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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
` HOLDINGS, SA, GLENMARK
` PHARMACEUTICALS, LTD., MYLAN
` LABORATORIES LIMITED, TEVA
` PHARMACEUTICALS, FRESENIUS KABI USA,
` LLC AND WOCKHARDT BIO AG,
` Petitioners,
` vs.
` ELI LILLY & COMPANY,
` Patent Owner.
` ____________________________________
`
` Case No. IPR2016-00318
`
` Patent No. 7,772,209
`
` VIDEOTAPED DEPOSITION OF
` RON D. SCHIFF, M.D., PH.D.
` Tampa, Florida
` Friday, January 27, 2017
`
`Reported by:
`RHONDA HALL-BREUWET, RDR, CRR, LCR, CCR, FPR,
`CLR, NCRA Realtime Systems Administrator
`JOB NO. 118353
`
`TSG Reporting - Worldwide 877-702-9580
`
`Lilly Ex. 2136
`Sandoz v. Lilly IPR2016-00318
`
`

`

`Page 3
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`A P P E A R A N C E S:
`
` BRINKS GILSON & LIONE
` Attorneys for Petitioner Sandoz, Inc.
` 455 North Cityfront Plaza Drive
` Chicago, Illinois 60611
` BY: LAURA LYDIGSEN, ESQUIRE
` — and —
` 4721 Emperor Boulevard
` Durham, North Carolina 27703
` BY: BRYAN RICHARDSON, ESQUIRE
` (Via Telephone)
`
`Page 5
`
`A P P E A R A N C E S:
`
` ALSTON & BIRD
` Attorneys for Mylan
` 90 Park Avenue
` New York, New York 10016
` BY: THOMAS PARKER, ESQUIRE
`
` WILLIAMS & CONNOLLY
` Attorneys for Patent Owner
` 725 Twelfth Street, N.W.
` Washington, DC 20005
` BY: ADAM PERLMAN, ESQUIRE
` — and —
` BY: DAVID KRINSKY, ESQUIRE
`
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`Page 2
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` January 27, 2017
` 8:05 a.m.
`
` Videotaped Deposition of RON D.
`SCHIFF, M.D., PH.D., held at the
`Sheraton Tampa Riverwalk Hotel, 200 N.
`Ashley Drive, Tampa, Florida 33602, before
`Rhonda Hall-Breuwet, Registered Diplomate
`Reporter, Certified Realtime Reporter,
`Licensed Court Reporter (TN), Certified Court
`Reporter (GA), Florida Professional Reporter,
`Certified Livenote Reporter, NCRA Realtime
`Systems Administrator, and Notary Public of
`the State of Florida.
`
`Page 4
`
`A P P E A R A N C E S:
`
` RAKOCZY MOLINO MAZZOCHI SIWIK
` Attorneys for Petitioner Apotex, Inc.,
` and Apotex Corp.
` 6 West Hubbard Street
` Chicago, Illinois 60654
` BY: PATRICK KILGORE, ESQUIRE
`
` SKIERMONT DERBY
` Attorneys for Petitioner Neptune
` 2200 Ross Avenue
` Dallas, Texas 75201
` BY: SARAH SPIRES, ESQUIRE
` (VIA TELEPHONE)
`
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`Page 6
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`Page 7
`
` --------------- I N D E X -----------------
`WITNESS: EXAMINATION PAGE
`RON D. SCHIFF, M.D., Ph.D.BY MR. PERLMAN 9
` BY MS. LYDIGSEN 426
` BY MR. PERLMAN 428
`
` -------------- E X H I B I T S ------------
`
` (None marked.)
`
`Page 9
`
` RON D. SCHIFF, M.D., Ph.D.
` Brinks, Gilson & Lione on behalf of
` Sandoz, Inc.
` MR. PARKER: Thomas Parker,
` P-A-R-K-E-R; law firm, Alston & Bird,
` representing Mylan.
` MR. KILGORE: Patrick Kilgore, from
` Rakoczy Molino Mazzochi Siwik, on behalf
` of Apotex Inc. and Apotex Corp.
` THE VIDEOGRAPHER: Will the court
` reporter please swear in the witness.
` RON D. SCHIFF, M.D., Ph.D.
