UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`SANDOZ INC.,
`APOTEX INC., 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 USA, INC.,
`FRESENIUS KABI USA, LLC, and WOCKHARDT BIO AG,
`
`Petitioners
`
`v.
`
`ELI LILLY AND COMPANY,
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`Patent Owner.
`
`Case IPR2016-003181
`U.S. Patent 7,772,209
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`
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`PETITIONER SANDOZ INC.’S RESPONSE TO PATENT OWNER’S
`MOTION FOR OBSERVATIONS ON THE DEPOSITION OF EXPERT
`RON D. SCHIFF, M.D., PH.D.
`
`1 Cases IPR2016-01429, IPR2016-01393, and IPR2016-01340 have been joined
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`with the instant proceeding.
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`SANDOZ INC.,
`APOTEX INC., 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 USA, INC.,
`FRESENIUS KABI USA, LLC, and WOCKHARDT BIO AG,
`
`Petitioners
`
`v.
`
`ELI LILLY AND COMPANY,
`
`Patent Owner.
`
`Case IPR2016-003181
`U.S. Patent 7,772,209
`
`
`
`
`
`
`
`
`PETITIONER SANDOZ INC.’S RESPONSE TO PATENT OWNER’S
`MOTION FOR OBSERVATIONS ON THE DEPOSITION OF EXPERT
`RON D. SCHIFF, M.D., PH.D.
`
`1 Cases IPR2016-01429, IPR2016-01393, and IPR2016-01340 have been joined
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`with the instant proceeding.
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`
`
`I.
`
`PATENT OWNER’S MOTION FOR OBSERVATIONS INCLUDES
`IMPROPER ARGUMENTS AND SHOULD BE EXPUNGED
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`Petitioner respectfully requests that the Board dismiss Patent Owner’s
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`Motion for Observations on the Deposition of Petitioner Sandoz’s Expert Dr. Ron
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`Schiff (“Motion” or “Mot.”) and expunge its supporting exhibits because the
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`purported observations in the Motion are a masked attempt to submit additional
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`argumentative sur-reply pages in contravention of the Board’s guidance and prior
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`decisions. Instead of a short statement of relevance, Patent Owner’s observations
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`include argument, some of which spans several sentences or is strung together with
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`a series of semicolons. E.g., Paper 67, Mot. at 3, 7, 9, 10. Moreover, many of
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`Patent Owner’s arguments are new; they do not match the positions taken on the
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`portions of the prior briefing Patent Owner cites. Sandoz discusses particularly
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`egregious examples in further detail in its responses below.
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`As the Office Patent Trial Practice Guide makes clear, “[a]n observation
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`should be a concise statement of the relevance of identified testimony to an
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`identified argument or portion of an exhibit . . . . [I]t is not an opportunity to raise
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`new issues, re-argue issues, or pursue objections.” 77 Fed. Reg. 48,755, 48,767-68
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`(Aug. 14, 2012). The Board has further noted that “each item included as an
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`observation on cross-examination should be precise, preferably no more than one
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`short sentence in the explanation of relevance. Observations on cross-examination
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`1
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`
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`are not meant to serve the purpose of an argumentative surreply.” Atrium Med.
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`Corp. v. Davol Inc., IPR2013-00189, Paper 48 at 2 (February 28, 2014).
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`“The Board may refuse entry of excessively long or argumentative
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`observations (or responses),” such as the observations contained in Patent Owner’s
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`Motion. See 77 Fed. Reg. 48,755, 48,767-68 (Aug. 14, 2012). In fact, the Board
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`has previously considered proposed observations similar to the Patent Owner’s
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`submissions and dismissed them as containing improper argument. In Medtronic,
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`Inc. v. Nuvasive, Inc., the Board reviewed proposed observations that “cite[d]
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`several pages of [the witness’s] testimony, as opposed to one portion” and
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`“proceed[ed] to present an argument that the testimony is relevant . . . .” IPR2013-
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`00506, Paper 37 at 3-4 (October 15, 2014). The Board found the statements
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`improper, dismissed the Motion, and expunged the relevant exhibits. Id.; see also
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`LG Elecs., Inc. v. ATI Techs. ULC, IPR2015-00325, Paper 52 at 2-5 (January 25,
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`2016). While Petitioner maintains that the Board should dismiss the Motion
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`without considering Patent Owner’s proposed observations due to their inclusion
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`of argument, Petitioner has responded to the proposed observations below.
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`II.
