throbber
UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Case IPR 2016-00318
`Patent 7,772,209
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`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`
`
`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
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`PATENT OWNER’S SUR-REPLY2
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`1 Cases IPR2016-01429, IPR2016-01393, and IPR2016-01340 have been joined
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`with the instant proceeding.
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`2 Pursuant to the Board’s authorization (see Ex. 2131), a combined sur-reply,
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`identical except for the caption, case number header, and certificate of service, is
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`being filed in IPR2016-00237, IPR2016-00240, and IPR2016-00318.
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`TABLE OF CONTENTS
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`Case IPR 2016-00318
`Patent 7,772,209
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`I. 
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`Petitioners’ New Biochemical Theories Arguing that Folate Is Not an
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`“Antidote” Only Emphasize the Nonobviousness of the Invention ................ 1 
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`A. 
`
`The Potency of Pemetrexed’s Enzyme Inhibition Would Not
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`Have Addressed the POSA’s Efficacy Concerns .................................. 2 
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`B. 
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`The POSA Would Have Expected Any Beneficial Effect of
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`Vitamin B12 To Be Accompanied by a Reduction in Efficacy ............. 6 
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`II. 
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`The FDA’s Reaction to Vitamin Supplementation Shows that the
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`POSA Would Have Believed Vitamin Pretreatment Would Harm
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`Efficacy ............................................................................................................ 8 
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`III.  Lilly’s Post-Priority Date Statements Are Irrelevant .................................... 10 
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`IV.  Petitioners Apply a New and Incorrect Standard for Evaluating
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`Dosage Claims ............................................................................................... 13 
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`V. 
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`The Board Should Take Notice of the Federal Circuit’s Related
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`Decision ......................................................................................................... 15 
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`TABLE OF AUTHORITIES
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`Case IPR 2016-00318
`Patent 7,772,209
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`FEDERAL CASES
`Eli Lilly & Co. v. Teva Parenteral Medicines, Inc., 845 F.3d 1357
`(Fed. Cir. 2017) ................................................................................................... 15
`
`In re Wilson, 311 F.2d 266 (C.C.P.A. 1962) ........................................................... 11
`
`Kinetic Concepts, Inc. v. Smith & Nephew, Inc., 688 F.3d 1342 (Fed.
`Cir. 2012) ........................................................................................................ 2, 13
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`KSR Int’l Co. v. Teleflex, Inc., 127 S. Ct. 1727 (2007) ........................................... 10
`
`Osram Sylvania v. Am. Induction Techs., 701 F.3d 698 (Fed. Cir.
`2012) ................................................................................................................... 14
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`PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342 (Fed.
`Cir. 2007) ............................................................................................................ 12
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`Thomas & Betts Corp. v. Litton Sys., Inc., 720 F.2d 1572 (Fed. Cir.
`1983) ................................................................................................................... 10
`
`OTHER AUTHORITIES
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`Federal Rule of Evidence 801 .................................................................................. 12
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`iii
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`In its Patent Owner Responses, Lilly described how the person of ordinary
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`Case IPR 2016-00318
`Patent 7,772,209
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`skill in the art (POSA) would have expected folic acid and vitamin B12
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`pretreatment to reduce pemetrexed’s efficacy, and therefore would not have been
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`led to the claimed invention. Tellingly, in their Replies, Petitioners do not contest
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`that the POSA would have been concerned with pemetrexed’s efficacy in addition
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`to its toxicity. Instead, they put forward a raft of new arguments about why the
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`POSA allegedly would have expected the claimed regimen not to reduce efficacy.
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`They also focus on how Lilly—after the priority date and with knowledge of the
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`invention—advocated for its own invention in publications and to the FDA. For
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`the reasons discussed below, Petitioners’ arguments are post hoc rationalizations
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`for the invention that constitute improper hindsight reasoning, fail to rebut Lilly’s
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`points, and cannot support Petitioners’ claims of obviousness.3
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`I.