`acknowledged having been duly sworn to tell
`the truth and testified upon his oath as
`follows:
` THE WITNESS: I do.
` DIRECT EXAMINATION
`BY MR. PERLMAN:
` Q. Good morning, Dr. Schiff.
` A. Good morning, Mr. Perlman.
` Q. Good to see you again.
` A. Same. Likewise.
` Q. I put in front of you what has been
`marked as Exhibit 1075 to these proceedings,
`your reply declaration.
`
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`A P P E A R A N C E S:
`
`ALSO PRESENT:
` JAMES P. LEEDS, ESQUIRE
` Eli Lilly and Company
` Assistant General Patent Counsel
`
`VIDEOGRAPHER:
` DONALD J. BREUWET
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`Page 8
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` RON D. SCHIFF, M.D., Ph.D.
` THE VIDEOGRAPHER: This is the start
`of Media Label Number 1 in the
`video-recorded deposition of Dr. Ron
`Schiff in the matter of Sandoz, Inc., et
`al., v. Eli Lilly & Company, in the
`United States Patent and Trademark
`Office, Case Number IPR2016-00318.
` This deposition is being held at 200
`North Ashley Drive, Tampa, Florida, on
`January 27th of 2017. The time is 8:05.
` My name is Don Breuwet. I'm the
`legal video specialist from TSG
`Reporting, Incorporated, headquartered
`at 747 Third Avenue, New York, New York.
`The court reporter is Rhonda Breuwet, in
`association with TSG Reporting.
` Counsel, please identify yourselves.
` MR. PERLMAN: Adam Perlman, from
`Williams & Connolly, on behalf of the
`patent owner, Eli Lilly & Company.
` With me is David Krinsky, also of
`Williams & Connolly, on behalf of Eli
`Lilly; and James Leeds of Eli Lilly.
` MS. LYDIGSEN: Laura Lydigsen of
`
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`
`3
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`Lilly Ex. 2136
`Sandoz v. Lilly IPR2016-00318
`
`

`

`Page 10
`
` RON D. SCHIFF, M.D., Ph.D.
` Do you see that?
` A. I do.
` Q. And when's the last time you had the
`opportunity to review your reply declaration?
` A. Yesterday.
` Q. Okay. Did you review the whole
`thing?
` A. No, just selected portions.
` Q. Okay. When's the last time you
`reviewed the entirety of it?
` A. That would have been approximately
`Sunday and Monday, but I may be off by a day
`or so.
` Q. Okay. Do you feel comfortable that
`you recall the contents of your declaration?
` A. I do, but I would like to reserve
`the right to refer to it as needed.
` Q. Certainly. And all I would ask is
`if you are going to be reading from your
`declaration, that you identify the paragraph
`and page number for us --
` A. I certainly will.
` Q. -- so that we can all follow along.
` A. Correct.
`
`Page 12
`
` RON D. SCHIFF, M.D., Ph.D.
` Q. Okay. So this is -- this
`declaration by you is intended, to summarize,
`to be responsive to the arguments and
`evidence that Lilly put forward a few months
`ago in response to what Sandoz had initially
`put forward?
` A. Exactly.
` Q. And can you estimate for us how much
`time you spent considering your opinions and
`response prior to drafting your reply
`declaration?
` A. I did not give that prior thought or
`calculate it. I would have to say perhaps 10
`to 20 hours before I started working on it.
` Q. And then from that point forward, in
`terms of preparing the declaration, how many
`additional hours do you think it took?
` A. I worked on that for pretty close to
`three weeks, just about every day and didn't
`do a whole lot else on those days. So I
`can't really tell you hours, but that was
`labor intensive.
` Q. Were you doing full days during this
`time?
`
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`Page 11
`
` RON D. SCHIFF, M.D., Ph.D.
` Q. Okay. I'd like to direct -- before
`I direct you to something, am I correct that
`this reply declaration is intended by you to
`be your response to the opinions Dr. Chabner
`and Zeisel put forward on behalf of Eli
`Lilly?
` A. And also Lilly's reply declaration
`following my prior deposition in late August.
` Q. Lilly's reply declaration? You
`mean -- Lilly's brief, you mean? Lilly's --
` A. It wasn't labeled a brief.
` Q. Lilly's response?
` A. Perhaps.
