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` UNITED STATES PATENT AND TRADEMARK OFFICE
` --------------------------
` BEFORE THE PATENT TRIAL AND APPEAL BOARD
` --------------------------
`SANDOZ INC., ) U.S. Patent 7,772,209
` Petitioner, ) Issue Date: Aug. 10, 2010
` vs. ) Title: Antifolate
`ELI LILLY AND COMPANY, ) Combination Therapies
` Patent Owner. )
`
` VIDEOTAPED DEPOSITION OF RON D. SCHIFF, M.D.
` August 25, 2016
` Chicago, Illinois
` 8:33 a.m.
`
`Reported By:
`Sheri E. Liss, CSR, RPR, CRR, CLR, RSA
`Job No. 46017
`
`Lilly Ex. 2026
`Sandoz v. Lilly IPR2016-00318
`
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` UNITED STATES PATENT AND TRADEMARK OFFICE
` --------------------------
` BEFORE THE PATENT TRIAL AND APPEAL BOARD
` --------------------------
`SANDOZ INC., ) U.S. Patent 7,772,209
` Petitioner, ) Issue Date: Aug. 10, 2010
` vs. ) Title: Antifolate
`ELI LILLY AND COMPANY, ) Combination Therapies
` Patent Owner. )
`
` VIDEOTAPED DEPOSITION OF RON D. SCHIFF, M.D.
` August 25, 2016
` Chicago, Illinois
` 8:33 a.m.
`
`Reported By:
`Sheri E. Liss, CSR, RPR, CRR, CLR, RSA
`Job No. 46017
`
`Lilly Ex. 2026
`Sandoz v. Lilly IPR2016-00318
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` The videotaped deposition of RON D.
`SCHIFF, M.D., called by the Patent Owner for
`examination, taken pursuant to the Code of Civil
`Procedure and the Rules of the Supreme Court of the
`State of Illinois pertaining to the taking of
`depositions for the purposes of evidence, taken
`before Sheri E. Liss, CSR NO. 084-002600, a
`Certified Shorthand Reporter within and for the
`State of Illinois, Registered Professional Reporter,
`Certified Realtime Reporter, at the offices of
`Brinks Gilson & Lione, NBC Tower, 455 North
`Cityfront Plaza Drive, Suite 3600, Chicago,
`Illinois, on August 25, 2016 at the hour 8:33
`o'clock a.m.
`
`DAVID FELDMAN WORLDWIDE, INC.
`450 Seventh Avenue - Ste 500, New York, NY 10123 1.800.642.1099
`
`Lilly Ex. 2026
`Sandoz v. Lilly IPR2016-00318
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`APPEARANCES:
`ON BEHALF OF THE SANDOZ:
` BRINKS GILSON & LIONE
` NBC Tower, 455 North Cityfront Plaza Drive
` Suite 3600
` Chicago, Illinois 60611
` BY: LAURA LYDIGSEN, ESQ.
` llydigsen@brinksgilson.com
` JOSHUA JAMES, ESQ.
` jjames@brinksgilson.com
`
`
` SANDOZ, INC.
` 100 College Road W
` Princeton, NJ 08540
` BY: JOSEPHINE LIU, Ph.D., ESQ.
`
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`DAVID FELDMAN WORLDWIDE, INC.
`450 Seventh Avenue - Ste 500, New York, NY 10123 1.800.642.1099
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`Lilly Ex. 2026
`Sandoz v. Lilly IPR2016-00318
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`APPEARANCES (continued):
`ON BEHALF OF ELI LILLY:
` WILLIAMS & CONNOLLY, LLP
` 725 Twelfth Street, N.W.
` Washington, D.C. 20005
` BY: ADAM PERLMAN, ESQ.
` aperlman@wc.com
` DAVID M. KRINSKY, ESQ.
` dkrinsky@wc.com
` DOV P. GROSSMAN, ESQ.
` dgrossman@wc.com
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` ELI LILLY AND COMPANY
` Lilly Corporate Center
` Indianapolis, Indiana 46285
` BY: JAMES P. LEEDS, ESQ.