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`Petitioners’ New Biochemical Theories Arguing that Folate Is Not an
`“Antidote” Only Emphasize the Nonobviousness of the Invention
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`Having largely ignored in their Petitions the expected negative impact of the
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`3 Consistent with the Board’s direction, this brief responds only to improper new
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`Reply arguments. Petitioners also made arguments, such as attacks on the
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`credibility of Lilly’s witnesses, that are meritless but do not fall within the Board’s
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`direction. As necessary, Lilly will respond to such arguments at oral argument.
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`claimed vitamin pretreatments on pemetrexed’s efficacy, Petitioners now advance
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`several theories to argue that folic acid and vitamin B12 do not act as antidotes to
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`pemetrexed. Critically, the question is not whether, today, Petitioners’ experts can
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`come up with a scientific hypothesis as to how folic acid and vitamin B12
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`pretreatment might be able to reduce pemetrexed’s toxicity without harming
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`efficacy. We know today that there must be some explanation, as we now know
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`from experience that Dr. Niyikiza’s invention in fact works. But that is always
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`true for successful inventions. The question for obviousness, however, is whether
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`the prior art taught or suggested any such rationale which would make Dr.
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`Niyikiza’s invention obvious to the POSA. E.g., Kinetic Concepts, Inc. v. Smith &
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`Nephew, Inc., 688 F.3d 1342, 1369 (Fed. Cir. 2012).
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`There are no such teachings, and, in any event, Petitioners’ new scientific
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`arguments are unavailing.
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`A. The Potency of Pemetrexed’s Enzyme Inhibition Would Not Have
`Addressed the POSA’s Efficacy Concerns
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`Neptune argues that folic acid does not act as pemetrexed’s “antidote” by
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`observing that pemetrexed is a potent inhibitor of DHFR, the enzyme responsible
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`for converting folic acid to useful “reduced” forms. Neptune Reply 12-14;
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`Neptune Ex. 1077 ¶¶ 19-23; Neptune Ex. 1078 ¶¶ 22-35, 40-46. Accordingly,
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`Neptune argues that because pemetrexed would be expected to completely block
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`DHFR, any folic acid administered in the presence of pemetrexed would never be
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`Patent 7,772,209
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`converted to a useful form and thus would not affect pemetrexed’s efficacy.
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`Neptune Reply 13.
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`Neptune’s new theory is fundamentally inconsistent with the prior art.
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`Worzalla’s preclinical testing showed that folic acid administration led to a
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`dramatic increase in the amount of pemetrexed needed for an antitumor response,
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`see Worzalla (Neptune Ex. 1005, Sandoz Ex. 1013) at 3235-38; Neptune Ex. 1077
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`¶ 21, and Hammond likewise observed a decrease in antitumor responses after folic
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`acid pretreatment in humans, Ex. 2120 ¶ 96. These data clearly show a reduction
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`in efficacy accompanied any reduction in toxicity.
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`Neptune’s theory also conflicts with Petitioners’ previous arguments. The
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`only way anyone has suggested that folic acid can reduce pemetrexed’s toxicity
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`requires the action of “reduced folates”—the very forms of folate into which,
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`according to Neptune, folic acid will not be converted if pemetrexed blocks DHFR.
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`Healthy cells need reduced folates in order to make DNA and survive antifolate
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`chemotherapy. Ex. 2120 ¶¶ 37, 45, 49. And even if (contrary to the evidence),
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`homocysteine had a role in pemetrexed’s toxicity independent of its role as a
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`biomarker for “functional folate status,” see Calvert I (Neptune Ex. 1014, Sandoz
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`Ex. 1007) at 8; Zervos (Neptune Ex. 1016, Sandoz Ex. 2064), the form of folate
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`that lowers homocysteine is also a reduced folate, 5-MTHF. Neptune Ex. 1077 ¶
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`40(b); Neptune Ex. 1078 ¶ 32. If DHFR really were blocked and folic acid were
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`not converted to a reduced folate, folic acid administration would have no effect on
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`homocysteine levels. If Neptune’s theory that pemetrexed “is not pemetrexed’s
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`antidote” made it impossible for folic acid to reduce pemetrexed’s efficacy, the
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`POSA therefore would understand it not to ameliorate pemetrexed’s toxicity, and
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`Neptune’s proffered reason why the POSA would administer it would be absent.