` Q. Let me tell you, we filed three
`things: We filed a patent owner response; we
`filed Dr. Chabner's declaration; we filed
`Dr. Schiff's declaration. Is it responding
`to all three of those?
` A. Zeisel, you mean.
` Q. Zeisel. That's --
` A. It was -- yeah, all three what you
`described as patent owner's response is what
`I refer to as a reply declaration by Lilly.
`So that's the same thing.
`
`Page 13
`
` RON D. SCHIFF, M.D., Ph.D.
` A. Most of the time, yes. I mean, I
`did certain other activities, but most of
`what I did on the creative side was working
`on this. That was last fall.
` Q. And as you sat down to work on your
`declaration and you were discussing
`particular references, did you have the
`references with you at that time so that you
`could sort of consult the reference as you
`prepared the relevant paragraph about the
`reference?
` A. Yes, I did that.
` Q. And so if you have testimony in your
`reply declaration about the teaching of a
`reference, you weren't doing that from
`memory; you were doing that from
`contemporaneously reviewing the reference as
`you were writing your opinion?
` A. I'm more meticulous than to rely on
`memory for that, so, yes, I looked at the
`actual references as I worked on my reply.
` Q. And as you were considering your
`opinions about the teachings of the various
`references you talked about, did you -- was
`
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`
` RON D. SCHIFF, M.D., Ph.D.
`it important to you to consider the reference
`as a whole?
` A. I would say yes. I mean, I tried
`not to just fish out individual statements
`but to look at everything in context to
`understand what a particular report was about
`and to see where that fit into the scientific
`or clinical issue that I was dealing with.
` Q. And do you think that's the approach
`that the person of ordinary skill in the art
`would take when reviewing the literature and
`references in this case; that is, they would
`review the entirety of the reference and come
`to a conclusion about what it teaches as a
`whole?
` A. Well, that's the proper way to do
`it. And I think a person of ordinary skill
`in the art would know better than to seek out
`statements out of context.
` Q. Okay. And just to get a direct
`answer to my question, your view is that the
`person of ordinary skill would have
`approached the teachings of references the
`same way you did, looking at the reference as
`
`Page 16
`
` RON D. SCHIFF, M.D., Ph.D.
` record. The time is 8:12.
` MR. PERLMAN: Okay. So I will just
` state for the record what's happened
` here. Certain of the pages have color
` highlighting on them. And when the
` exhibit was originally printed, it was
` printed in black and white. I requested
` that that page be replaced with the
` color page, which, in fact, happened,
` but the original page was left in the
` exhibit with a line through it. So that
` appears to be the only alteration that
` was done. I'm hopeful that won't cause
` any confusion, but that's what's
` happened here.
`BY MR. PERLMAN:
` Q. There you go, Doctor.
` A. Thank you.
` Q. And if that ministerial problem
`causes you difficulty later, just let me
`know, and we'll resolve it. We're looking at
`page 70, paragraph 102.
` And would you read that to yourself,
`and tell me when you're done.
`
`Page 15
`
` RON D. SCHIFF, M.D., Ph.D.
`a whole rather than looking at select bits of
`it potentially out of context?
` A. I would think so, sure.
` Q. Okay. Could you turn to
`paragraph 102, which is on page 70. I'm
`sorry. Is that a line?
` A. It is.
` Q. Can I see that?
` MS. LYDIGSEN: Yeah. There -- there
` are lines through pages that were black
` and white where there was also -- there
` were color copies, apparently, and it
` looks like it was printed black and
` white and the replacement pages were put
` in. It's 38, 39, and 61 --
` MR. PERLMAN: Okay.
` MS. LYDIGSEN: -- in my copy.
` MR. PERLMAN: Let's go off the
` record for one second.
` THE VIDEOGRAPHER: Going off the
` record. The time is 8:12.
` (Off the record from 8:12 a.m.
` to 8:12 a.m.)
` THE VIDEOGRAPHER: Going on the
`
`Page 17
`
` RON D. SCHIFF, M.D., Ph.D.
` A. (Reviewing document.)
` I'm finished.
` Q. Okay. Am I correct that in
`paragraph 102 you were discussing
`Dr. Chabner's opinion that he expressed that
`there were a number of antifolates in
`clinical trials in the 1990s where folic acid
`pretreatment was not being used?