` jleeds@lilly.com
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`DAVID FELDMAN WORLDWIDE, INC.
`450 Seventh Avenue - Ste 500, New York, NY 10123 1.800.642.1099
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`Sandoz v. Lilly IPR2016-00318
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`APPEARANCES (continued):
`ON BEHALF OF MYLAN:
` ALSTON & BIRD, LLP
` 90 Park Avenue, 15th Floor
` New York, New York 10016
` BY: THOMAS PARKER, ESQ.
` thomas.parker@alston.com
` ELLEN CHEONG, ESQ.
` Ellen.cheong@alston.com
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`ON BEHALF OF APOTEX:
` RAKOCZY MOLINO MAZZACHI SIWIK LLP
` 6 West Hubbard Street, Suite 500
` Chicago, Illinois 60654
` BY: PATRICK C. KILGORE, ESQ.
` pkilgore@rmmslegal.com
`
`ON BEHALF OF WOCKHARDT:
` PILLSBURY WINTHROP SHAW PITTMAN, LLP
` 401 Congress Avenue, Suite 1700
` Austin, TX 78701
` BY: DAVID N. PATARIU, ESQ.,
` david.patariu@pillsburylaw.com
`
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`DAVID FELDMAN WORLDWIDE, INC.
`450 Seventh Avenue - Ste 500, New York, NY 10123 1.800.642.1099
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`Lilly Ex. 2026
`Sandoz v. Lilly IPR2016-00318
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`APPEARANCES (continued):
`ON BEHALF OF TEVA:
` CARLSON, CASPERS, VANDENBURGH, LINDQUIST &
` SCHUMAN, P.A.
` 225 South Sixth Street, Suite 4200
` Minneapolis, MN 55402
` BY: GARY J. SPEIER, ESQ.
` gspeier@carlsoncaspers.com
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`
`ALSO PRESENT:
` JEREMY MANGAN, Videographer
`
`DAVID FELDMAN WORLDWIDE, INC.
`450 Seventh Avenue - Ste 500, New York, NY 10123 1.800.642.1099
`
`Lilly Ex. 2026
`Sandoz v. Lilly IPR2016-00318
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`7
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` I N D E X
`
`RON D. SCHIFF, Ph.D., M.D.,
`EXAMINATION PAGE
` Mr. Perlman 8
`
` E X H I B I T S
`NO. DESCRIPTION MARKED/REFERRED TO
` Exhibit 1004 Previously marked 6
` Exhibit 2020 Excerpt from 1999 PDR 21
` Exhibit 2021 Document 30
` Exhibit 1001 Previously marked 56
` Exhibit 1009 Previously marked 74
` Exhibit 1016 Previously marked 112
` Exhibit 1006 Previously marked 112
` Exhibit 1007 Previously marked 162
` Exhibit 1033 Previously marked 170
` Exhibit 1014 Previously marked 180
` Exhibit 1015 Previously marked 180
` Exhibit 2022 Rinaldi abstract 187
` Exhibit 1013 Previously marked 207
` Exhibit 1045 Previously marked 233
` Exhibit 1005 Previously marked 244
` Exhibit 1011 Previously marked 265
` Exhibit 1012 Previously marked 284
` Exhibit 1023 Previously marked 304
` Exhibit 1027 Previously marked 317
` Exhibit 1026 Previously marked 318
` Exhibit 1002 Previously marked 322
` Exhibit 1028 Previously marked 335
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` DEPOSITION OF RON D. SCHIFF, M.D.
` THE VIDEOGRAPHER: We are now on the
`record. This marks the beginning of Media No. 1 in
`the deposition of Ron D. Schiff, M.D., in the matter
`of Sandoz Inc. versus Eli Lilly company in the U.S.
`Patent Trademark Office. This deposition is being
`held at 455 City Front Plaza, Chicago, Illinois on
`August 25, 2016, and the time is now 8:33 p.m. All
`attorneys present will be noted on the stenographic
`record.
` (Whereupon, the witness was
` sworn.)
