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`Case IPR 2016-00318
`Patent 7,772,209
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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 No: IPR2016-003181
`Patent No. 7,772,209
`__________________
`
`PATENT OWNER’S MOTION FOR OBSERVATIONS ON THE
`DEPOSITION OF PETITIONER SANDOZ’S EXPERT
`RON D. SCHIFF, M.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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`
`
`Case IPR 2016-00318
`Patent 7,772,209
`Pursuant to 77 Fed. Reg. 48756, Patent Owner Eli Lilly & Company
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`(“Lilly”) submits this motion for observations regarding cross-examination of
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`Petitioner Sandoz’s reply declarant Ron D. Schiff, M.D.
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`Observation 1. Dr. Schiff testified that Farber demonstrated in the 1940s
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`“the principle . . . that folic acid and vitamin B-12 can be administered to patients
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`who are also treated with antifolates for malignancy. And in some cases, the
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`results were better with historical controls than they were if the antifolate was not
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`used or than they were without the B vitamins.” Ex. 2136 at 45:10-18. Dr. Schiff
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`further testified that at least by 1959, “there would have been a reason to conclude
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`that vitamin B-12 would have been of interest” in antifolate treatment. Id. at
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`46:15-47:10. This testimony is relevant to Lilly’s argument that vitamin B12
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`pretreatment would not have been obvious because over many decades of the use
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`of antifolates and recognition of antifolate toxicity problems, vitamin B12
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`pretreatment was not used, suggesting that its use was not in fact obvious. Paper
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`36 at 2, 4, 8-9, 34-35.
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`Observation 2. Dr. Schiff testified that it would “certainly be a mistake to
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`assume that what one found with one antifolate compound would apply exactly to
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`another, which is why someone who's interested in developing pemetrexed for
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`clinical applications would pay the greatest attention to the pemetrexed research
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`leading up to that point and then after that would diverge the study to other
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`Case IPR 2016-00318
`Patent 7,772,209
`antifolates.” Ex. 2136 at 31:5-14. This testimony is relevant because it supports
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`Patent Owner’s argument that if (contrary to Patent Owner’s position) the POSA
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`were to use folic acid pretreatment with pemetrexed, the POSA would look to a
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`reference such as Hammond, which described a pemetrexed clinical trial, when
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`determining the appropriate dosage of folic acid, rather than to trials of other drugs
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`or doses used in other contexts. Paper 36 at 52.
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`Observation 3. Dr. Schiff agreed that “it was known in 1999 that
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`pemetrexed[’s] clearance is primarily renal [i.e., through the kidneys].” Ex. 2136
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`at 80:25-81:4. He further agreed that if the POSA believed a drug that was cleared
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`renally were nephrotoxic, the POSA “would expect that you would see increased
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`toxicity from those who had kidney impairment.” Id. at 82:1-21. This testimony is
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`relevant to Lilly’s argument that the POSA would not expect folic acid
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`supplementation to permit a useful escalation of pemetrexed’s dose, because (1)
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`dose escalation is not useful without an increase in efficacy; (2) the POSA would
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`expect folic acid to reduce efficacy, thus counteracting any efficacy benefit that
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`might arise from a higher dose; and (3) worse, the Hammond study revealed signs
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`of kidney toxicities at higher doses that would not have been ameliorated by folic
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`acid (or vitamin B12) pretreatment. Paper 36 at 28-29; Ex. 2120 ¶¶ 49, 73-74, 76-
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`82.
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`Case IPR 2016-00318
`Patent 7,772,209
`Observation 4. Dr. Schiff agreed that “the possibility of dose reductions is
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`a routine part of oncology practice.” Ex. 2136 at 87:3-7. This testimony is
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`relevant because it supports Lilly’s argument that dose and schedule reductions
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`would have been an obvious way for the POSA to manage any pemetrexed
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`toxicities that might be encountered, and that pemetrexed’s toxicities were
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`regarded as tolerable and manageable using “conventional dose and schedule
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`adjustments.” Paper 36 at 21-23 (quoting Ex. 1052 at 1194, 1198).