` A. There were some where folic acid
`were not being used and there were others
`where folic acid was being used.
` Q. No, no; correct. What I'm trying to
`orient you here to, Doctor, is the argument
`that you're responding to. And is the
`argument that you're responding to here
`Dr. Chabner's argument that in the 1990s the
`majority of antifolates that were being
`tested were not being tested with folic acid?
` A. I cannot speak to the assessment
`whether it was a majority or some other
`proportion of studies. I know there were
`some with and some without, some supplemented
`and some unsupplemented. You know, I'm
`comfortable with the way I constructed that
`
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`

`Page 18
`
` RON D. SCHIFF, M.D., Ph.D.
`sentence, however.
` Q. Okay. Well, let me ask you this:
`Other than lometrexol and pemetrexed, are you
`aware of any other antifolates that were in
`clinical trials in the 1990s where a folic
`acid pretreatment was being used?
` A. For clinical trials, I would have to
`say that there was involvement with
`methotrexate or at least published data on
`that. The work with 1843U89 did not rise to
`the level of a clinical trial that I was
`aware of. And in terms of the -- that's the
`889 compound; do I have that correct?
` Q. 887?
` A. 887 compound. That it was more or
`less getting to that point. But I had not
`seen any -- well, actually, I think that
`Halford had clinical trial data with folic
`acid. So, you know, there was at least one
`other.
` Q. All right. So pemetrexed,
`methotrexate, the 887 compound, and
`lometrexol are the antifolates that you are
`aware of that had had a clinical trial with
`
`Page 20
`
` RON D. SCHIFF, M.D., Ph.D.
`rheumatologic disorders.
` Q. Okay. In the treatment of cancer,
`okay, between 1948 and lometrexol -- and
`we're talking about the folate analog
`antifolates -- can you identify any
`antifolate that was in a clinical trial with
`folic acid pretreatment?
` A. Again, I would include 5-FU as an
`antifolate, recognizing, as we discussed in
`the earlier deposition, that it's not a
`folate analog and folic acid was used with
`that. But otherwise, no, your statement is
`correct.
` Q. Okay. And do you agree with me that
`between 1948 and 1999, there were more
`antifolate drugs put into clinical trials
`without folic acid pretreatment than with
`folic acid pretreatment, or have you simply
`not studied that question?
` A. That's my impression from looking at
`it, although I did not investigate that
`question specifically.
` Q. It wouldn't surprise you if that
`were correct?
`
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` RON D. SCHIFF, M.D., Ph.D.
`folic acid pretreatment by 1999?
` A. Well, you know, again, it's a
`question of definition, but I certainly would
`also include 5-FU with that because I regard
`that as an antifolate. And, you know, we can
`also reflect back to the pioneering work of
`Sidney Farber where folic acid was given
`presumably in a nonprotocol fashion with two
`very early generation antifolates.
` Q. Okay. Dr. Farber gave it
`concurrently with the antifolate, correct?
` A. Well, in some cases he gave it
`before, in some cases he gave it after, and
`in some cases he gave it concurrently.
` Q. Okay. And in the -- and that was in
`1948?
` A. That's correct.
` Q. And other than 5-FU, between 1948
`and the clinical testing with lometrexol, are
`you aware of any antifolate being tested with
`folic acid pretreatment?
` A. Well, again, the answer was that it
`was done with methotrexate in the setting of
`rheumatoid arthritis and related
`
`Page 21
`
` RON D. SCHIFF, M.D., Ph.D.
` A. That's correct.
` Q. All right. Let's go to the second
`sentence. You say that the -- "The fact that
`Hammond existed would be more probative to
`the person of ordinary skill than the absence
`of such studies for other antifolates."
` Do you see that sentence?
` A. Yes.
` Q. And then you say "many of which were
`not primary TS inhibitors."
` A. Correct.
` Q. And then you list one, two -- four
`antifolates there.
` Do you see that?
` A. That's correct.
` Q. What is the relevance to you of the
`fact that these other antifolates were not
`primary TS inhibitors to the question?
` MS. LYDIGSEN: Counsel, I think
` there's five there.
` MR. PERLMAN: What's the fifth?