` RON D. SCHIFF, M.D.,
`having been first duly sworn, was examined and
`testified as follows:
` EXAMINATION
` BY MR. PERLMAN:
` Q. Good morning, Dr. Schiff.
` A. Good morning, Mr. Perlman.
` Q. We met earlier. My name is Adam
`Perlman, and I represent Eli Lilly in this case.
` A. Yes.
` Q. Is there any reason that you feel that
`you won't be able to give truthful and accurate
`testimony today?
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`DAVID FELDMAN WORLDWIDE, INC.
`450 Seventh Avenue - Ste 500, New York, NY 10123 1.800.642.1099
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` DEPOSITION OF RON D. SCHIFF, M.D.
` A. No.
` Q. Are you under any medical treatment or
`taking any medications that would impair your
`ability to understand my questions?
` A. None.
` Q. And let's just do it this way: I'm
`going to hand you what's previously been marked as
`Exhibit 1004, which is your declaration.
` Let me say that I have three copies
`for the other side of the table. I underestimated
`the number of joining petitioners that we would have
`live but everyone can share.
` Doctor, is that the declaration you
`prepared for this case?
` A. It is.
` Q. And have you had an opportunity recently
`to review your declaration?
` A. I have.
` Q. When is the most recent time you
`reviewed it?
` A. Looked at it overnight.
` Q. Last night?
` A. Last night and this morning, yes.
` Q. Okay. And do you -- as you sit here
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`DAVID FELDMAN WORLDWIDE, INC.
`450 Seventh Avenue - Ste 500, New York, NY 10123 1.800.642.1099
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` DEPOSITION OF RON D. SCHIFF, M.D.
`now, are there any corrections or errors that -- any
`corrections you would like to make or any errors
`you've noted?
` A. There are five very minor things that
`have come to my attention that I'm happy to explain
`to you.
` Q. Why don't you tell me what paragraph?
` A. The first one is in Paragraph 8. And in
`the phrase "the exhibits," the word "the" does not
`belong there. It should just be "exhibits."
` Q. Show me where you're talking about?
` A. Again, Paragraph 8, in the second line
`it says, "as well as the exhibits referenced in
`Sandoz's petition." That should just be "as well as
`exhibits referenced in Sandoz's petition."
` Q. Is that because you reviewed some of the
`exhibits but not all of the exhibits?
` A. I reviewed most of them, yes.
` Q. Okay. And what's the next one?
` A. The second one is in Paragraph 15. And
`I just want to call attention that claims that are
`not independent claims were not enumerated there, so
`I think that's like 2 and 5 or something like that,
`but they're all discussed in the body of the
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`450 Seventh Avenue - Ste 500, New York, NY 10123 1.800.642.1099
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` DEPOSITION OF RON D. SCHIFF, M.D.
`declaration.
` Q. Okay. What's the next one?
` A. The third one is Paragraph 32. And in
`Paragraph 32, the issue there is that it refers to
`purine synthesis at the bottom of the paragraph.
`And the correct thing, there's one of two, you could
`say pyrimidine synthesis or you could say, more
`specifically, thymidine synthesis. But purine is
`incorrect in that context.
` Q. Okay. If I was going to make a change,
`would you prefer to say pyrimidine or thymidine?
` A. The most accurate and specific is
`thymidine.
` Q. Okay.
` A. Pyrimidine of course is the one that's
`parallel to purine but, you know, it's involved in
`both synthesis. There are pathways that are common
`to the purines, all of them, and then there's a
`pathway that is common to thymidine only. So
`thymidine is probably the right one.
` Q. How did you discover this particular
`error?
` A. Reading through it doesn't fit. I have
`been aware of that one a little while.
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`DAVID FELDMAN WORLDWIDE, INC.
`450 Seventh Avenue - Ste 500, New York, NY 10123 1.800.642.1099
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` DEPOSITION OF RON D. SCHIFF, M.D.
` Q. Okay. Do you have any understanding of
`how it crept in, in the first place?
` A. No. And I don't know if I caught it at
`the time that the draft was first reviewed or
`whether it was sometime after that, but I did -- I
`caught that one relatively early on.
