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` UNITED STATES PATENT AND TRADEMARK OFFICE
` _______________________________________________
` BEFORE THE PATENT TRIAL AND APPEAL BOARD
` _______________________________________________
` SANDOZ INC.,
` APOTEX INC., and APOTEX CORP.,
` EMCURE PHARMACEUTICALS LTD.,
` HERITAGE PHARMA LABS INC.,
` HERITAGE PHARMACEUTICALS INC.,
` GLENMARK PHARMACEUTICALS, INC., USA,
` GLENMARK HOLDING SA,
` GLENMARK PHARMACEUTICALS, LTD., MYLAN LABORATORIES
` LIMITED, TEVA PHARMACEUTICALS,
` FRESENIUS KABI USA, LLC and WOCKHARDT BIO AG,
` Petitioners,
`
` v.
` ELI LILLY & COMPANY
` Patent Owner.
` _________________
` Case IPR2016-00318
` U.S. Patent No. 7,772,209
` _________________
`
` VIDEOTAPED DEPOSITION OF PATRICK J. STOVER, PH.D.
` Chicago, Illinois
` Friday, February 10, 2017
`Reported by: PAULA CAMPBELL, CSR, RDR, CRR, CRC
`Job No: 118359
`
`TSG Reporting - Worldwide - 877-702-9580
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`Lilly Ex. 2137
`Sandoz v. Lilly IPR2016-00318
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`A P P E A R A N C E S:
` WILLIAMS & CONNOLLY
` Attorneys for the Patent Owner
` 725 Twelfth Street Northwest
` Washington, DC 20005
` BY: DAVID KRINSKY, ESQ.
`
` ELI LILLY AND COMPANY
` Attorneys for the Patent Owner
` Eli Lilly Corporate Center
` Indianapolis, IN 46285
` BY: JAMES LEEDS, ESQ.
`
` BRINKS GILSON & LIONE
` Attorneys for Sandoz Inc.
` 455 North Cityfront Plaza Drive
` Chicago, IL 60611
` BY: LAURA LYDIGSEN, ESQ.
`
` BRINKS GILSON & LIONE
` 4721 Emperor Boulevard
` Durham, NC 27703
` BY: BRYAN RICHARDSON, ESQ.
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` February 10, 2017
` 9:11 A.M.
`
` Videotaped discovery deposition of
`PATRICK J. STOVER, Ph.D., held at the offices
`of BRINKS GILSON & LIONE, 455 North Cityfront
`Plaza Drive, Chicago, Illinois, pursuant to
`notice before Paula Campbell, CSR, RDR, CRR,
`CRC.
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` VIDEOGRAPHER: Good morning. This is the
`start of tape labeled number one of the
`videotaped deposition of Patrick J. Stover,
`Ph.D., in the matter of Sandoz, Inc, et al.,
`versus Eli Lilly and Company in the United
`States Patent and Trademark Office, before the
`Patent Trial and Appeal Board, Case
`Number IPR2016-00318.
` This deposition is being held at Brinks
`Gilson & Lione at NBC Tower, 455 North
`Cityfront Plaza Drive, Suite 3600, Chicago,
`Illinois, 60611, on February 10th, 2017, at
`approximately 9:11 A.M.
` My name is Robert Zellner, from TSG
`Reporting, Inc., and I am the legal video
`specialist. The court reporter is Paula
`Campbell in association with TSG Reporting.
` And will counsel please introduce
`yourselves for the record?
` MR. KRINSKY: David Krinsky of Williams &
`Connelly, LLP on behalf of Patent Owner Eli
`Lilly and Company. With me is James Leeds of
`Eli Lilly and Company.
` MS. LYDIGSEN: Laura Lydigsen of Brinks
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`A P P E A R A N C E S:
` ALSTON & BIRD
` Attorneys for Mylan Laboratories Limited
` 90 Park Avenue
` New York, NY 10016
` BY: THOMAS PARKER, ESQ. (telephone)
`
` SKIERMONT DERBY
` Attorneys for Neptune Generics, LLC
` 2200 Ross Avenue
` Dallas, TX 75201
` BY: SARAH SPIRES, ESQ. (telephone)
`
` CARLSON CASPERS VANDENBURGH
` Attorneys for Teva Pharmaceuticals USA, Inc.