` MS. LYDIGSEN: MDAM, trimetrexate,
` pralatrexate, edatrexate.
` MR. PERLMAN: That's four.
`
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`Page 22
`
` RON D. SCHIFF, M.D., Ph.D.
` MS. LYDIGSEN: Okay.
`BY MR. PERLMAN:
` Q. Let me ask the question again. What
`is the relevance to your opinion that these
`other antifolates were not primary TS
`inhibitors?
` A. There, I'm just trying to emphasize
`that while pemetrexed is a multitargeted
`antifolate, which is the main reason that it
`was at so much interest for clinical
`development, that its primary locus of enzyme
`inhibitory activity is with thymidylate
`synthase. So, you know, that really was the
`only point there.
` Q. Okay. And my question is -- I agree
`with you that its primary locus was TS. My
`question is, what is the relationship between
`that fact and the point you were making that
`these other antifolates were not primary TS
`inhibitors and they weren't tested with folic
`acid pretreatment?
` A. That the data would be most relevant
`for pemetrexed, that what a POSA -- what a
`"person of ordinary skill in the art" would
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` RON D. SCHIFF, M.D., Ph.D.
`that on the basis of mechanism,
`pharmacokinetics, and toxicity, pemetrexed is
`very similar to the pure GARFT inhibitors
`that were being studied just beforehand and
`at the same time.
` Q. Is -- was pemetrexed in 1999 known
`as a stronger GARFT inhibitor than DHFR
`inhibitor?
` A. No, it was not. But, again, it was
`recognized that it was multitargeted in terms
`of its enzyme inhibition capabilities, and
`the relevant enzyme inhibition kinetics had
`already been worked out at least to some
`extent.
` Q. Right. But in terms of rank
`ordering the enzymes which pemetrexed
`inhibited, it would be TS as the primary, and
`what would be the second?
` A. The second one would indeed be DHFR.
` Q. And what would be third?
` A. That would be GARFT.
` Q. And do you recall the relative
`strength of the inhibition that pemetrexed
`displays as to DHFR as opposed to GARFT?
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` RON D. SCHIFF, M.D., Ph.D.
`consider would emphasize the pemetrexed
`literature to that point. But, again, a POSA
`would look at whatever reliance materials
`were available.
` Q. Well, but do you think that work
`with antifolates that are not primary TS
`inhibitors is less relevant to the question
`of whether you should use folic acid
`pretreatment with pemetrexed? Is that what
`you're trying to say in this paragraph?
` A. In -- well, I was only speaking
`there about TS enzyme inhibition. I think
`that the greatest relevance is for pemetrexed
`data. And the -- you know, I would say that
`the next degree of relevance is probably for
`other GARFT inhibitors -- if I need to spell
`that out -- and then other antifolates after
`that.
` Q. And why do you put GARFT second?
` A. Well, because, you know, pemetrexed
`was an outgrowth of Lilly's GARFT drug
`development program. It definitely has GARFT
`inhibitory activity. And because I think,
`you know, any objective observer would state
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` RON D. SCHIFF, M.D., Ph.D.
` A. No. I mean, I would -- I would
`prefer to look at the references documenting
`that in order to comment on that, but I think
`that the order that you and I have agreed
`upon is supported by the available
`literature.
` Again, I do want to point out that
`only because we discussed this in the prior
`deposition, one item on this group, which is
`pralatrexate, did have vitamin pretreatment
`studies that were completed after the
`critical or priority period, and it came into
`FDA approval and clinical utility with such a
`vitamin pretreatment regimen. But, no, that
`was not before June 30, 1999.
` Q. In fact, that -- those vitamin
`pretreatment studies were done after Lilly's
`pemetrexed vitamin pretreatment studies were
`publicly known?
` MS. LYDIGSEN: Objection.
` Foundation.
`BY MR. PERLMAN:
` Q. Correct?
` A. I'm not 100 percent on the time
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` RON D. SCHIFF, M.D., Ph.D.
`course for the pralatrexate work.
` Q. Would the person of ordinary skill
`in 1999 have understood that lometrexol and
`pemetrexed had similar or different toxicity
`profiles?
` A. Oh, I think the toxicity profiles
`were overlapping. They were closely
`overlapping, and there was some resemblance.