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`Moreover, as Neptune itself emphasizes, the claims require pretreatment
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`with folic acid before pemetrexed is administered. Neptune Reply 14. Folic acid
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`is converted by DHFR to reduced folates—which Neptune and its experts concede
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`can reverse pemetrexed’s effects—before any pemetrexed is administered.
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`Neptune Ex. 2135 at 212, 320-23, 342-44; Neptune Ex. 2134 at 49. Neptune
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`argues that this somehow means folic acid would have a beneficial effect on
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`toxicity, Neptune Reply at 14, but again, whatever protective effect the folic acid
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`would have on healthy cells, the POSA would have expected the same effect on
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`cancerous ones. Neptune’s new theory does nothing to refute that. In addition,
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`there is no suggestion in the prior art that pretreatment alone with folic acid—
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`without concurrent and post-treatment administration—would reduce pemetrexed’s
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`toxicity. Hammond’s prior art folic acid regimen was not limited to pretreatment,
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`and there is no evidence that pretreatment alone would have reduced toxicity.
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`Finally, even if Neptune’s DHFR argument somehow undermined the
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`POSA’s expectation that folic acid pretreatment would reduce efficacy, it does
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`Patent 7,772,209
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`nothing to ameliorate the POSA’s significant concerns with vitamin B12
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`pretreatment. THF, the form of folate that vitamin B12 administration releases, is
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`downstream of DHFR, so the release of THF is unaffected by DHFR inhibition.
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`Neptune’s new arguments about DHFR thus do not provide any reason to believe
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`that vitamin B12 pretreatment would not harm efficacy; to the contrary, if the POSA
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`believed them, they would be a reason to administer folic acid without vitamin B12.
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`For its part, Sandoz uses enzyme binding constants to make a different and
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`inconsistent argument. One of its new experts, Dr. Stover, opined that the binding
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`of folates to the enzyme TS—not DHFR—would have been expected to be
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`blocked. Sandoz Ex. 2137 at 60. He thus hypothesized that what he called “off-
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`target” toxicities caused by, for example, DHFR inhibition might be ameliorated by
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`folic acid pretreatment, while pemetrexed’s efficacy against cancer cells, deriving
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`from TS inhibition, would be unaffected. But Dr. Stover admitted that he had no
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`idea what causes pemetrexed’s principal toxicities, id. at 15-16—and if they are
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`caused by TS inhibition, even in substantial part, his entire unsupported musing
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`falls completely apart. And his hypothesis about folate’s effects on pemetrexed
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`efficacy is flatly contradicted by the balance of the evidence—the experimental
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`results of Worzalla and Hammond, as well as the testimony of other experts that
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`reduced folates would be expected to reduce pemetrexed’s activity against TS. See
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`Neptune Ex. 2135 at 320-23; Neptune Ex. 2134 at 49; Ex. 2120 ¶¶ 62-65.
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`Patent 7,772,209
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`The POSA Would Have Expected Any Beneficial Effect of
`Vitamin B12 To Be Accompanied by a Reduction in Efficacy
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`B.
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`As Lilly previously explained, and Petitioners do not dispute, the enzyme
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`methionine synthase (MS) relies on vitamin B12 to function. -00237, Paper 33 at 7;
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`-00240, Paper 32 at 7; -00318, Paper 36 at 6. In the presence of vitamin B12, MS
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`converts a form of folate called 5-MTHF to another form called THF. THF is used
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`by the folate enzymes that make DNA and RNA precursors required for cell
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`division (in both healthy and cancerous cells). And when vitamin B12 pretreatment
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`is administered, that can convert an unpredictable quantity of 5-MTHF into the
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`more-useful THF, thereby providing more useful reduced folate that can reverse
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`the effect of pemetrexed and promote tumor growth. Ex. 2120 ¶¶ 37-39, 85-87.