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`SANDOZ’S RESPONSES TO PATENT OWNER’S OBSERVATIONS
`Response to Observation 1
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`
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`Patent Owner’s observation concerns Dr. Schiff’s testimony relating to the
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`use of vitamin B12 (in the form of crude liver extract) and folic acid, as described in
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`2
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`
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`Farber’s 1948 study. According to Lilly, Farber’s early work with aminopterin
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`somehow shows “that vitamin B12 pretreatment would not have been obvious
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`because over many decades of the use of antifolates and recognition of antifolate
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`toxicity problems, vitamin B12 pretreatment was not used” since Farber 1948 was
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`published. Paper 67 at 2. Not only is this an improper new argument under the
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`Board’s rules, but it also ignores Dr. Schiff’s full testimony. Dr. Schiff explained
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`that Farber’s early experiments involving other antifolates provided proof of
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`principle that folic acid and vitamin B12 can alleviate antifolate toxicity (Exhibit
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`2136 at 45:10-46:25, 52:7-53:21) and that vitamin B12 was in fact used with other
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`antifolates such as 5-FU between Farber’s work in the 1940s and the discovery in
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`the 1990s of pemetrexed (e.g., Ex. 2136, at 102:8-105:5 (citing Ex. 1028,
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`Tisman)).
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`Response to Observation 2
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`
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`Patent Owner makes an improper argument that a POSA would look only to
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`the folic acid dose used in Hammond “rather than to trials of other drugs or doses
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`used in other contexts,” which, as noted above, violates the Board’s rules and
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`should be expunged. Paper 67 at 3.
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`Moreover, in making this improper argument, Patent Owner’s observation
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`ignores Dr. Schiff’s testimony. Dr. Schiff explained that for various antifolates
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`“certain findings will be transferable from one situation to another” but that a
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`3
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`
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`POSA would understand it “would certainly be a mistake to assume that what one
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`found with one antifolate compound would apply exactly to another . . . .”
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`Ex. 2136 at 30:23-31:14. Likewise, Patent Owner omits Dr. Schiff’s explanation
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`of how a POSA would understand that Hammond used a very “high dose” of folic
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`acid in order to offset toxicities that might occur while escalating the dose of
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`pemetrexed beyond the known safe Phase II dose. Ex. 2136 at 196:16-197:20. Dr.
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`Schiff’s explained that a POSA would look to published literature concerning the
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`use of folic acid with other antifolates such as lometrexol and the “community
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`standard for folic acid dose” in order to determine an appropriate dosage of folic
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`acid outside the context of pemetrexed dose escalation of Hammond. Ex. 2136 at
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`212:25-214:13. The referenced testimony is provided below:
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`Q. . . . . Would the person of ordinary skill have understood
`why Hammond was structured as a dose escalation study as opposed
`to simply giving the folic acid with the maximum tolerated dose that
`had previously been seen and seeing if the toxicity could be reduced?
`A. Yes.
`Q. What's the reason for that?
`A. I think a person of ordinary skill would have understood
`that and attributed it to the fact that if you wanted to see whether folic
`acid has a protective effect on toxicity, you would want to use high
`doses of pemetrexed, which includes dose escalation and not just the
`Phase II dose, and you'd want to use a high dose of folic acid itself. So
`maybe I misspoke. You'd want to use a high dose of pemetrexed in a
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`4
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`
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`dose escalation format to, you know, try and max out the toxicity to
`find out whether you're approaching a maximum tolerated dose with
`folic acid that is higher than what was established by the
`unsupplemented studies, and you would want to use a high dose of
`folic acid so that if you believe that folic acid would mitigate
`pemetrexed toxicity, you were giving enough of it to see that.
`
`Ex. 2136 at 196:16-197:20.
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`Dr. Schiff further testified:
`
`A. But in terms of folic acid administration with pemetrexed,
`Hammond was it. But, you know, a POSA would know how folic acid
`is administered under a variety of different conditions, what the
`pharmacokinetics of that B vitamin are, and what was done with folic
`acid and folic acid dosing in conjunction with other antifolates.
`Q. Let me -- let me ask you this, Doctor: In those other
`contexts in which the low dose of between 350 or 1,000 micrograms
`of folic acid were used in the prior art, was that in the presence of an
`antifolate?
`
`*
`*
`*
`THE WITNESS: In some cases, I think those doses were used
`with lometrexol.
`BY MR. PERLMAN: Q. No. The only clinical study that
`you've cited for lometrexol is Laohavinij, which had the 5 milligrams
`a day, as you said, starting a week before, and then there's one patient
`referred to in the 974 patent, right?
