`
`How does methotrexate prevent the
`
`folate from binding -- strike that.
`
`How does methotrexate prevent the
`
`folate completely or partially from being
`
`converted to the reduced form that it can be
`
`used it?
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`STEVEN H. ZEISEL, M.D., Ph.D.
`
`A
`
`It inhibits the activity of the
`
`enzyme that is converting folic acid to
`
`tetrahydrofolate.
`
`Q
`
`A
`
`Q
`
`And that enzyme is DHFR?
`
`Yeah.
`
`Are there any other enzymes that
`
`DHFR competes with folates for binding?
`
`MR. KRINSKY: Objection to the form
`
`of the question; scope.
`
`THE WITNESS: Your question didn't
`
`make sense to me. That -- are there any
`
`other enzymes that dihydrofolate binds to?
`
`BY MS. SPIRES:
`
`Q
`
`Strike that.
`
`Are there any other enzymes that
`
`methotrexate competes with folates for binding
`
`to?
`
`MR. KRINSKY: Object to the form;
`
`scope.
`
`THE WITNESS:
`
`I am not sure whether
`
`methotrexate binds to other folate enzymes
`
`as well as it binds to dihydrofolate
`
`reductase.
`
`So I just don't know that
`
`answer.
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`STEVEN H. ZEISEL, M.D., Ph.D.
`
`BY MS. SPIRES:
`
`Q
`
`When antifolates are competing with
`
`folate for binding to an enzyme, do the
`
`antifolates bind more strongly to the enzyme
`
`than does folic acid?
`
`A
`
`I'm trying to think if there are any
`
`exceptions. But usually there is a binding
`
`constant for folate and the antifolate. And
`
`the anti folate either has to be able to knock
`
`folate off, and so that it -- often they have a
`
`better binding affinity. But if you had enough
`
`of an antifolate, someone with a lower binding
`
`affinity still would be an effective competitor
`
`to some extent.
`
`So that it depends on the ability of
`
`the structure, the antifolate, to bind to the
`
`binding site compared to the -- the endogenous
`
`folic acid or folate, reduced folate that's
`
`binding to it.
`
`Q
`
`Do you happen to know the binding
`
`the binding constant for folic acid to DHFR?
`
`A
`
`Q
`
`I don't.
`
`Do you happen to know the binding
`
`constant for methotrexate to DHFR?
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`STEVEN H. ZEISEL, M.D., Ph.D.
`
`I don't.
`
`Do you happen to know the binding
`
`A
`
`Q
`
`content for pemetrexed to DHFR?
`
`A
`
`Q
`
`I don't recall the numbers.
`
`Those are the type of things that
`
`you could look up somewhere?
`
`A
`
`Yes.
`
`I mean, they're available.
`
`Again, I would defer to an oncologist who is
`
`working about which anti folate to use to
`
`inhibit which set of enzymes; and I just don't
`
`memorize those constants.
`
`Q
`
`So you're not an expert in which
`
`antifolates inhibit which enzymes?
`
`MR. KRINSKY: Objection to the form;
`
`misstates.
`
`THE WITNESS:
`
`I would not consider
`
`myself an expert.
`
`I'm aware of which
`
`enzymes pemetrexed inhibits; and
`
`methotrexate is a very common one, and I
`
`know what it inhibits.
`
`BY MS. SPIRES:
`
`Q
`
`And how are you aware of which
`
`enzymes pemetrexed and methotrexate inhibit?
`
`A
`
`In articles in the public literature
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`STEVEN H. ZEISEL, M.D., Ph.D.
`
`in 1999, they reported what enzymes pemetrexed
`
`had efficacy for.
`
`Q
`
`And which enzymes does pemetrexed
`
`have efficacy for?
`
`A
`
`Well, it's primarily a TS,
`
`thymidylate synthase, inhibitor.
`
`It also has
`
`some activity against DHFR.
`
`It has some
`
`activity against GARFT and AICARFT.
`
`Q
`
`Why do you call pemetrexed primarily
`
`a TS inhibi tor?
`
`A
`
`That's what the literature said,
`
`that its primary activity was inhibiting TS.
`
`Q
`
`Do you have a view as to what the
`
`literature meant when it said that?
`
`A
`
`My -- my view would that it -- TS
`
`was most effectively inhibited by pemetrexed.
`
`Q
`
`If I told you that the binding
`
`constant for DHFR by pemetrexed pentaglutamate
`
`is 7.2 nanomolar, does that sound right?
`
`MR. KRINSKY: Object to the form;
`
`foundation, asked and answered.