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`The POSA would thus not have wanted to administer vitamin B12 prior to
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`pemetrexed; it would have been expected to reverse pemetrexed’s effects to an
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`unpredictable—and thus uncontrollable—degree.
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`In their Replies, Petitioners attempt to deny this concern by arguing that
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`appreciable amounts of folate can only be released if there is a “methyl trap”—i.e.,
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`if folate is stuck in the form of 5-MTHF due to a vitamin B12 deficiency;
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`Petitioners argue that this circumstance is rare. Neptune Reply at 27; Sandoz
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`Reply at 19-20. Neptune even suggests that the POSA would have been motivated
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`to administer vitamin B12 only in “non-B12-deficient patients,” Neptune Reply at
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`27. These are startling positions, as these same Petitioners’ rationale for using
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`vitamin B12 pretreatment in the first place is that pemetrexed patients may have
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`such a deficiency. E.g., Neptune Reply at 26. Missing the point that it is their
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`burden to show an affirmative reason to use vitamin B12 pretreatment, Petitioners
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`then suggest that the concern for trapped 5-MTHF would not have given the POSA
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`reason to avoid administering vitamin B12 prior to pemetrexed chemotherapy.
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`Neptune Reply at 27; Sandoz Reply at 19.
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`Petitioners’ newly-minted arguments suffer from another fatal flaw. If
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`Petitioners were right that vitamin B12 pretreatment would not release folate from
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`the “methyl trap,” it follows that it also would have no benefit on toxicity. The
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`only way that vitamin B12 would have been thought to have any potential effect on
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`pemetrexed toxicity is through the action of MS and its role in the folate pathway.
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`If vitamin B12 does anything, the POSA would understand that it is through the
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`methionine synthase reaction that converts 5-MTHF to THF. Neptune Ex. 1078
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`¶¶ 27; Neptune Ex. 2134 at 11-14; Neptune Ex. 1077 ¶ 47; Sandoz Ex. 2136 at
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`375-76, 379; Sandoz Ex. 2137 at 91-92, 110-13. Thus, to the extent vitamin B12
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`counteracts pemetrexed’s toxicities to healthy cells, it is by releasing folate into the
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`useful form, THF. Ex. 2120 ¶¶ 37-39, 85-87; Ex. 2118 ¶¶ 31-34, 52-56.
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`Petitioners cannot (and do not) argue that vitamin B12 pretreatment would be
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`expected to serve any useful purpose without creating THF and thus making more
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`folate available to cancer cells as well as healthy ones. Accordingly, if Petitioners
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`were correct that providing vitamin B12 would not be understood to release more
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`reduced folate, it would not be expected to ameliorate pemetrexed toxicity.
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`II. The FDA’s Reaction to Vitamin Supplementation Shows that the POSA
`Would Have Believed Vitamin Pretreatment Would Harm Efficacy
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`As Lilly explained in its POR, the FDA expressed skepticism about the use
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`of vitamin pretreatment with pemetrexed, for example requesting Lilly’s “basis for
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`[its] determination that the addition of vitamins will not affect efficacy.” Ex. 2100
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`at ELAP00008719. Apparently worried about what Lilly’s dialogue with the FDA
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`shows, Petitioners each commissioned a new expert witness (Dr. Ross and Dr.
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`Feigal) to opine that FDA was not skeptical of the claimed folic acid and vitamin
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`B12 pretreatment regimen. Neptune Ex. 1080; Sandoz Ex. 1093. Petitioners’
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`attempts to dismiss the evidence of skepticism do not bear scrutiny.