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`Observation 5. Dr. Schiff testified that the POSA “would not want to do
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`anything to compromise response rates if at all possible.” Ex. 2136 at 91:15-92:12.
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`This testimony is relevant to Lilly’s argument that the POSA would not have
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`adopted or modified a pemetrexed dosing regimen in a way that compromised
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`pemetrexed’s promising efficacy. Paper 36 at 19-23.
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`Observation 6. Dr. Schiff agreed that “the fact that betaine hadn't been
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`used” to pretreat an antifolate patient was “a contributing factor” that “would cause
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`a person of ordinary skill not to focus on it.” Ex. 2136 at 98:21-99:17; see also id.
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`at 106:10-17 (stating that Quinn, which discussed the use of betaine to lower
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`homocysteine, “does not propose an alternative that has a track record”). This
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`testimony is relevant because it contradicts Petitioner’s argument that the POSA
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`would pretreat pemetrexed patients with vitamin B12, because it had never been
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`Case IPR 2016-00318
`Patent 7,772,209
`used to pretreat a cancer patient receiving a folate analogue antifolate such as
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`pemetrexed. Paper 36 at 34-35.
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`Observation 7. Dr. Schiff testified that he “ha[s] a little bit of a hard time
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`thinking of fatigue specifically as a central nervous system toxicity,” that fatigue is
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`“very, very nonspecific,” and that the POSA “hears complaints about fatigue from
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`virtually every patient in their practice.” Ex. 2136 at 121:18-124:12. Dr. Schiff
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`further testified that “the hematologic toxicities as well as gastrointestinal
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`toxicities—by which I would mean things like mucositis, diarrhea, even liver
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`function test elevation—would be of greater concern to the person of ordinary skill
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`than fatigue.” Id. at 123:16-124:12. This testimony is relevant because it supports
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`the opinion of Dr. Chabner that fatigue is “a common side effect of virtually all
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`cancer treatments,” would not be understood as a neurotoxicity, would not have
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`been understood to correlate with homocysteine levels in the Niyikiza abstracts,
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`and would not provide a motivation for the POSA to administer vitamin B12. Ex.
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`2120 ¶ 129. The testimony is therefore also relevant to Lilly’s argument that the
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`slow-onset neurotoxicities that are sometimes observed in cases of severe vitamin
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`B12 deficiency (outside the context of antifolate chemotherapy) would not have
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`motivated the POSA to administer vitamin B12 pretreatment to patients receiving
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`pemetrexed. Paper 36 at 45.
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`5
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`Case IPR 2016-00318
`Patent 7,772,209
`Observation 8. Dr. Schiff agreed that “Hammond doesn’t give any reason
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`that it would be beneficial to lengthen the pretreatment period.” Ex. 2136 at
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`241:21-242:8. Dr. Schiff also agreed that the POSA would not have reason to
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`believe “that if you kept the same regimen as Hammond but just started a few days
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`earlier, that you would get better results.” Id. at 242:15-21. This testimony is
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`relevant because it supports Patent Owner’s argument that the POSA would not
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`have reason to administer folic acid earlier than when Hammond did (2 days prior
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`to treatment), and therefore claims 6 and 19 that recite folic acid pretreatment “1 to
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`3 weeks prior” to pemetrexed administration would not have been obvious. Paper
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`36 at 53.
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`Observation 9. Dr. Schiff testified:
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`Q. Let me ask a different question. Given what you
`believe is the clarity of the teaching of Niyikiza and
`given the ethical constraints on doctors, would you
`expect that following the publication of Niyikiza, all
`pemetrexed clinical trials would have included either
`testing patients for pretreatment homocysteine levels and
`giving vitamins to those who had an elevated level, or
`giving everyone vitamins?
`*
`*
`*
` BY MR. PERLMAN:
`Q. Would that have been your expectation?