` and Fresenius Kabi USA, LLC
` 225 South Sixth Street
` Minneapolis, MN 55402
` BY: GARY SPEIER, ESQ. (telephone)
`
`ALSO PRESENT:
` Robert Zellner, Videographer
`
`2 (Pages 2 to 5)
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`Sandoz v. Lilly IPR2016-00318
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`Page 6
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` P. STOVER
` Gilson & Lione for petitioner, Sandoz Inc., and
` with me is Bryan Richardson, also of Brinks
` Gilson & Lione.
` VIDEOGRAPHER: Thank you.
` Will the court reporter please swear in the
` witness?
` REPORTER: Would you please raise your
` right hand.
`P A T R I C K S T O V E R,
` called as a witness, having been duly sworn,
` was examined and testified as follows:
` MR. KRINSKY: And just before we begin, to
` make it clear for the record, I understand
` there are a number of other parties who are on
` the telephone who will be identified by e-mail
` later?
` MS. LYDIGSEN: Correct. We will contact
` them.
`EXAMINATION
`BY MR. KRINSKY:
` Q. All right. Good morning, Dr. Stover.
` A. Good morning, David.
` Q. Have you ever been deposed before?
` A. I have not.
`
`Page 8
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` P. STOVER
` A. Biochemistry -- biochemistry and molecular
`biophysics.
` Q. And what do you see -- for purposes of this
`proceeding, how would you categorize your expertise?
`What do you see yourself as an expert in --
` A. Certainly.
` Q. -- for today's purposes?
` A. Absolutely. I am an expert in folate
`metabolism. I think I am recognized as one of the
`global leaders in that area, just in terms of
`knowledge of the metabolism and the work that I have
`contributed to that field.
` My Ph.D. focused primarily on enzymology.
`So I am very familiar with enzymes, how enzymes are
`analyzed, how inhibitors are designed, how
`inhibitors are characterized.
` My current position is Director of the
`Division of Nutritional Sciences at Cornell
`University. I've been there since 1994. Prior to
`that -- in the Division of Nutritional Sciences, so
`I am a -- also considered an expert in nutrition and
`human nutrition, and I did my post doc at UC
`Berkeley in the Department of Nutritional Sciences.
` So my background, I guess, I would put in
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` P. STOVER
` Q. Okay. Well, I'll give you the -- you have
`probably heard this from your counsel, but just so
`you understand the flow of the proceedings --
` A. Sure.
` Q. -- I'm here to ask you questions. Your
`answer suggests that one rule that perhaps you need
`to get used to is I'll ask questions, your counsel
`will object if she has an objection, and then, you
`should give your answer, but for the court
`reporter's sake, we should all try to avoid talking
`over each other. I will try not to interrupt you.
`You try not to interrupt me. It will go more
`smoothly that way.
` A. Certainly.
` Q. And regardless of whether your counsel
`objects, you're obligated to answer my questions
`unless she instructs you not to answer and you
`follow her instruction.
` A. I understand.
` Q. You're not a medical doctor, are you?
` A. I am not.
` Q. You have a -- you have a Ph.D.?
` A. I do.
` Q. What is that Ph.D. in?
`
`Page 9
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` P. STOVER
`three spheres. One is in knowledge of one-carbon
`metabolism, including folate and B-12, and the
`functioning of enzymes and enzymology, and in the
`broader area of nutrition.
` Q. Do you have a familiarity with the drug
`pemetrexed?
` A. I do.
` Q. Is that something you have been familiar
`with prior to your work on this case?
` A. Yes, I actually acquired that compound from
`Lilly in some publication -- a characterization of
`an enzyme called methylenetetrahydrofolate synthase,
`and we used that drug, along with other Lilly drugs,
`to try to understand the trafficking of folate and
`how it's trafficked intracellularly, how decisions
`are made of whether the folate to make purines or
`goes to make thymidylate.