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`Petitioners’ experts focus on the potential problems with altering a clinical
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`trial that has already begun. But that concern only affects, at most, the
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`communications between Lilly and the FDA after the priority date, during the
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`Phase III trial of pemetrexed in mesothelioma. Neither Dr. Ross nor Dr. Feigal
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`disputes—or even substantively discusses—that in 1998, before the trial started,
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`the FDA expressed concern that “providing vitamins[] might reduce the efficacy of
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`pemetrexed.” Sandoz Ex. 2132 at 112-13; see Neptune Ex. 1080 ¶ 35 (citing Ex.
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`2100 and noting that in 1998, “FDA noted the risk of decreasing pemetrexed’s
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`efficacy but left the decision to Lilly whether to incorporate folate supplementation
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`into the protocol”). That is contemporaneous, objective evidence supporting the
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`testimony of Lilly’s experts that the POSA would have expected vitamin
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`pretreatment to reduce pemetrexed’s efficacy, and refuting Petitioners’ contrary
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`testimony.
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`Petitioners have no answer to this point, so they focus instead on the Lilly-
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`FDA communications after the Phase III trial began in 1999. But even then, the
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`evidence demonstrates that the FDA was still concerned about efficacy.
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`Petitioners make much of how Lilly characterized the prior art; for example, they
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`highlight Lilly’s citation of the Worzalla and Hammond references in an attempt to
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`persuade the FDA that it might be “possible to decrease toxicity to healthy tissue
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`while maintaining antitumor effect,” e.g., Sandoz Reply at 9 (quoting Ex. 1084 at
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`ELAP0013767); see also Neptune Reply at 8-9. As will be discussed below,
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`whether Lilly found prior art support for its invention after the invention was made
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`is irrelevant. What is relevant is the fact that the FDA still needed persuading.
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`The FDA clearly believed that folic acid and vitamin B12 had the potential to
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`reduce pemetrexed’s efficacy. If it were so obvious that Lilly’s invention would
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`not decrease pemetrexed’s efficacy, there would have been no need to persuade the
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`FDA of that fact. Instead, as Petitioners themselves highlight, Lilly was forced to
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`argue in document after document in the face of FDA skepticism that it believed its
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`invention would work. Sandoz Exs. 1077, 1084; Ex. 2103, 2107. The FDA
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`evidence supports Lilly, not Petitioners.
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`Patent 7,772,209
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`III. Lilly’s Post-Priority Date Statements Are Irrelevant
`Petitioners raise several new arguments in reply about how Lilly
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`contemporaneously characterized the conclusions of the prior art references at
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`issue in this case; Petitioners argue that these characterizations should be believed
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`over the expert testimony about how the POSA would have understood those
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`references. Neptune Reply at 6-11; Sandoz Reply at 2-9. Indeed, Petitioners go so
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`far as to suggest that Lilly is somehow barred from contesting Petitioners’
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`interpretation of the references based on its characterizations of the art after the
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`priority date and with knowledge of the invention. E.g., Sandoz Reply at 2-3.
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`Petitioners’ arguments are without merit.
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`A. As a threshold matter, the Board should reject as a matter of law
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`Petitioners’ attempts to use post-priority date evidence to establish obviousness.
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`Neptune cites to scattered cases discussing rare circumstances in which evidence
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`from after a patent’s priority date can be treated as probative of what would have
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`been known to the POSA. Neptune Reply at 6. But the unusual fact patterns of
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`those cases are exceptions that prove the rule; it is a hornbook principle of
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`obviousness that it is “based on a review of the prior art.” KSR Int’l Co. v.
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`Teleflex, Inc., 127 S. Ct. 1727, 1739 (2007). Neptune’s cases are not to the
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`contrary. In Thomas & Betts Corp. v. Litton Sys., Inc., for example, the court—
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`considering the doctrine of equivalents rather than an obviousness defense—ruled
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`that non-prior-art internal documents could provide evidence that certain
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`information was known before the priority date. 720 F.2d 1572, 1580-81 (Fed. Cir.
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`1983). And in In re Wilson, the court approved the use of a non-prior-art
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`publication to establish a scientific fact about the properties of certain prior-art
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`foams; the date of the publication did not matter, because the scientific fact was not
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`one that changed with time. 311 F.2d 266, 268-269 (C.C.P.A. 1962).