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`Case IPR 2016-00318
`Patent 7,772,209
`A. I think that either of those was a reasonable
`approach.
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`Ex. 2136 at 341:23-342:15 (objection omitted). This testimony is relevant because
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`it undermines Petitioner’s argument that vitamin pretreatment would have been
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`obvious; if the POSA had believed, following Niyikiza, that folic acid and vitamin
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`B12 pretreatment would have been able to reduce toxicity without harming efficacy,
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`pemetrexed clinical trials would naturally have included it, but in fact, people in
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`the field (including the FDA) expressed skepticism. Paper 36 at 10-11, 57-59.
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`Even though vitamin supplementation was discussed with the FDA at the
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`pemetrexed End of Phase II Meeting, Lilly did not include it when designing a
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`Phase III clinical trial for pemetrexed in mesothelioma. Id.; Ex. 2100 at
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`ELAP00008719. Dr. Schiff’s “expectation” therefore does not jibe with the reality
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`of what skilled artisans did in the period before the priority date.
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`Observation 10. Dr. Schiff testified:
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`Q. Doctor, you've cited a bunch of articles from
`the mid and early '90s from the nutrition literature about
`using folate to lower homocysteine, right?
`A. That's correct.
`Q. Okay. And so certainly by that time that those
`articles came out, it was known in the medical literature,
`at least, that elevated homocysteine was indicative of
`folate deficiency, correct?
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`7
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`Case IPR 2016-00318
`Patent 7,772,209
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`A. Yes.
`Q. Okay. And it was also known that folate
`deficiency would be related to antifolate toxicity,
`correct?
`A. That's correct.
`Q. And so the person of ordinary skill years before
`Niyikiza, if someone had asked them the question, would
`have expected that elevated homocysteine would be
`correlated with increased antifolate toxicity. Isn't that
`fair?
`
`A. There I think we are still dealing with the
`decade of the 1990s. We're not dealing with something
`that extends back way before that.
`Q. No --
`A. All of this was going on at the same time in
`research.
`Q. Right. So the early 1990s is what you're saying?
`A. Early to mid, but yes.
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`Ex. 2136 at 417:16-418:22. This testimony is relevant because it undermines
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`Petitioner’s assertion that Niyikiza would have motivated the POSA to pretreat
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`with vitamins. Even though the motivation to pretreat with folic acid was
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`purportedly known to the POSA years before the priority date—as Dr. Schiff
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`testified—the vast majority of pemetrexed trials during that time did not have
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`vitamin supplementation. See Paper 36 at 25. The purported motivations
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`8
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`Case IPR 2016-00318
`Patent 7,772,209
`Petitioner relies upon did not, in fact, motivate artisans to adopt vitamin
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`pretreatment.
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`
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`Date: February 14, 2017
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`Respectfully submitted,
`
`/David M. Krinsky/
`David M. Krinsky
`Reg. No. 72,339
`Back-up Counsel for
`Patent Owner
`
`Williams & Connolly LLP
`725 Twelfth Street, N.W.
`Washington, D.C. 20005
`202-434-5338 (Telephone)
`202-434-5029 (Facsimile)
`dkrinsky@wc.com
`
`
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`9
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`Case IPR 2016-00318
`Patent 7,772,209
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`CERTIFICATE OF SERVICE
`(37 C.F.R. § 42.6(e))
`
`The undersigned hereby certifies that the foregoing document was served on
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`
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`February 14, 2017 by delivering a copy via electronic mail on the following
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`attorneys of record for the Petitioners:
`
`Ralph J. Gabric
`Reg. No. 34,167
`rgabric@brinksgilson.com
`
`Joshua H. James
`Reg. No. 72,568
`jjames@brinksgilson.com
`
`Brinks Gilson & Lione
`455 Cityfront Plaza Drive
`Suite 3600 NBC Tower
`Chicago, IL 60611-5599
`T: 312-321-4200; F: 312-321-4299
`
`Bryan T. Richardson, Ph.D.