` Q. Okay. You said there were a couple
`more?
` A. Yes. The next one is in Paragraph 50
`where there is an enzyme that is specified first by
`its initials or abbreviation and then it's spelled
`out. The one that's spelled out is incorrect. The
`FPGS, of course, should be folylpolyglutamate
`synthase, not what's written there.
` Q. And when did you discover that error?
` A. As a matter of fact, I only discovered
`that one overnight.
` Q. Last night?
` A. Yes.
` Q. And FPGS is an enzyme that adds
`additional glutamates to the types of antifolates
`that we're talking about in this case?
` A. That's correct.
` Q. It's not an enzyme that is part of
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`DAVID FELDMAN WORLDWIDE, INC.
`450 Seventh Avenue - Ste 500, New York, NY 10123 1.800.642.1099
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` DEPOSITION OF RON D. SCHIFF, M.D.
`one-carbon transfers like TS or DHFR?
` A. Yes, that's the distinction, correct.
` Q. Okay. And what's the --
` A. The final one is in Paragraph 67. And,
`you know, I would like to say there may be others
`but these are the only five that I'm aware of; and
`as you can see, they're all minor.
` The one in Paragraph 67 is a
`citation to one of the Niyikiza abstracts, and it
`lists that it's from the proceedings of the AACR and
`in actual fact it's from the proceedings of ASCO.
`Those are two closely related organizations, but
`that cite is incorrect.
` Q. This is the one on Page 33?
` A. I'll check it. Yes, it's Roman Numeral
`small 2 or small Roman Numeral Two. So instead of
`proceedings of AACR, it's proceedings of ASCO. But
`it's the same abstract with the same content.
` Q. And anything else?
` A. Those are the only ones I'm aware of.
`Perhaps we'll discover others in today's deposition.
` Q. Okay. Let's turn to the beginning of
`your declaration. In Paragraph 5, you say you
`"worked as a practicing physician in the field of
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`DAVID FELDMAN WORLDWIDE, INC.
`450 Seventh Avenue - Ste 500, New York, NY 10123 1.800.642.1099
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` DEPOSITION OF RON D. SCHIFF, M.D.
`oncology for 29 years."
` Do you see that?
` A. That's correct.
` Q. Do I take it from your phrasing there
`that you are no longer working as a practicing
`physician?
` A. I retired from private practice in May
`of last year, in May of 2015.
` Q. So the 29 years began when?
` A. 1986 when I completed my fellowship
`training.
` Q. Okay. And in Paragraph 6, you discuss
`that you "frequently treated patients with
`antifolates, particularly methotrexate."
` A. Correct.
` Q. Prior to the year 2000, you hadn't
`treated any patients with any antifolate other than
`methotrexate, right?
` A. That's not correct. The other major one
`that I used that was FDA approved was 5FU.
` Q. And does 5FU -- 5FU does not inhibit one
`of the -- let me back up.
` 5FU is not an anti-metabolite of
`one of the reduced folates, correct?
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`DAVID FELDMAN WORLDWIDE, INC.
`450 Seventh Avenue - Ste 500, New York, NY 10123 1.800.642.1099
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` DEPOSITION OF RON D. SCHIFF, M.D.
` A. That's not correct. It is. It's also a
`thymidylate synthase inhibitor.
` Q. Right. But it is a -- it's meant to be
`a mimic of uracil, right, not the folate?
` A. That's correct.
` Q. So in that sense, it's not an antifolate
`in the same way that methotrexate or pemetrexed is
`in that they are intended to mimic the reduced
`folate.
` A. It's grouped among the antifolates and
`it does play an inhibitory role in one of the
`pathways for which folic acid is required. So in
`that regard, I think that most oncologists, as well
`as myself, probably virtually all oncologists would
`regard it as an antifolate. Its mechanism of action
`also overlaps with that of some of the other
`antifolates.
` Q. All right. Do you consider it a reduced
`folate analog?
` A. It is not a reduced folate analog.
` Q. Other than 5FU and methotrexate, you
`didn't use any other antifolates prior to the year
`2000 because none were approved in the US; is that
`correct?