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`These cases do nothing to support Neptune’s flagrant attempt to use post-
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`priority date documents—written by the patentee, no less—to suggest that the
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`invention would have been obvious. Neptune Reply at 6-11. Neptune, for
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`example, cites an article published in 2001 and co-authored by the inventor, Dr.
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`Niyikiza, which discusses some of the prior art at issue in this IPR and states that it
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`“supported” the idea of vitamin supplementation. Neptune Ex. 1047 at 371. But
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`whether Dr. Niyikiza—after having conceived of the invention—saw the prior art
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`as supportive is entirely irrelevant to whether the POSA would have done so. By
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`definition, inventors glean insights from the prior art that the POSA would not. It
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`is no answer to how the POSA would have understood the art to say that the
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`inventor himself drew particular insights from that art.
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`B.
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`Sandoz also contends that Lilly is not allowed to “rewrite Lilly’s own
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`prior art,” and suggest that Lilly is somehow bound to the conclusions of articles
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`published by its employees (which do not support Petitioners in any event). E.g.,
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`Sandoz Reply at 2-3.4 Putting aside that Lilly is not “rewriting” anything, this
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`contention, however, rests on a gross misreading of a single Federal Circuit case,
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`PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1361-63 (Fed. Cir.
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`2007). PharmaStem involved a patentee who sought to adduce expert testimony
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`that directly contradicted a characterization of prior art in the specification of the
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`patent itself. Id. There is no such issue here. Rather, Lilly’s experts have opined
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`about what the prior art references, taken as a whole, teach. Even Sandoz’s own
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`expert, Dr. Schiff, agreed that the “approach that the person of ordinary skill in the
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`art would take when reviewing the literature and references in this case,” is to
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`“review the entirety” of the reference and “come to a conclusion about what it
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`teaches as a whole.” Sandoz Ex. 2136 at 8-9. And there also is absolutely no basis
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`(and Petitioners cite no authority) for the proposition that prior art that was
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`published by someone affiliated with the assignee of a patent should be treated
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`differently from any other prior art in conducting the obviousness analysis.
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`C.
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`Finally, Petitioners attempt to argue that Lilly’s characterizations of
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`4 Neptune invokes Federal Rule of Evidence 801 (Neptune Reply at 7), but at most
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`this establishes that certain statements made by or on behalf of Lilly are
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`admissible, not that their authorship is relevant to the obviousness analysis.
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`the prior art, including Hammond and Worzalla, to the FDA should be treated as
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`probative of how the POSA would understand those reference because they are
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`“near contemporaneous” with the priority date. Sandoz Reply at 8-9; see Neptune
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`Reply at 8-9. Petitioners miss the point entirely. The characterizations to which
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`they point occurred after Lilly had come up with the invention, and after severe
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`toxicities had arisen in clinical trials that meant that continuing to administer
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`pemetrexed without vitamin supplementation was no longer a realistic or ethical
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`option. Exs. 2103, 2107, 2116 at 795-98; Sandoz Ex. 1085. In other words,
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`having conceived of the invention, Lilly was advocating it to a skeptical FDA. Its
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`efforts to justify the invention it had already made have no bearing whatsoever on
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`how the POSA, without hindsight knowledge of the invention, would have
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`interpreted those references. Kinetic Concepts, 688 F.3d at 1369. They certainly
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`do not suggest that the POSA would have identified the same statements and drawn
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`the same conclusions.
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`IV. Petitioners Apply a New and Incorrect Standard for Evaluating Dosage
`Claims
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`For the first time in Reply, Petitioners argue that the doses of folic acid and
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`vitamin B12 recited in many of the challenged claims are not “critical” and thus
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`cannot confer patentability. Sandoz Reply at 23; Neptune Reply at 31. Petitioners
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`err in their interpretation and application of the criticality doctrine.