` Q. And when --
` (A short interruption in the proceedings
` was had.)
`BY MR. KRINSKY:
` Q. When was that roughly?
` A. Oh, that paper was published in '90 -- or
`no, in 2008, I believe. Martha Field is the first
`
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` P. STOVER
`author.
` Q. So that was published at a time when
`pemetrexed was already an approved anticancer
`therapy?
` A. I can't speak to that. It was my
`understanding as it was, but I'm not a clinician.
` Q. And you don't have any particular
`experience in the area of oncology?
` A. I don't. I work with veterinary
`oncologists to try to understand how folate
`metabolism changes during cellular transformation.
`Much of my research focuses on uses of cancer
`models. So I am interested in how cellular
`transformation modifies the metabolic pathway to
`achieve the goals of the cancer cell.
` So I have made transgenic mice where we
`have altered metabolism. We have crossed those mice
`to colon cancer models and measured things like
`tumor number, tumor multiplicity, so forth and so
`on.
` So our cancer work is limited to a
`fundamental understanding of how nutrition interacts
`with genetics in cancer.
` Q. So is it fair to say that you've done work
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` P. STOVER
`analogs that would inhibit DNA synthesis, because
`they knew that this compound that they had isolated
`from biological material was needed for DNA
`synthesis. Almost immediately they came out with
`compounds to try to inhibit DNA synthesis.
` So pemetrexed is a multitargeted
`antifolate. It has a hierarchy in terms of its
`targets. It binds most tightly to thymidylate
`synthase, but also is an effective inhibitor of
`dihydrofolate reductase, and it also has weaker --
`this is all relative of course, it's a hierarchy --
`weaker affinity for -- for FGAR transformylase.
` Q. Is FGAR transformylase sometimes known as
`GARFT?
` A. It is.
` Q. I'm going to call it that for simplicity's
`sake.
` A. We'll call it GARFT, absolutely.
` Q. And thymidylate synthase is often referred
`to as TS?
` A. Well, actually now the nomenclature they
`like TYMS, but I'll -- happy to go with TS.
` Q. Okay. I think -- I think we lawyers
`settled on TS a while ago.
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` P. STOVER
`on sort of the pure science underlying the
`biochemistry of cancer, but not -- you haven't done
`work directly on human cancer treatment?
` A. That would be absolutely correct. I have
`done work with some agencies in terms of expert
`guidance and consulting on the role of folate and
`cancer risk at the population level, but we are not
`talking about treatment. We are talking about
`prevention there.
` Q. And just to be clear in what you're talking
`about, you are talking about the effects of folate
`on the incidence of cancer in the population?
` A. That's correct, but it would include
`effects not only on incidence but on mortality at
`the population level.
` Q. Okay. From -- from your standpoint as --
`as a biochemist and an expert in folate metabolism,
`how does pemetrexed work to treat cancer?
` A. So pemetrexed is known as a multitargeted
`antifolate. It's -- there is a long generation of
`these antifolates. Early in the 1940s, when Lederle
`Labs first elucidated the structure of folate and
`synthesized folic acid, almost immediately
`thereafter they began to design inhibitors or
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` P. STOVER
` A. Okay. There you go. Well, we had too, but
`then these, you know, boards who change the names of
`genes for this and that changed it to TYMS.
` Q. Okay. Well, we'll -- we'll go with TS for
`today, if that's all right.
` A. That's fine.
` Q. What is the relevance of pemetrexed's
`ability to inhibit these various enzymes to the
`treatment of cancer?
` A. I'm sorry. Could you repeat?
` Q. What is the relevance of pemetrexed's
`ability to inhibit these various enzymes to the
`treatment of cancer?
` MS. LYDIGSEN: Objection. Vague.
