Case No. IPR2016-00237
`Patent 7,772,209
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`
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`NEPTUNE GENERICS, LLC,
`APOTEX INC., and APOTEX CORP.,
`Petitioner,
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`v.
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`ELI LILLY & COMPANY,
`Patent Owner.
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`
`
`Case No. IPR2016-002371
`Patent No. 7,772,209
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`PATENT OWNER’S RESPONSE
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`
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`1 Case IPR2016-01190 has been joined with the instant proceeding.
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`
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`Patent 7,772,209
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`NEPTUNE GENERICS, LLC,
`APOTEX INC., and APOTEX CORP.,
`Petitioner,
`
`v.
`
`ELI LILLY & COMPANY,
`Patent Owner.
`
`
`
`Case No. IPR2016-002371
`Patent No. 7,772,209
`
`
`
`
`
`PATENT OWNER’S RESPONSE
`
`
`
`1 Case IPR2016-01190 has been joined with the instant proceeding.
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`
`
`
`
`
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`Case No. IPR2016-00237
`Patent 7,772,209
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`TABLE OF CONTENTS
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`I.
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`Development of the Claimed Invention .............................................. 10
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`Background ...................................................................................................... 5
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`A. Antifolates and Folates .......................................................................... 5
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`B. Antifolates and Vitamin B12 .................................................................. 6
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`C. Homocysteine and MMA ...................................................................... 8
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`D. Antifolate Research ............................................................................... 9
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`E.
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`F.
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`The District Court Litigation ............................................................... 13
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`The Critical Date of the ’209 Patent .............................................................. 13
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`II.
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`III. The Person of Ordinary Skill in the Art ........................................................ 14
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`IV. Claim Construction ........................................................................................ 16
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`V. Neptune Has Failed to Demonstrate That the Challenged Claims Are
`Obvious .......................................................................................................... 16
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`A.
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`The POSA Would Have Avoided Folic Acid and Vitamin B12
`Pretreatment Because Doing So Would Have Been Expected to
`Lower Pemetrexed’s Efficacy ............................................................. 18
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`B. Neptune’s Own Central Argument Fails To Give the POSA
`Reason To Administer Vitamin B12 .................................................... 29
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`C.
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`The Correlation Between Pemetrexed Toxicity and
`Homocysteine Levels in Niyikiza I Would Not Have Given the
`POSA a Reason to Pretreat Patients With the Claimed Regimen ....... 33
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`1.
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`Elevated Homocysteine Levels Do Not Cause
`Pemetrexed Toxicity ................................................................. 33
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`The POSA Would Have No Reason To Treat Pemetrexed
`Patients’ Homocysteine Levels ................................................. 35
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`The POSA Would Not Risk Reducing Efficacy To Lower
`Homocysteine ............................................................................ 38
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`2.
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`3.
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`Petitioner’s Additional Arguments Would Not Give the POSA
`Reason To Administer the Claimed Pretreatment Regimen ............... 40
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`The POSA Would Not Use the Doses and Schedules Claimed
`in the ’209 Patent ................................................................................. 47
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`1.
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`Claims 9, 10, 12, 13-15, and 17-22 Would Not Have
`Been Obvious Because the POSA Would Not
`Simultaneously Lower the Folic Acid Dose in Hammond
`and Add Vitamin B12 to the Regimen ....................................... 47
`
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`D.
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`E.
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`2.
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`Neptune’s Other Dose and Schedule Arguments Are
`Without Merit ............................................................................ 50
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`VI. Secondary Considerations of Non-Obviousness Support Patentability ........ 54
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`Case No. IPR2016-00237
`Patent 7,772,209
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`TABLE OF AUTHORITIES
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`FEDERAL CASES
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`Eli Lilly & Co. v. Teva Parenteral Medicines, et al., Case No. 1:10-
`cv-1376-TWP-DKL (S.D. Indiana) .................................................................... 13
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`Eli Lilly & Co. v. Teva Parenteral Medicines, Inc., et al., No. 2015-
`2067 (Fed. Cir.) ................................................................................................... 13
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`Envtl. Designs, Ltd. v. Union Oil Co., 713 F.2d 693 (Fed. Cir. 1983) .................... 32
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`In re Applied Materials, Inc., 692 F.3d 1289 (Fed. Cir. 2012) ......................... 51, 52
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`In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003) ................................................ 52, 53
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`Kinetic Concepts, Inc. v. Smith & Nephew, Inc., 688 F.3d 1342 (Fed.