`*
`*
`
`*
`
`5
`
`
`
` BY MR. PERLMAN: Q. That's all we have.
`A. That patient may also have been present in Young and
`received half a milligram to one milligram a day of folic acid. And
`regardless of what attribution we make to -- you know, to that patient,
`that's another significant piece of data, one reason being that it is in
`line with the community standard for folic acid dose and schedule.
`
`Ex. 2136 at 212:25-214:13 (objections omitted)
`
`Response to Observation 3
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`
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`Patent Owner’s observation that Dr. Schiff agreed that pemetrexed is
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`renally cleared is irrelevant to Dr. Schiff’s opinions and does not support Patent
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`Owner’s contention that pemetrexed is a nephrotoxic drug. Paper 67 at 3; Ex.
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`1075, Schiff Reply ¶¶ 51-54. Further, Patent Owner omits Dr. Schiff’s testimony
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`that the “the person of ordinary skill would not agree that pemetrexed was a
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`nephrotoxic drug.” Ex. 2136 at 82:15-17. In addition, Patent Owner omits Dr.
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`Schiff’s testimony that a POSA would not have been concerned about kidney
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`toxicity in light of Hammond’s clinical study involving the use of pemetrexed with
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`folic acid pretreatment:
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`A. So Hammond only reported grades I and II nephrotoxicity,
`about which a person of ordinary skill of the art would not have been
`concerned.
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`Id. at 176:17-20
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`Response to Observation 4
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`6
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`
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`
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`Patent Owner’s observation that Dr. Schiff agreed generally that dose
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`reductions are routine in oncology practice is irrelevant. Patent Owner omits Dr.
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`Schiff’s explanation that dose reductions are undesirable and thus regimens are
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`“expressly designed to reduce the requirement for potentially harmful dose
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`reductions . . . .” Ex. 2136 at 86:17-25. Further, Dr. Schiff testified that such
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`reductions would be required to a lesser degree with vitamin supplementation:
`
`Q. I'm asking a different question, Doctor. What I'm suggesting
`to you is that the possibility of dose reductions is a routine part of
`oncology practice, correct?
`A. That's true.
`Q. And that's true for pemetrexed even with vitamin
`supplementation, correct?
`A. But I would say that it is required less, to a lesser degree
`with vitamin supplementation than it would be in the absence thereof.
`
`Ex. 2136 at 87:3-13.
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`Response to Observation 5
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`
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`Patent Owner’s characterization of Dr. Schiff’s testimony regarding not
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`doing anything that would affect response rates is misleading. Dr. Schiff testified
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`that “if you have a means to preserve or enhance efficacy while improving toxicity,
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`you want to take advantage of that rather than relying on dose reductions,
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`interruptions, delays, and so forth.” Id. at 92:8-12. As Dr. Schiff testified, this
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`means for preserving toxicity while enhancing efficacy was pretreatment with folic
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`7
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`
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`acid and vitamin B12 based upon the prior art, including the Worzalla, Hammond,
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`and Niyikiza references.
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`Dr. Schiff testified:
`
`
`
`Q. Okay. Okay. Now, Doctor, I want to switch gears for a
`second. Am I correct that it was, in your view, based on Worzalla and
`Hammond and Niyikiza and all the other references you've cited, that
`it would have been obvious in 1998 that pretreating pemetrexed
`patients with folic acid and B-12 would reduce toxicity and not affect
`efficacy?
`
`*
`*
`*
`Q. No, I'm asking your opinion, Doctor.
`A. Yeah, my opinion is yes, that's what a person of ordinary
`skill would and should have concluded.
`
`Ex. 2136 at 74:9-25.
`
`Response to Observation 6
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`
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`Patent Owner’s observation argues that Dr. Schiff’s testimony that betaine
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`has not been used with antifolate patients somehow contradicts the obviousness of
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`using vitamin B12 with antifolates. Paper 67 at 4-5. As noted above, this argument
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`is not properly raised in an observation and should be expunged.
`
`Further, Patent Owner omits Dr. Schiff’s testimony that “vitamin B-12
`
`already had a track record” in antifolate chemotherapy, having been administered
`
`8
`
`
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`to patients receiving another antifolate, aminopterin, by Dr. Sidney Farber as early
`
`as 1948. Ex. 2136 at 102:8-19. Dr. Schiff testified:
`
`But other things that he [Farber] did, which included
`administering folates and antifolates to the same patients,
`administering antifolate and vitamin B-12 to the same patients, those
`are as applicable in 1999 as they were in 1948.