` A. The -- they are folate analogs. So they
`are structurally similar to substrates of
`folate-dependent enzymes. They bind to those
`enzymes in a competitive way so that the natural
`substrate can't bind, and they tend to bind more
`tighter than the natural substrate, thereby they
`inhibit the activity.
` And in the case of TS, they prevent the
`synthesis of thymidylate, which is one of the four
`required bases for DNA synthesis.
`
`4 (Pages 10 to 13)
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` Q. So pemetrexed has the effect, then, of
`inhibiting DNA synthesis?
` A. Correct.
` Q. And in order to divide, cancer cells need
`to perform DNA synthesis?
` A. That's correct.
` Q. And so, the idea then is that the
`pemetrexed kills the cancer cell, because it can't
`make DNA?
` MS. LYDIGSEN: Objection to form.
` A. It's more complicated than that. What you
`actually get is stalling of the replication fork
`that triggers other cellular events, among those
`is -- can be a ptosis or other biological event. So
`it isn't -- it's more complicated than you're
`describing it.
` Q. Okay. But the -- is it fair to say that
`the primary mechanism by which pemetrexed works on
`cancer cells is by inhibiting DNA synthesis?
` A. That's the leading hypothesis and the most
`likely explanation. I would agree with that.
` Q. And that would have been the understanding
`of a person of ordinarily skill in the art in this
`case?
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` P. STOVER
` A. I -- I am not an expert in how pemetrexed
`causes neutropenia, no.
` Q. Okay. So to the extent other experts in
`this case have opined that pemetrexed can cause
`neutropenia by inhibiting DNA synthesis, you don't
`agree with that opinion?
` A. I have --
` MS. LYDIGSEN: Objection. Outside the
` scope.
` A. I have no opinion on that.
` Q. Is the same true of other particular
`hematological toxicities?
` MS. LYDIGSEN: Objection. Outside the
` scope.
` A. Which would you be referring to, to a
`megaloblastic anemia or -- which -- which --
` Q. Any other hematologic toxicity.
` A. Rapidly dividing cells require DNA
`synthesis. So if you impair DNA synthesis, you will
`have -- you are more likely to have both chromosomal
`abnormalities in those cells as well as lower rates
`of cell division proliferation.
` Q. So one of the mechanisms by which
`pemetrexed can cause, and would have been understood
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` A. I would agree with that.
` Q. How does -- you understand that one of the
`issues in this case surrounds the toxicities that
`pemetrexed had been observed to cause prior to 1999?
` A. I didn't address that in my declaration.
` Q. You understand that pemetrexed does cause
`toxicities?
` A. Yes, I do.
` Q. And how does pemetrexed cause toxicities?
` MS. LYDIGSEN: Objection. Outside the
` scope.
` A. Pemetrexed is a multitargeted antifolate.
`So not only does it inhibit its primary target, or
`at least its highest affinity target, TYMS, but it
`targets other enzymes as well, as I indicated.
` Toxicities, depending on the nature of the
`toxicity, could originate from any off-target
`effect. Calling -- if we are referring to the
`target effect as the inhibition of TS.
` Q. Are you familiar with a particular toxicity
`called neutropenia?
` A. I am not an expert in neutropenia, no.
` Q. Okay. So do you know how pemetrexed causes
`neutropenia?
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`to be able to cause, toxicities is by inhibiting DNA
`synthesis in noncancerous but rapidly dividing
`cells; is that fair?
` A. That would be a hypothesis. Pemetrexed has
`off-target effects that can have other effects, such
`as its effects on dihydrofolate reductase.
` Q. Well, and dihydrofolate -- you say
`off-target, but does dihydro -- excuse me.
` Does dihydrofolate reductase inhibition
`have any bearing on pemetrexed's ability to treat
`cancer?
` MS. LYDIGSEN: Objection. Outside the
` scope.
` A. I need clarification in terms of what you
`are meaning in terms of treating cancer.
` Q. Well, a few moments ago we discussed the,
`at least at a very general level, and I understand
`there is -- there is underlying complexity --
` A. Absolutely.