`
`The question of whether a claim limitation is “critical” arises when the
`
`
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`13
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`

`Case IPR 2016-00318
`
`
`Patent 7,772,209
`
`
`difference between a claim and the prior art is that the claim is limited to a
`
`particular value or sub-range within a prior art range. Osram Sylvania v. Am.
`
`Induction Techs., 701 F.3d 698, 705-06 (Fed. Cir. 2012). It has no application here
`
`because folic acid dosages of 1000 µg or less—as recited in claims 9, 10, and 12-
`
`22—are found nowhere in the art in combination with pemetrexed or vitamin B12.
`
`There was only one example of folic acid pretreatment with pemetrexed in
`
`the literature: the Hammond study (reported in Hammond I, Neptune Ex. 1022,
`
`Sandoz Ex. 1015, and Hammond II, Neptune Ex. 2035, Sandoz Ex. 1014).
`
`Hammond used a folic acid dose of 5 mg and no vitamin B12. There were no
`
`examples of vitamin B12 pretreatment with pemetrexed, or indeed with any other
`
`folate analogue antifolate, in the prior art. These facts do not fit the criticality
`
`cases; Lilly is claiming a new combination, not a subrange of an existing range.
`
`On these facts, therefore, the question is therefore not whether the claimed dosages
`
`of folic acid are “critical,” but whether the claimed combination would have been
`
`obvious. The onus, moreover, is on Petitioners to show that the POSA would have
`
`put together all of the elements of the claims in the recited way. True, there were
`
`(non-cancer related) precedents for 1000 µg doses of vitamin B12, and the ’974
`
`patent encompasses doses of folic acid lower than Hammond’s. But the fact that
`
`Petitioners can cherry-pick dosage values from scattered prior art references does
`
`nothing to help Petitioners unless they can show that the POSA would have
`
`
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`14
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`

`Case IPR 2016-00318
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`
`Patent 7,772,209
`
`
`combined the doses in the recited way, i.e., selected a dose of folic acid much
`
`lower than those in Hammond (under 1 mg versus 5 mg), and combined it doses of
`
`vitamin B12 that are larger than those favored by the very reference, EP 005, that
`
`Petitioners chose to make the centerpiece of their case as to vitamin B12.
`
`Petitioners cannot do this. The only conceivable reason to lower the folic
`
`acid dose would be a concern for efficacy. Sandoz’s conclusory statement that
`
`Hammond used more pemetrexed than the claims (implicitly) contemplate is no
`
`answer; there is no reason why lower doses of folic acid would be “appropriate
`
`with correspondingly lower doses of pemetrexed” other than a concern that using
`
`too much folic acid would be deleterious. Sandoz Reply at 24. But a reason to
`
`minimize the dose of folic acid is equally a reason to avoid adding vitamin B12,
`
`which can have the effect of releasing more folate. Moreover, there is no evidence
`
`from which to conclude that a low (<1 mg) folic acid dose would even be effective
`
`at lowering pemetrexed toxicity. In short, the POSA would not have reason to
`
`combine the particular doses in the recited way.
`
`V. The Board Should Take Notice of the Federal Circuit’s Related Decision
`In its POR, Lilly cited a district court decision rejecting obviousness
`
`challenges to claims 9, 10, 12, 14, 15, 18, 19, and 21 of the ’209 patent. On
`
`January 12, 2017, the Federal Circuit affirmed the district court. See Eli Lilly &
`
`Co. v. Teva Parenteral Medicines, Inc., 845 F.3d 1357 (Fed. Cir. 2017).