`
`Id. at 41:9-14; see also id. 103:14-104:12. Dr. Schiff also testified that vitamin B12
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`was used prior to June 1999 with 5-FU for antifolate chemotherapy and that the
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`Niyikiza abstracts provide a “scientific rationale for its [vitamin B12] use.” Id. at
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`102:20-103:4. This testimony is relevant because it undercuts the premise of
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`Patent Owner’s improper new argument that vitamin B12 “had never been used to
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`pretreat a cancer patient . . . .” Paper 67 at 4-5.
`
`Response to Observation 7
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`Patent Owner’s observation regarding fatigue includes improper argument,
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`which should be expunged.
`
`In arguing that slow-onset neurotoxicity would not motivate a POSA to use
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`vitamin B12 pretreatment, Patent Owner omits Dr. Schiff’s testimony that vitamin
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`B12 deficiencies cause severe neurological toxicities that can arise “insidiously.”
`
`Ex. 2136 at 358:4-359:9. Dr. Schiff testified:
`
`9
`
`
`
`Q. Okay. And in terms of the neurological symptoms of a
`vitamin B-12 deficiency, am I correct that they develop, if at all, after
`the anemia?
`A. No. No. Unfortunately, that's not correct at all. There's a
`couple of things that have to be said about that. We -- we tend to -- a
`person of ordinary skill has been educated to the fact that the
`neurologic symptoms of vitamin B-12 deficiency can develop
`insidiously. The point is that it's not just how they're developing in
`terms of the neuropathology, it's when they become apparent.
`Q. Right.
`A. So for things like peripheral neuropathy and spinal cord
`degeneration and so on, it probably is an insidious process where a
`patient might eventually recognize a symptom and then say that he or
`she has had a lesser degree of that symptom for a certain period of
`time. But by the time there's a cognitive dysfunction problem, which
`has been called megaloblastic madness, cognitive impairment
`becomes apparent relatively acutely.
`
`Ex. 2136 at 358:4-359:5.
`
`In addition, Dr. Schiff testified:
`
`A. Yes. I think that would actually be quite a stress -- quite a
`stretch because I think that calling fatigue neurotoxicity does not bear
`the same weight as things like peripheral neuropathy, altered level of
`consciousness, spinal cord symptoms, cognitive impairment, and so
`forth.
`
`10
`
`
`
`Ex. 2136 at 126:4-10. This testimony is relevant because it shows, contrary to
`
`Patent Owner’s characterization of Dr. Schiff’s testimony, that Dr. Schiff did not
`
`exclude fatigue as a symptom of neurotoxicity as Patent Owner claims, but instead
`
`stated that fatigue would “not bear the same weight” as other more specific
`
`symptoms of neurotoxicity.
`
`Response to Observation 8
`
`
`
`Patent Owner’s observation is misleading and argumentative. Dr. Schiff did
`
`not suggest that a person of ordinary skill would strictly apply the exact period of
`
`pretreatment used in Hammond but instead testified:
`
`Q. Okay. Does Hammond give any reason that the two-day
`pretreatment period was insufficient?
`A. No, it does not. You cannot judge that comparatively
`because that was the only experimental condition.
`Q. No, does Hammond --
`*
`*
`*
`THE WITNESS: But the situation there is that interpretation of
`Hammond and application to the clinical setting would indeed be
`conditioned by the person of ordinary skill's understanding of the
`principles of folic acid administration and pharmacokinetics.
`
`Exhibit 2136 at 240:23-241:14.
`
`
`11
`
`
`
`Q. Right. And would the person of ordinary skill have any
`reason to believe that if you kept the same regimen as Hammond but
`just started a few days earlier, that you would get better results?
`A. No. I think a person of ordinary skill would probably
`consider that a wash.
`
`Id. at 242:15-21. This testimony is relevant because it shows Patent Owner is
`
`incorrect in arguing that a POSA would not pretreat any longer than Hammond did
`
`(2 days); instead, a POSA would recognize that Hammond did not attempt to find
`
`the optimum pre-treatment period and that it was likely that extending the
`
`pretreatment period by a few days would be “a wash,” i.e., make no difference.
`
`Response to Observation 9
`
`
`
`Patent Owner’s observation includes extensive argument concerning FDA
`
`documents that are outside the scope of Dr. Schiff’s testimony and were not
`
`discussed at his deposition. Paper 67 at 7. Patent Owner’s incorrect reading of
`
`those FDA documents is discussed in the declaration of Dr. David Ross, M.D.