` Q. -- we discussed at a general level the way
`in which by inhibiting TS pemetrexed can treat
`cancer.
` A. Correct.
` Q. My question is: Does pemetrexed's
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`inhibition of DHFR also contribute to its anticancer
`effects?
` A. It would depend on the tumor, but one
`certainly could not rule that out. And there are
`inhibitors of dihydrofolate reductase that are used
`as anticancer agents.
` Q. Methotrexate for example?
` A. Boom.
` Q. By "boom" you mean yes?
` A. Yes, correct.
` Q. That's one of the types of responses that I
`think would be very apparent on the video, but may
`be a little less apparent on the transcript.
` A. Yes, okay. Understood.
` Q. And you haven't looked into the question of
`which enzyme targets have what role in pemetrexed's
`desirable effects on cancer cells, have you?
` A. Personally I have not researched that area.
`I am familiar with the mechanism of action of
`antifolates and their physiological effects on
`one-carbon metabolism.
` Q. And you understand that, you know,
`pemetrexed may have an impact on cancer cells
`through its inhibition of TS?
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` P. STOVER
`one would do, kinetic modeling, one would infer that
`pemetrexed would have an effect both through its
`effect on TYMS as well as through DHFR.
` Q. And, similarly, pemetrexed may have an
`effect on rapidly dividing healthy cells through the
`inhibition of one or both of those enzymes?
` A. So you worry about toxicities in normal
`cells, absolutely.
` Q. And I understand there is a debate among
`the experts about the incidence of these toxicities,
`but there had been toxicities reported to rapidly
`dividing cells as of 1999?
` A. Correct.
` Q. That would have been understood by the
`person of ordinarily skill to be arising from the
`inhibition of some combination of these same
`enzymes?
` A. I'm not a clinician, so I can't speak to
`what a POSA would -- would infer.
` Q. But it was -- it was -- from your
`standpoint as a biochemist and based on what was
`known in the art as of 1999, it was -- it was
`understood that pemetrexed had an impact on rapidly
`dividing healthy cells, at least in part by
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` A. That's correct.
` Q. And it may also, or it may not, have a
`practical effect on cancer sells through his
`inhibition of DHFR?
` A. That's correct. I think it would unlike --
`I think it would be unlikely that it would not have
`some effect through its inhibition of DHFR, given
`what we my about methotrexate.
` Q. But given the relative levels of enzyme
`inhibition, you don't know what the relative
`contributions are of these two enzymes --
` MS. LYDIGSEN: Objection.
` Q. -- to pemetrexed's effects on cancer?
` MS. LYDIGSEN: Objection.
` Mischaracterizes.
` A. This would likely vary. This -- one would
`predict that this could likely vary by cancer. It
`would depend on what the relative expression levels
`of the two enzymes are, because that affects
`efficacy. How well you can inhibit one of the
`parameters is how much enzyme is being expressed.
`How does the expression of the enzyme vary after
`exposure to the drug?
` But certainly based on any modeling that
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`inhibiting these same enzymes that contribute to its
`anticancer effects?
` A. I -- that would be an accurate statement,
`yes. One has to be concerned.
` Q. And I assume, given your -- what I
`understand your focus here to be, you have not
`yourself opined on the -- whether it's obvious or
`not to administer folic acid to reduce pemetrexed
`toxicities?
` A. I would rather not get into the legal
`realm, so I don't want to comment specifically on
`that word "obvious."
` So what I can tell you is, as was one of
`the documents in the materials that we provided,
`Sidney Farber back in 1947 recognized that
`administration of vitamins overcame some of the
`toxicities associated with, in this case,
`aminopterin use, which was one of the early
`generation antifolates.
` Q. Well, I think you've -- I think you've
`anticipated my next question, and I want to talk a
`little more specifically about Farber in a bit.
` But just at a general level, as of 1999 how
`would the person of ordinary skill in the art have
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`understood that folic acid could work to reduce
`pemetrexed toxicities?
` A. Again, I don't want to speak to what -- I
`am not a clinician, so I don't want to speak as a
`clinician.