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`DAVID FELDMAN WORLDWIDE, INC.
`450 Seventh Avenue - Ste 500, New York, NY 10123 1.800.642.1099
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` DEPOSITION OF RON D. SCHIFF, M.D.
` A. I may have been exposed to some on an
`investigational basis during my training, but that
`was a long time ago.
` Q. When did your training end?
` A. '86.
` Q. Can you turn to Exhibit A or Attachment
`A to your declaration, Appendix A, your CV?
` A. I'm there.
` Q. Is that your current CV?
` A. I believe so, yes. I believe that this
`version was revised after I retired and looking at
`the first page, that is correct.
` Q. Okay. And if you look at Page 61 of the
`exhibit, which you can see in the lower right
`corner, there's a numbering. It says Exhibit 1004
`dash and some numbering?
` A. I see it.
` Q. At the bottom of Page 61 there's a
`heading "PUBLICATIONS:"?
` A. Correct.
` Q. And moving forward from there, three
`more pages, is that all of your publications?
` A. It is.
` Q. And so am I correct that your most
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` DEPOSITION OF RON D. SCHIFF, M.D.
`recent publication was an abstract in 1991?
` A. That's correct.
` Q. And --
` A. I went into private practice in 1992.
` Q. Okay. So it is correct that --
` A. It is correct.
` Q. -- let's not talk over each other.
` And prior to 1991 -- let me ask it
`a different way: Are any of the publications that
`you have listed in your CV from 1991 or prior, do
`any of them have to do with antifolates?
` A. None.
` Q. Did you ever use methotrexate to treat
`diseases other than cancer?
` A. I had patients who were taking
`methotrexate for autoimmune disorders such as
`rheumatoid arthritis. In those cases I had to
`coordinate the methotrexate administration and
`monitoring with the rheumatologist who had
`prescribed it.
` Q. In those situations did you consider
`yourself responsibile for the treatment of the
`rheumatoid arthritis?
` A. I certainly felt responsible for
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` DEPOSITION OF RON D. SCHIFF, M.D.
`monitoring the methotrexate effects and any
`interactions that it may have had with
`anti-neoplastic treatments.
` Q. Were you the one who decided that the
`patient should be treated with methotrexate for
`rheumatoid arthritis?
` A. No.
` Q. And do you have any expertise in the
`treatment of rheumatoid arthritis?
` A. To the extent that someone who has gone
`through an internal medicine residency is trained in
`rheumatology, I would, plus which, I am interested
`in some of the overlaps in rheumatology and medical
`oncology and hematology in terms of involvement in
`the immune system and so on.
` In short, what I'm saying is I
`always found it interesting and I followed some of
`the key developments. And of course if you find
`rheumatologic disorders that are treated with what I
`regard as chemotherapy, that's obviously of interest
`to me.
` Q. Do you agree with me that the doses of
`methotrexate used to treat rheumatoid arthritis are
`much lower than the doses used to treat cancer?
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` DEPOSITION OF RON D. SCHIFF, M.D.
` A. That's correct. But administration is
`prolonged in the treatment of rheumatoid arthritis
`and related autoimmune disorders.
` Q. That was going to be my next question.
`And also for rheumatoid arthritis, methotrexate is
`given as a low dose over a long period of time,
`whereas for cancer it's given at a high dose for a
`relatively short period of time.
` Is that true?
` A. As a rule, yes.
` Q. And was it -- you've given some opinions
`in this case from the perspective of a person of
`ordinary skill in the art.
` Do you recall that?
` A. I do.
` Q. And when I ask you about the person of
`ordinary skill in the art or person of ordinary
`skill today, I'm referring to a person having the
`qualifications and background that you describe in
`your declaration. Okay?
` A. I understand.
` Q. Okay. Would the person of ordinary
`skill have known in 1999 that when used to treat
`cancer, methotrexate could cause severe toxicities?
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` DEPOSITION OF RON D. SCHIFF, M.D.
` A. Absolutely.