`
`THE WITNESS: As I said, I don't
`
`recall the binding affinity.
`
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`STEVEN H. ZEISEL, M.D., Ph.D.
`
`Q
`
`Let's assume that the binding
`
`constant of DHFR by pemetrexed pentaglutamate
`
`is 7.2 nanomolar versus 1.3 nanomolar for TS.
`
`What is the difference in inhibition
`
`level for these two enzymes?
`
`MR. KRINSKY: Object to the form;
`
`foundation, scope.
`
`THE WITNESS:
`
`The two numbers again
`
`were 7.2 and 1 point something?
`
`BY MS. SPIRES:
`
`Q
`
`A
`
`1 .3.
`
`So that means that 1.3 micromolar,
`
`half of the activity was inhibited by one, and
`
`it took 7.2 micromolar to get to the same
`
`efficacy
`
`to get to the same inhibition.
`
`Q
`
`In terms of enzyme kinetics, 7.2 and
`
`1.3 are fairly equivalent; correct?
`
`MR. KRINSKY: Object to the form;
`
`scope.
`
`THE WITNESS:
`
`It all depends on what
`
`the concentrations are in the actual
`
`situation. To get 7 times more
`
`concentration could be a huge difference.
`
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`STEVEN H. ZEISEL, M.D., Ph.D.
`
`Q
`
`And to get 7 times more
`
`concentration could also be very little
`
`difference; correct?
`
`A
`
`I have no way to assess that.
`
`I
`
`mean, seven times more concentration is a big
`
`change in concentration, normally, in a cell.
`
`So I just -- without details of what you're
`
`how you would conduct the experiment or
`
`whatever -- you treat the patient, it's hard to
`
`understand. But 7 times is a big difference.
`
`Q
`
`What concentration -- strike that.
`
`Are you aware of the strength of
`
`pemetrexed's inhibition of DHFR versus the
`
`strength of methotrexate's inhibition of DHFR?
`
`A
`
`Again, I would defer to an
`
`oncologist around use of the drug. But the
`
`literature that I've read about the drug says
`
`that it is less effective than methotrexate at
`
`inhibiting DHFR.
`
`I don't have -- haven't looked more
`
`deeply into that literature because it wasn't
`
`part of what I was asked to consider.
`
`Q
`
`You agree that by June of 1999, a
`
`POSA would have known that elevated
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`STEVEN H. ZEISEL, M.D., Ph.D.
`
`pretreatment plasma homocysteine levels were a
`
`predictor for pemetrexed toxicities; correct?
`
`A
`
`Could I see my declaration just so I
`
`can be precise of what I said in the
`
`declaration?
`
`Q
`
`Sure.
`
`I'll hand you what's been previously
`
`marked as Exhibit 2118. And I'm handing you a
`
`declaration from the 237 proceeding, but I
`
`understand that you submitted the same
`
`declaration in both proceedings.
`
`Is that
`
`correct?
`
`A
`
`I believe so.
`
`And could you repeat the question
`
`again.
`
`Q
`
`Sure. You would agree that by June
`
`of 1999, a POSA would have known that elevated
`
`pretreatment plasma homocysteine levels were a
`
`predictor for pemetrexed toxicities; correct?
`
`A
`
`A POSA would have known that there
`
`were abstracts that had been published that
`
`reported that homocysteine above the level of
`
`10 micromolar was predictive of toxicity when
`
`pemetrexed was administered.
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`STEVEN H. ZEISEL, M.D., Ph.D.
`
`Q
`
`And you specify abstracts. Do you
`
`view abstracts differently than other
`
`publications?
`
`A
`
`I think abstracts indicate a
`
`suggestion of the direction of a scientific
`
`result and that they're usually followed up by
`
`more detailed reports of the data. And so
`
`they're useful to a POSA for understanding the
`
`possible direction of an effect.
`
`Q
`
`And you specified abstracts, I think
`
`you said, that reported homocysteine above the
`
`level of 10 micromolar was predictive of
`
`toxicity when pemetrexed is administered; is
`
`tha t correct?
`
`A
`
`Let me just find what I said in my
`
`thing, but I believe that's correct. Let me
`
`just look a minute.
`
`Yes.
`
`In the Niyakiza abstract, it
`
`was at or about 10 micromolar.
`
`Q
`
`And I believe you've testified that
`
`a POSA would not consider 10 micromolar
`
`homocysteine levels to be elevated; is that
`
`correct?
`
`A
`
`Yes.
`
`In 1999, the normal range
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`877-702-9580
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`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1086-0026
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`Page 27
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`STEVEN H. ZEISEL, M.D., Ph.D.