` What I can -- can tell you that I am very
`active in the scientific community around one-carbon
`metabolism, folate and B12. At our scientific
`meetings, which are held annually, we have a blend
`of people in nutrition, people who are biochemists
`and clinicians. And so, these discussions occur in
`that context, an intermingling of the sort of
`translational spectrum of scientists.
` So specifically to your question, it was
`certainly known at that time, and certainly I was
`part of those discussions, that inhibition of
`dihydrofolate reductase, for example, causes a
`accumulation of dihydrofolate, which is a very
`unstable folate, which then degrades and, therefore,
`depletes cellular folate levels. And this is one of
`the bases for its effect. It is not that it targets
`dihydrofolate activity, per se, but that it has this
`effect on reducing cellular folate levels that
`essentially starve all the metabolic pathways for
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`nutrition programs in the country, that nutrition is
`the due care about maintaining adequate nutrition in
`both healthy and diseased populations, that we train
`nutrition practitioners, registered dieticians in
`medical nutrition therapy, and that nutrition is an
`important part of cancer treatment.
` So to the degree to which nutrition is
`important in the treatment of patients, I am -- I am
`familiar with that literature. I am -- speak to
`that literature. I have an article in -- an opinion
`piece in JAMA Internal Medicine on a topic related
`to this, of nutrition and chronic disease,
`specifically folate.
` But I do not treat patients, per se, so I
`don't want to speak for a clinician.
` Q. Well, and part of why I'm covering this is
`so that I can ask clear questions that won't --
` A. I understand.
` Q. -- cause you to give these caveats
`repeatedly. Because I also understand -- I would --
`I would much rather talk about the science, because,
`frankly, it's more interesting, and we'll -- we'll
`do more of that --
` A. Okay.
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`folate.
` And so -- so when you have higher rates of
`turnover, it's like a bathtub, right. If the -- if
`you have more water leaving the tub, you have to add
`more water to maintain the water level. And,
`therefore, increased levels of folate help restore
`intracellular folate levels to where you get
`functioning of the pathways.
` Q. That was a lengthy but helpful answer, but
`I want to unpack a few different aspects of it, if I
`may.
` A. Sure.
` Q. So just to be clear, you are not providing
`opinions in this case from the perspective of the
`person of ordinary skill in the art?
` A. I am not a clinician. And to the degree to
`which a POSA is a person who is a clinician who
`treats patients, no, I am not.
` Q. And do you not have any opinions about how
`the person of ordinary skill in the art would have
`approached the problem of pemetrexed toxicity as of
`1999?
` A. I can tell you as someone who is involved
`in nutrition, someone who runs one of the largest
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` Q. -- but just to make sure we're on the same
`page, you're not -- to the extent the person of
`ordinary skill in the art is an oncologist, you are
`not rendering opinions about what that person of
`ordinary skill in the art would have known?
` A. I can tell you what information was
`available to that person at that time, but I can't
`tell you what any one individual would or would not
`have known. I can tell you what the state of
`knowledge was in terms of both biochemistry and
`nutrition at that time.
` Q. Right.
` And, but in particular you can speak to the
`state of knowledge in biochemistry and nutrition but
`not to the state of oncology; is that fair?
` A. I can tell you -- I don't think that's
`completely fair, no. I think that I can tell you
`what information would be available to an oncologist
`at that time.
` Q. If the oncologist thought to go to an
`expert in biochemistry and inquire or thought to go
`to a library that covered, you know, biochemical
`works --
` A. Or nutrition, and nutrition is an important
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`component of clinical care and has been.
` Q. Sure.
` But the -- you're not here to opine about
`the knowledge of an oncologist?
` A. That would be correct. I can only tell you
`what the state of the knowledge that would be
`available to them at that time.
` Q. Okay. And, but my question is: Have
`you -- have you made any effort in your mind to
`separate out, you know, what you know and what
`people with your type of expertise would have known
`from the standpoint of an expert in one-carbon
`metabolism and biochemistry from what the person of
`ordinary skill in the art for purposes of this case
`would have known?