`Were they identical? No. But, you know, I
`mean, again, here "similar" is kind of a
`value judgment. But I think there were
`similarities, and I think that pemetrexed's
`toxicity profile was similar to the GARFT
`inhibitors known at the time.
` Q. What were the major toxicities for
`lometrexol?
` A. The things that proved to be dose
`limiting and, in fact, prevented the
`progression of lometrexol into Phase II
`trials were myelosuppression and mucositis.
`And, of course, pemetrexed, especially
`unsupplemented, does include those among its
`toxicities.
` Q. Do all antifolates cause problems
`
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` RON D. SCHIFF, M.D., Ph.D.
`the provision of an antifolate would have
`that as one of the expected toxicities,
`although the pemetrexed development research
`was indicating that there was a very good
`approach to managing that. But, you know,
`the folate pools -- the folate requirement is
`greater in malignant cells than in normal
`cells generally and is greater in rapidly
`dividing cells -- more slowly dividing cells
`as another general principle.
` Q. And are the -- the bone marrow cells
`that you talked about, are those rapidly
`dividing cells?
` A. Not necessarily relative to cancer
`cells but certainly relevant to cells of the
`linings of various solid organs and so forth.
` Q. So you're saying relative to other
`normal cells, bone marrow cells are faster
`dividing?
` A. I would say yes.
` Q. Now, back to paragraph 102,
`lometrexol is not a TS inhibitor; is that
`correct?
` A. It's a pure GARFT inhibitor as far
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` RON D. SCHIFF, M.D., Ph.D.
`with myelosuppression?
` A. You know, I can't really answer the
`question with regard to all antifolates
`because I'm not familiar with all
`antifolates. The ones that are in clinical
`use, the one that's least likely to be
`myelosuppressive is 5-FU, but in about
`2 percent of people you will see decreased
`blood counts. I believe that the percentages
`are higher in the GARFT inhibitors that were
`not FDA approved that were part of Lilly's
`development program and in methotrexate and
`pemetrexed.
` Q. Okay based on what the person of
`ordinary skill understood about the mechanism
`of action of the folate analog antifolates,
`would it have been surprising to find that
`folate analog antifolates would cause
`myelosuppression toxicities?
` A. No, it would not.
` Q. Why is that?
` A. Well, the reason is that the blood
`cell progenitors in the bone marrow have
`significant requirements for folates. And
`
`Page 29
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` RON D. SCHIFF, M.D., Ph.D.
`as I know.
` Q. And methotrexate is not a TS
`inhibitor?
` A. Methotrexate does indeed inhibit TS
`as one of its activities.
` Q. Does it directly inhibit TS or does
`its DHFR inhibition lead to downstream
`effects on TS?
` THE REPORTER: I'm sorry. Could you
` repeat that?
` MR. PERLMAN: Sure.
`BY MR. PERLMAN:
` Q. Does methotrexate directly inhibit
`TS, or do its effects on DHFR cause
`downstream inhibition of TS?
` A. Well, I think you're asking about --
`what's that called? -- the Kiriluk effect and
`so on. I did not look into that in great
`deal, but I do think there is some degree of
`direct TS inhibition.
` Q. Okay. And so would you consider
`methotrexate, then, to be analogous to
`pemetrexed in that both inhibit TS and DHFR?
` A. I think that, you know, they do have
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` RON D. SCHIFF, M.D., Ph.D.
`those two enzyme inhibitory mechanisms in
`common, although pemetrexed also is a GARFT
`inhibitor.
` Q. Right. Right. I guess what I'm
`getting at, Doctor, is, with respect -- with
`respect to the question of folic acid
`pretreatment, would the person of ordinary
`skill expect that pemetrexed would behave
`similarly to methotrexate because both are TS
`and DHFR inhibitors?
` A. I think that one would expect there
`to be a certain degree of overlap, but a
`person of ordinary skill in the art would
`want to look at the studies documenting it
`before deciding what applications to
`pemetrexed development there might be.
` Q. And is that because, before you do
`the testing with any particular antifolate,
`it's impossible to really know what the
`effect of vitamin supplementation will be
`with that particular antifolate?
` A. I think that, you know, one has to
`examine the particulars. One can expect
`principles. One can expect that things --
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`Page 32
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` RON D. SCHIFF, M.D., Ph.D.