`
`
`
`15
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`

`

`
`
`Dated: February 14, 2017
`
`
`
`
`
`
`
`
`
`
`Case IPR 2016-00318
`Patent 7,772,209
`Respectfully submitted,
`
`
`
`/David M. Krinsky/
`David M. Krinsky
`Reg. No. 72,339
`Williams & Connolly, LLP
`725 12th St., NW
`Washington, DC 20005
`Telephone: 202-434-5338
`Facsimile: 202-434-5029
`Email: dkrinsky@wc.com
`
`Back-up Counsel for
`Patent Owner
`
`
`
`16
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`
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`

`

`Case IPR 2016-00318
`Patent 7,772,209
`
`
`CERTIFICATE OF SERVICE
`(37 C.F.R. §§ 42.6(e))
`
`The undersigned hereby certifies that the document above was served on
`
`
`
`this 14th day of February, 2017, on the Petitioners by delivering a copy via
`
`electronic mail to the following individuals at the email addresses below:
`
`Laura Lydigsen
`Pro hac vice
`llydigsen@brinksgilson.com
`
`
`
`
`
`
`
`
`
`Deanne M. Mazzochi
`Reg. No. 50,158
`dmazzochi@rmmslegal.com
`
`
`
`
`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
`
`Counsel for Sandoz Inc.
`
`John D. Polivick
`Reg. No. 57,926
`jpolivick@rmmslegal.com
`
`
`

`

`William A. Rakoczy
`Pro hac vice to be filed
`wrakoczy@rmmslegal.com
`
`Rakoczy Molino Mazzochi Siwik LLP
`6 West Hubbard Street, Suite 500
`Chicago, IL
`P: 312-527-2157/F: 312-527-4205
`
`Attorneys for Apotex Inc. and Apotex
`Corp.
`
`Thomas J. Parker
`Reg. No. 42,062
`thomas.parker@alston.com
`
`Alston & Bird LLP
`90 Park Avenue, 15th Floor
`New York, NY 10016
`P: 212-210-9529/F: 212-210-9444
`
`Counsel for Mylan Laboratories
`Limited
`
`Gerard A. Haddad
`Reg. No. 41,811
`GHaddad@BlankRome.com
`
`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.
`
`Paul M. Zagar
`
`
`
`
`
`
`
`
`
`Case IPR 2016-00318
`Patent 7,772,209
`
`Patrick C. Kilgore
`Reg. No. 69,131
`pkilgore@rmmslegal.com
`
`
`
`
`
`
`
`
`
`
`
`
`2
`
`

`

`Reg. No. 52,392
`PZagar@BlankRome.com
`
`Blank Rome LLP
`The Chrysler Building
`405 Lexington Ave.
`New York, NY 10174
`P: 212-885-5290/F: 917-332-3063
`
`Counsel for Emcure Pharmaceuticals
`Ltd., Heritage Pharma Labs Inc., and
`Heritage Pharmaceuticals Inc.
`
`Patrick A. Doody
`Reg. No. 35,022
`patrick.doody@pillsburylaw.com
`
`Pillsbury Winthrop Shaw Pittman LLP
`1650 Tysons Boulevard
`McLean, VA 22102
`P: 703-770-7755/F: 703-770-7901
`
`Counsel for Wockhardt Bio AG
`
`Gary J. Speier
`Reg. No. 45,458
`gspeier@carlsoncaspers.com
`
`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
`
`Goodwin Procter LLP
`
`
`
`
`
`
`Case IPR 2016-00318
`Patent 7,772,209
`
`
`
`
`
`
`
`Bryan P. Collins
`Reg. No. 43,560
`bryan.collins@pillsburylaw.com
`
`
`
`Mark D. Schuman
`Reg. No. 31,197
`mschuman@carlsoncaspers.com
`
`
`
`
`
`
`3
`
`

`

`
`
`
`Case IPR 2016-00318
`Patent 7,772,209
`
`/David M. Krinsky/
`David M. Krinsky
`Attorney for Patent Owner
`Registration No. 72,339
`Back-up Counsel for
`Patent Owner
`
`
`
`
`The New York Times Building
`620 Eighth Avenue
`New York, NY 10018-1405
`P: 212-813-8800
`F: 212-355-3333
`
`Attorneys for Teva Pharmaceuticals
`USA, Inc. and Fresenius Kabi USA,
`LLC
`
`Date: February 14, 2017
`
`
`
`
`
`4
`
`

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