`
`Ex. 1093.
`
`Response to Observation 10
`
`
`
`Patent Owner’s observation contains three sentences of improper argument,
`
`which should be expunged. Paper 67 at 8-9. Moreover, Patent Owner’s argument
`
`is new; the only cite Patent Owner includes to its prior briefing does not contain
`
`12
`
`
`
`the argument Patent Owner now presents about the timing of the motivation to add
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`vitamin pretreatment. See Paper 67 at 8 (citing Paper 36 at 25).
`
`In addition, Patent Owner mischaracterizes the quoted portion of Dr.
`
`Schiff’s testimony, which actually explains a motivation to pretreat patients with
`
`vitamins before administering pemetrexed. Specifically, Dr. Schiff’s testimony
`
`explains that by the early- to mid-1990s, i.e., just a few years before the June 1999
`
`priority date, a POSA would have understood a link existed between folate
`
`deficiency and antifolate toxicity generally. Ex. 2136 at 417:16-418:22.
`
`In order to make its new and improper argument about the timing of vitamin
`
`pre-treatment, Patent Owner misleadingly omits Dr. Schiff’s testimony concerning
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`pemetrexed-specific publications from the late-1990s indicating the benefits of
`
`folic acid pretreatment with pemetrexed, including Dr. Schiff’s explanation that the
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`1998 Worzalla paper showed that pemetrexed’s “therapeutic window was
`
`tremendously broadened” with folic acid pretreatment (Ex. 2136 at 248:12-25) and
`
`the 1999 Hammond abstracts “support[ ] the POSA’s interpretation that
`
`coadministration of folic acid mitigates pemetrexed toxicity” (id. at 145:12-16).
`
`This testimony is relevant because it contradicts Patent Owner’s new argument that
`
`motivation to treat pemetrexed patients with folic acid was the same in the early- to
`
`mid-1990s as in the late-1990s.
`
`
`
`13
`
`
`
`
`Dated: February 21, 2017
`
`
`
`
`
`
`
`
`
`
`
`Respectfully submitted,
`
`/s/ Ralph J. Gabric
`Ralph J. Gabric (Reg. No. 34,167)
`Laura L. Lydigsen
`Bryan T. Richardson, Ph.D. (Reg. No.
`70,572)
`Joshua H. James (Reg. No. 72,568)
`Brinks Gilson & Lione
`NBC Tower – Suite 3600
`455 N. Cityfront Plaza Dr.
`Chicago, Illinois 60611
`
`14
`
`
`
`CERTIFICATE OF SERVICE
`
`I hereby certify that true and correct copies of the foregoing document were
`served on February 21, 2017, via email to the following individuals at the email
`addresses below.
`
`Dov P. Grossman (Reg. No. 72,525)
`Williams & Connolly LLP
`725 Twelfth St. NW
`Washington DC 20005
`Direct Phone: 202-434-5812
`Facsimile: 202-434-5029
`dgrossman@wc.com
`
`David M. Krinsky (Reg. No. 72,339)
`Williams & Connolly LLP
`725 Twelfth St. NW
`Washington DC 20005
`Direct Phone: 202-434-5338
`Facsimile: 202-480-8302
`dkrinsky@wc.com
`
`Adam L. Perlman
`Williams & Connolly LLP
`725 Twelfth St. NW
`Washington DC 20005
`Direct Phone: 202-434-5244
`aperlman@wc.com
`
`James P. Leeds (Reg. No. 35,241)
`Eli Lilly and Company
`Lilly Corporate Center
`Indianapolis, IN 46285
`Direct Phone: 317-276-1667
`Facsimile: 317-277-6534
`leeds_james@lilly.com
`
`John C. Demeter (Reg. No. 30,167)
`Eli Lilly and Company
`Lilly Corporate Center
`
`
`
`
`
`
`
`
`
`
`
`/s/ Ralph J. Gabric
`Ralph J. Gabric (Reg. No. 34,167)
`Laura L. Lydigsen
`Bryan T. Richardson, Ph.D. (Reg. No.
`70,572)
`Joshua H. James (Reg. No. 72,568)
`Brinks Gilson & Lione
`NBC Tower – Suite 3600
`455 N. Cityfront Plaza Dr.
`Chicago, Illinois 60611
`
`Indianapolis, IN 46285
`Direct Phone: 317-276-3785
`Facsimile: 317-276-3861
`Email: demeter_john_c@lilly.com
`
`
`
`
`
`
`
`
`
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`
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