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`reported by laboratories would have been up to
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`13 to 15 to 16 micromolar as the upper end of
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`the normal distribution of homocysteine. And
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`many research studies would have also reported
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`cutoff levels of somewhere that high before
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`they would have considered that they were
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`dealing with somebody with abnormally high
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`homocysteine.
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`10
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`Q
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`And you said that 13 to 16
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`11 micromolar were the upper end of normal;
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`correct?
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`A
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`In my declaration, I say 13 to 15,
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`but EP-005 defines a cutoff level of 16.3. And
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`in 1999 a clinical laboratory where a physician
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`would have sent a homocysteine off to to be run
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`routinely would have reported upper end of
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`normal somewhere in the 13 to 15. But that
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`and it varied by laboratory and the method
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`used.
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`But those were still within normal
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`range up to those levels. So 10 definitely was
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`well within normal range for homocysteine.
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`Q
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`So is it your view that, because a
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`homocysteine level of, say, 10 or 11 micromolar
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`TSG Reporting - Worldwide
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`877-702-9580
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1086-0027
`
`
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`Page 28
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`STEVEN H. ZEISEL, M.D., Ph.D.
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`would not be viewed as an abnormal homocysteine
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`level, that a POSA would ignore the correlation
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`with pemetrexed toxicity at that level?
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`A
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`So you're asking whether a POSA,
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`because the normal range extended up to 15,
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`would have said that a finding that patients
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`with more than 10 -- or the range more than 10
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`would have had some increased risk of
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`pemetrexed.
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`And the answer is that a POSA would
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`have regarded that association as suggesting
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`that there was an effect; and that the way
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`these types of studies are done is you segment
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`your population into pieces, quartiles and
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`quintiles, and then you say, At what cut can I
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`show that the group seems different
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`statistically from the lower group?
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`And a POSA would have regarded that
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`as indicative that there might be something
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`there, certainly, worth consideration.
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`Q
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`You said that the numbers at 10 were
`
`suggesting that there was an effect. What did
`
`you mean by that?
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`A
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`So in the Niyakiza abstracts, they
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`TSG Reporting - Worldwide
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`877-702-9580
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1086-0028
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`Page 29
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`STEVEN H. ZEISEL, M.D., Ph.D.
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`found statistically that patients who grouped
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`in the group that had homocysteine
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`concentrations greater than a cutoff level of
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`10 micromolar had an association with an
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`increased toxicity from pemetrexed.
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`So that suggests that there might be
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`something about having a higher level than 10
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`that was related to why people were getting
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`toxicity from pemetrexed, and that's what a
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`POSA would have taken out of that set of
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`studies.
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`Q
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`So a POSA would not have simply
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`ignored a homocysteine level from 10 to, say,
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`13, so within the normal range?
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`MR. KRINSKY: Objection; asked and
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`answered.
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`THE WITNESS:
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`So, again, in the
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`realm of thinking about hypotheses for how
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`you might predict who might have toxicity
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`from pemetrexed, this is useful.
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`In the realm of a physician in their
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`clinical office seeing a patient, getting
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`a laboratory value of 10 back, they would
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`not have been compelled to do something
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`TSG Reporting - Worldwide
`
`877-702-9580
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1086-0029
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`Page 30
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`STEVEN H. ZEISEL, M.D., Ph.D.
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`for that patient because they would have
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`regarded that as a normal level.
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`So a physician thinking about how to
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`structure pemetrexed therapy, and
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`whatever, it would have been suggestive of
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`something, but it would not have compelled
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`treatment for lowering homocysteine.
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`It
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`just suggests there's some relationship.
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`BY MS. SPIRES:
`
`Q
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`Would a physician have taken any
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`action based on receiving a lab result of a
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`homocysteine level of 10 in a patient about to
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`receive pemetrexed?
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`A
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`In 1999, I don't think -- I don't
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`think they would have.
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`But again, I would have to defer to
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`an oncologist, because I'm dealing with
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`nutrition. And if you're talking about what an
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`oncologist would do, I'd defer to Dr. Chabner
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`as oncologist for what they we would do.
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`As a nutrition person, I would have
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`said this is not a level of homocysteine that I
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`feel I'm compelled to treat.
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`Q
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`As a physician, would you feel
`
`TSG Reporting - Worldwide
`
`877-702-9580
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1086-0030
`
`
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`Page 31
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`STEVEN H. ZEISEL, M.D., Ph.D.
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`compelled to address the -- strike that.
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`Do you agree that based on the
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`Niyaki
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