` Q. And do you agree with me that the
`standard of care in giving methotrexate for the
`treatment of cancer was to follow methotrexate with
`leucovorin rescue?
` A. As a rule, yes, that's how toxicity was
`modulated. That's correct.
` Q. And what is leucovorin?
` A. Leucovorin is another folate analog that
`is interconverted with the other folates and is
`reduced, ultimately, so that it could be used for
`all of these processes in which folic acid
`functions. So another name for leucovorin is
`folinic acid.
` Q. And when methotrexate was given with
`leucovorin rescue, am I correct that the
`methotrexate was given, a period of time was allowed
`to elapse, and then the leucovorin rescue was given?
` A. Well, I mean, there were two separate
`approaches that were taken. In some cases it was
`indeed to rescue toxicity after the toxicity had
`already begun. But in other cases it was given on a
`predetermined schedule with the goal of preventing
`the development of toxicity.
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` DEPOSITION OF RON D. SCHIFF, M.D.
` Q. And the predetermined schedule was after
`the administration of methotrexate?
` A. Yes.
` Q. Would the person of ordinary skill have
`been familiar in 1999 with the approved labeling for
`methotrexate?
` A. Yes, I would say yes. However, that
`drug was in such common use that it was hardly
`necessary to refer to the PDR each time one would
`order methotrexate-based chemotherapy for a patient.
` Q. And is that because a person of ordinary
`skill, having used it so many times, would already
`be familiar with the contents of the PDR?
` A. Exactly. And familiar with the
`community standards of how it was used, familiar
`with the standard of care for administration,
`indications, including off label and so forth.
` Q. Okay. I'm going to mark this as
`Exhibit 2020.
` (Whereupon, Exhibit 2020
` marked as requested.)
` (Whereupon, the document was
` tendered.)
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` DEPOSITION OF RON D. SCHIFF, M.D.
`BY MR. PERLMAN:
` Q. Doctor, we've handed you what's been
`marked as Exhibit 2020, which is an excerpt from the
`1999 Physician's Desk Reference or PDR.
` Is that a book you were familiar
`with during your time in practice?
` A. Yes, it is.
` Q. And do you see what I have given you is
`the excerpt related to methotrexate?
` A. I see that.
` Q. And during your course of time in
`practice, you didn't look at this every time, but do
`you believe you were generally familiar with the
`contents of this labeling?
` A. I was very familiar with methotrexate
`use, certainly by the end of my first fellowship
`year.
` Q. Okay. And would that include the
`information contained in the label?
` A. I would think so, yes.
` Q. Could you turn -- there is a heading, so
`what we have is a cover page, the spine, then an
`interior title page, then the first page of the
`methotrexate listing. I want to go to the second
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` DEPOSITION OF RON D. SCHIFF, M.D.
`page of the methotrexate listing, and there is a
`heading at the bottom of the middle column that says
`"Precautions"?
` A. I see it.
` Q. And the first sentence is "Methotrexate
`has the potential for serious toxicity"?
` A. I see it.
` Q. And would the person of ordinary skill
`in 1999 have agreed with that?
` A. Yes.
` Q. And then if you turn to the next page,
`at the very top of the left column it says, the
`first paragraph, first full paragraph, it says,
`"Folate deficiency states may increase methotrexate
`toxicity"?
` A. I see that.
` Q. And would the person of ordinary skill
`in the art in 1999 have agreed with that statement?
` A. I imagine so, yes.
` Q. And they would have understand that
`folate deficiency states could lead to a patient
`suffering more toxicity from methotrexate
`administration, correct?
` A. That's correct.
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` DEPOSITION OF RON D. SCHIFF, M.D.
` Q. And then if you turn back just to the
`page before, at the bottom, the last paragraph on
`the page says, "Vitamin preparations containing
`folic acid or its derivatives may decrease responses
`to systemically administered methotrexate."
` Do you see that?
` A. I do. However, that really was not
`applicable.
` Q. Well, Doctor, let me ask the question
`and then you can tell me what your answer to it is.
` A. Okay.
` Q. First of all, would the person of
`ordinary skill in the art have understood that this
`label was warning that vitamin preparations
`containing folic acid or its derivatives may
`decrease responses to systemically administered
`methotrexate?