`that, you know, we're going to move into this
`new situation and recover exactly the same
`findings. I think that one would look for
`patterns. One would look for -- my favorite
`term from the prior deposition -- proof of
`principle and so forth.
` But, you know, I want to emphasize
`that, here again, we're talking about the
`progression of research, clinical trials,
`preclinical, and so forth. We're not
`necessarily talking about, in this case, how
`a person of ordinary skill in the art would
`interpret the data for application in the
`community.
` Q. I don't -- I don't understand the
`last part of that answer. What do you mean
`by "application to the community"?
` A. Well, you know, again, during my
`first deposition, I tried repeatedly to make
`the point that certain principles of
`evaluation were applicable to the research
`setting and others were applicable to the
`application of studies to the treatment of
`patients in the real world, if you will.
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` RON D. SCHIFF, M.D., Ph.D.
`certain findings will be transferable from
`one situation to another. And, you know, I
`mean, I think that was extremely important in
`the development of pemetrexed. But it would
`certainly be a mistake to assume that what
`one found with one antifolate compound would
`apply exactly to another, which is why
`someone who's interested in developing
`pemetrexed for clinical applications would
`pay the greatest attention to the pemetrexed
`research leading up to that point and then
`after that would diverge the study to other
`antifolates.
` Q. And in terms of -- you talked about
`an expectation in that answer. In terms --
`before doing a clinical study with pemetrexed
`and folic acid pretreatment, would the person
`of ordinary skill have expected to see
`similar results as with folic acid
`pretreatment with methotrexate?
` A. I think that, you know, all research
`builds on research that was done previously.
`I think that one would look at the research,
`but one would not necessarily say I think
`
`Page 33
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` RON D. SCHIFF, M.D., Ph.D.
`That's the only distinction that I'm trying
`to make here, and I'm trying to make it as
`similarly to how I said it at the prior
`deposition as I could.
` Q. Okay. And which of those do you
`think the person of ordinary skill would have
`been concerned with in 1999?
` A. I'm sorry. Which of what?
` Q. Well, so you sort of created this
`dichotomy --
` A. Correct.
` Q. -- of the research setting and the
`real world. And I'm asking in your view, the
`perspective of the person of ordinary skill
`would have been focused on which or both or
`neither of those? What is the focus of the
`person of ordinary skill?
` MS. LYDIGSEN: Objection.
` Mischaracterizes. Objection to form.
` THE WITNESS: Well, the person of
` ordinary skill would obviously be
` looking at the research studies in an
` effort to drive his or her own
` decision-making process. The
`
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` RON D. SCHIFF, M.D., Ph.D.
` distinction is whether that person is
` applying it to the treatment of
` individual patients with cancer in the
` community setting, hospital or office.
` The principles of research
` development, preclinical studies,
` clinical trials and so on, are obviously
` a little bit different. So there are
` times that we will say that, you know,
` something becomes of interest in the
` research setting but may have different
` implications for a community-based
` practicing oncologist.
`BY MR. PERLMAN:
` Q. Okay. And what I'm trying to
`understand is, I understand the distinction
`you're drawing. What I don't understand is
`what pertinence it has to the issues in this
`case. Is there a -- is there a summary way,
`without giving me all your opinions in this
`case -- because they're of record and you
`need not repeat them -- but can you give me
`sort of a summary of how that distinction
`applies to this case?
`
`Page 36
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` RON D. SCHIFF, M.D., Ph.D.
` need a break, just let me know. It's
` not a -- this is not an emergent
` situation here.
` MS. LYDIGSEN: Yeah, I'll be okay,
` but I appreciate it. Thank you.
`BY MR. PERLMAN:
` Q. Would you read -- just read 96 to
`yourself and just tell me when you're done.
`It's kind of lengthy.
` A. (Reviewing document.)
` I've finished.
` Q. Okay. And in paragraph 96 you talk
`about what Dr. Farber termed an acceleration
`phenomenon that he had observed?
` A. That's correct.
` Q. And to summarize what Dr. Farber
`believed he observed, was that when children
`with leukemia were given folates, their
`growth -- the growth of their cancer
`accelerated, correct?
` A. That is how Farber conceptualized
`all of that.
` Q. Right. And that --
` A. However --
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