`Reg. No. 70,572
`brichardson@brinksgilson.com
`
`Brinks Gilson & Lione
`4721 Emperor Blvd.
`Suite 220
`Durham, NC 27703-8580
`T: 919-998-5700; F: 919-998-5701
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`Counsel for Sandoz Inc.
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`John D. Polivick
`Reg. No. 57,926
`jpolivick@rmmslegal.com
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`William A. Rakoczy
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`
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`Laura Lydigsen
`Pro hac vice
`llydigsen@brinksgilson.com
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`Deanne M. Mazzochi
`Reg. No. 50,158
`dmazzochi@rmmslegal.com
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`Patrick C. Kilgore
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`Pro hac vice to be filed
`wrakoczy@rmmslegal.com
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`Rakoczy Molino Mazzochi Siwik LLP
`6 West Hubbard Street, Suite 500
`Chicago, IL
`P: 312-527-2157/F: 312-527-4205
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`Attorneys for Apotex Inc. and Apotex
`Corp.
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`Thomas J. Parker
`Reg. No. 42,062
`thomas.parker@alston.com
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`Alston & Bird LLP
`90 Park Avenue, 15th Floor
`New York, NY 10016
`P: 212-210-9529/F: 212-210-9444
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`Counsel for Mylan Laboratories Limited
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`Gerard A. Haddad
`Reg. No. 41,811
`GHaddad@BlankRome.com
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`Blank Rome LLP
`The Chrysler Building
`405 Lexington Ave.
`New York, NY 10174
`P: 212-885-5135/F: 917-591-6921
`
`Counsel for Glenmark Pharmaceuticals
`Inc., USA, Glenmark Holding SA, and
`Glenmark Pharmaceuticals Ltd.
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`Paul M. Zagar
`Reg. No. 52,392
`PZagar@BlankRome.com
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`Case IPR 2016-00318
`Patent 7,772,209
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`Reg. No. 69,131
`pkilgore@rmmslegal.com
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`Blank Rome LLP
`The Chrysler Building
`405 Lexington Ave.
`New York, NY 10174
`P: 212-885-5290/F: 917-332-3063
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`Counsel for Emcure Pharmaceuticals
`Ltd., Heritage Pharma Labs Inc., and
`Heritage Pharmaceuticals Inc.
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`Patrick A. Doody
`Reg. No. 35,022
`patrick.doody@pillsburylaw.com
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`Pillsbury Winthrop Shaw Pittman LLP
`1650 Tysons Boulevard
`McLean, VA 22102
`P: 703-770-7755/F: 703-770-7901
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`Counsel for Wockhardt Bio AG
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`Gary J. Speier
`Reg. No. 45,458
`gspeier@carlsoncaspers.com
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`Carlson, Caspers, Vandenburgh,
`Lindquist & Schuman
`225 South Sixth Street, Suite 4200
`Minneapolis, MN 55402
`P: 612-436-9600
`F: 612-436-9605
`
`Cynthia Lambert Hardman
`Reg. No. 53,179
`chardman@goodwinprocter.com
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`Goodwin Procter LLP
`The New York Times Building
`620 Eighth Avenue
`New York, NY 10018-1405
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`Case IPR 2016-00318
`Patent 7,772,209
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`Bryan P. Collins
`Reg. No. 43,560
`bryan.collins@pillsburylaw.com
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`Mark D. Schuman
`Reg. No. 31,197
`mschuman@carlsoncaspers.com
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`P: 212-813-8800
`F: 212-355-3333
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`Attorneys for Teva Pharmaceuticals
`USA, Inc. and Fresenius Kabi USA,
`LLC
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`Case IPR 2016-00318
`Patent 7,772,209
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`/David M. Krinsky/
`David M. Krinsky
`Reg. No. 72,339
`Back-up Counsel for Patent
`Owner
`
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`Date: February 14, 2017
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