` A. I think that the person of ordinary
`skill in the art in 1999 would actually have
`disagreed with or discounted that statement.
` Q. Okay. Would they have understood that
`the approved labeling for methotrexate contained
`that warning?
` A. They would have read it there, but they
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` DEPOSITION OF RON D. SCHIFF, M.D.
`would have discredited its applicability to clinical
`practice.
` Q. And is it your testimony that the
`standard -- let me ask you this way: Did the
`standard of care in 1999 for giving methotrexate for
`the treatment of cancer include pretreatment of
`patients with folic acid or its derivatives?
` A. Not with pretreatment, that's correct.
` Q. All right. And you personally didn't
`pretreat patients with folic acid prior to giving
`them methotrexate for cancer, correct, in 1999?
` A. That is correct.
` Q. Okay. And you also didn't pretreat
`methotrexate patients for -- treated for cancer with
`vitamin B12 in 1999 or earlier, correct?
` A. That is also correct.
` Q. In fact, it was not the standard of care
`to do that, correct?
` A. Correct.
` Q. In fact, you are not aware of anyone
`doing that?
` A. Also correct.
` Q. Let's look back under "Clinical
`Pharmacology." Do you see that heading on the first
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` DEPOSITION OF RON D. SCHIFF, M.D.
`page of the methotrexate listing?
` A. I do.
` Q. And it starts out by saying,
`"Methotrexate inhibits dihydrofolic acid reductase"?
` A. That's correct.
` Q. And that is one of the enzymes that is
`involved in one-carbon transfers --
` A. It is.
` Q. Let me finish my question. -- in what
`we would call the folate pathway?
` A. Correct.
` Q. And it says a little farther down,
`"Actively proliferating tissues such as malignant
`cells, bone marrow, fetal cells, buccal and
`intestinal mucosa, and cells of the urinary bladder
`are, in general, more sensitive to this effect of
`methotrexate."
` Do you see that?
` A. The emphasis there is "in general,"
`because that is not a universal statement or
`conclusion.
` Q. Okay. Doctor, first of all, would the
`person of ordinary skill have agreed with this
`statement in the label?
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` DEPOSITION OF RON D. SCHIFF, M.D.
` A. Yes.
` Q. And the way that an antifolate's
`anti-proliferative effect works, if the antifolate
`is effective, is it inhibits the cell's ability to
`make DNA and therefore divide and grow, correct?
` A. That is a basic explanation but yes;
`that is correct.
` Q. And that would be the effect on cancer
`cells that would be desirable in the treatment of
`cancer and also the effect on rapidly dividing
`normal cells and could lead to toxicity, correct?
` A. That is correct.
` Q. And if you look a little farther down in
`the same column, the next full paragraph says, "The
`mechanism of action in rheumatoid arthritis is
`unknown. It may affect immune function." Correct?
` A. That's what it says.
` Q. And the person of ordinary skill would
`have agreed in 1999 that how methotrexate exactly
`worked to treat rheumatoid arthritis was unknown,
`correct?
` A. I think most persons of ordinary skill
`would have accepted that statement.
` Q. But they would not -- the person of
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` DEPOSITION OF RON D. SCHIFF, M.D.
`ordinary skill would not have believed in 1999 that
`the efficacy of methotrexate in the treatment of
`rheumatoid arthritis was due to its
`anti-proliferative effect, correct?
` A. I think the person of ordinary skill in
`1999 would have not known the answer to that
`question.
` Q. Doctor, one of the paragraphs you
`referred me to when we began today -- give me one
`second, unless you happen to remember which
`paragraph numbers it was.
` A. Well, I don't know what you are
`referring to.
` Q. You had five numbers, right? What were
`those five?
` A. What were those five?
` Q. Yes.
` A. That would have been 8, 15, 32, 50 and
`67.
` Q. That did the trick. Let's turn to
`Paragraph 32.
` A. Okay.
` Q. And you refer there to another
`antifolate known prior to 1999 as raltitrexed.
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