` A. I don't see those as distinct, because I
`can tell you that many of the leading antifolate
`oncologists attend the same meetings I do. We speak
`in the same sessions. The focus of the talks is
`different, but there is a free sharing of
`information among those groups.
` Q. And so, an oncologist -- are you familiar,
`by the way, with Dr. Bruce Chabner?
` A. I'm familiar with his work. I have never
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`knowledge of one of these oncologists who regularly
`goes to folate meetings?
` A. Would -- certainly a group of them would.
`I can't say that would be universally true, but
`certainly many of the leaders in the field, yes.
` Q. So your -- your understanding is that the
`person of ordinary skill in the art would have a
`high level of understanding of folate metabolism and
`one-carbon biochemistry?
` A. Some would, some would not. But if we
`expand that, because my declaration also focuses on
`nutrition, and I would say details of the detailed
`function of antifolates would -- this is
`speculative, but may be beyond some oncologists who
`are just following, you know, standard regimens.
` I would say that's not true for the space
`in nutrition, because, again, medical nutrition
`therapy is critical in virtually all areas of
`medicine and is something that is commonplace in
`clinical practice and is -- in my mind is an
`expectation.
` Q. Are you here to express opinions about how
`oncologists view nutrition?
` A. My declaration doesn't speak to that.
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`met him.
` Q. Would he be an example of an oncologist who
`has a high level of knowledge of folates?
` A. He is a respected member of the field. He
`does not attend, at least I have never met him, at
`any of the national folate meetings. So I'll leave
`it at that.
` Q. So I guess what I'm trying to understand is
`when it comes to knowledge of the -- the enzymology
`and the biochemistry and the underlying pure science
`of the folate pathway, would you say that someone
`like Dr. Chabner has more knowledge or less
`knowledge than what you understand the person of
`ordinary skill in the art would have in this case?
` MS. LYDIGSEN: Objection. Calls for
` speculation.
` A. I really can't speak to that. Again,
`I'm -- I'm aware of him. There are many other
`oncologists who work in that same area who I am very
`well aware of who are regular colleagues at
`meetings, who I collaborate with, who -- et cetera,
`et cetera. Dr. Chabner is not among those.
` Q. Okay. Do you -- would the person of
`ordinary skill in the art have the level of
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` Q. And because you're not a practicing
`physician and you're not -- certainly not a
`practicing oncologist, you can't speak to, as a
`practical matter, the role of nutrition in cancer
`care; is that fair?
` A. I can speak to the current knowledge of the
`role of nutrition in cancer care. I have, as I have
`stated, academic programs where we teach medical
`nutrition therapy. I am not a practicing clinician,
`but in terms of my nutrition knowledge, that is part
`of the scope of knowledge that would be expected of
`someone who holds the position that I hold.
` Q. Let's turn back to the second part of the
`answer you gave a little while ago about how it is
`that folic acid would be understood to potentially
`ameliorate antifolate toxicity, and particularly
`pemetrexed toxicity.
` I believe you referred to an accumulation
`of dihydrofolate in the presence of DHFR inhibition?
` A. That's correct.
` Q. Is that -- first of all, have you cited any
`literature that describes that as the way in which
`folic acid ameliorates chemotherapy toxicities?
` A. References are made that there -- within
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`the citations that are associated with my
`declaration. There is not a paper that explicitly
`focuses on that point. What you will find in there
`are statements that the mechanism of action of
`dihydrofolate reductase inhibitors is to lower
`cellular folate levels, yes.
` Q. Are there papers from prior to 1999 that
`you can cite that attribute folic acid's ability to
`ameliorate toxicity to this particular biochemical
`effect?
` MS. LYDIGSEN: Objection to form.
` A. I have cited papers that have demonstrated
`that tumor cells have lower concentrations of
`folate, intracellular folate, than normal cells. I
`have cited papers providing evidence that in tumors
`there is increased catabolism of folate. I have
`cite