`Cir. 2012) ............................................................................................................ 17
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`KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007) .......................................... 16, 54
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`Leo Pharm. Prod., Ltd. v. Rea, 726 F.3d 1346 (Fed. Cir. 2013) ............................. 54
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`WBIP, LLC v. Kohler Co., —F.3d—, 2016 WL 3902668 (Fed. Cir.
`Jul. 19, 2016) ....................................................................................................... 55
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`Wellman, Inc. v. Eastman Chem. Co., 642 F.3d 1355 (Fed. Cir. 2011) .................. 16
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`OTHER AUTHORITIES
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`35 U.S.C. § 103(a) ................................................................................................... 16
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`Institution Decision. Paper 13 .............................................................................. 4, 16
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`IPR2016-00318. Paper 1 .......................................................................................... 16
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`Wall Street Journal .................................................................................................. 55
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`Neptune’s Petition for inter partes review sets forth a simple-sounding but
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`fundamentally flawed obviousness case. Neptune’s argument—based on Niyikiza
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`I, EP 005, and the ’974 patent—is that because homocysteine levels were known to
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`correlate with pemetrexed toxicity, the person of ordinary skill in the art (POSA)
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`would thus be motivated to lower those levels. And, because folic acid and
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`vitamin B12 were known to lower homocysteine levels, the POSA would thus be
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`motivated to use them to lower homocysteine. Nothing in any of the references
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`that are part of Neptune’s ground actually discloses administering vitamin B12
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`pretreatment to a cancer patient receiving an antifolate, and the literature taught
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`that vitamin B12 was not relevant to pemetrexed’s toxicity. Even setting that basic
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`flaw aside, however, Neptune ignores half the story. And the whole story
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`demonstrates that the claimed invention—a method of administering a life-saving
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`cancer drug that saved the drug from failure during its development—was anything
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`but obvious.
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`The half of the story that Neptune omits is about pemetrexed’s efficacy
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`against cancer. Pemetrexed was the most promising antifolate in decades. And as
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`an antifolate, it works by depriving cells of the folate they need to divide and grow.
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`The folic acid supplementation that Neptune posits would have been so obvious
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`would have been understood by the POSA to act as pemetrexed’s antidote. That is,
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`folates and antifolates compete with one another for access to the relevant
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`enzymes, and the more folate there is, the less of an effect the antifolate will have.
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`Folic acid would counter the effects of pemetrexed on cancer cells and healthy
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`cells alike. Thus, to the extent that pretreating patients with folic acid reduced the
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`toxicity of pemetrexed, that same pretreatment would have been expected also to
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`decrease the drug’s efficacy against cancer. Worse still, folic acid would have
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`been expected to feed the tumor and cause it to grow, precisely the opposite of the
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`goal of the chemotherapy.
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`Vitamin B12 pretreatment would have been seen as even more problematic.
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`Administering vitamin B12 would have been expected to make more folate
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`available to the body’s cells, and thus to harm efficacy and encourage cancer
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`growth. But it would have been expected to do so to a more unpredictable and
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`potentially greater degree than folic acid, because unlike simply administering folic
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`acid, a small amount of vitamin B12 can release a variable and often large quantity
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`of folate. Pretreating pemetrexed patients with folic acid and vitamin B12 is the last
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`thing that a POSA, who was treating a patient with a deadly disease, would have
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`wanted to do.
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`Moreover, not only is there no affirmative teaching in the prior art to use
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`vitamin B12 pretreatment with an antifolate cancer patient, but the art taught that
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`pemetrexed toxicities did not correlate with the well-known biomarker for vitamin
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`B12, methylmalonic acid or MMA. This would have taught the POSA that vitamin
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`B12 was not relevant to pemetrexed toxicity. Neptune ignores this prior art
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`teaching. Even if the POSA sought to reduce toxicities by lowering homocysteine
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`as Neptune alleges, the POSA would not have included vitamin B12 in a regimen
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`for lowering those toxicities—especially given the expected deleterious effects of
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`vitamin B12 both on antifolate cancer chemotherapy and on the cancer itself. That
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`is fatal to Neptune’s case, because Neptune points to no other reason why the
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`POSA would have administered vitamin B12, nor did any such reason exist—none
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`of the references Petitioner cites teaches pretreating a cancer patient that was
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`receiving antifolate cancer chemotherapy with vitamin B12. Indeed, there is no
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`evidence in the prior art that in over half a century of research into ways of safely
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`and effectively administering antifolates, anyone had ever done so or suggested
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`doing so. This speaks volumes about the non-obviousness of the claimed
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`invention.
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`Finally, even if the Board concludes (contrary to the evidence) that the ’209
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`patent’s broadest claims are invalid, Petitioner has failed to demonstrate the
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`obviousness of the claims requiring particular doses and schedules of folic acid and
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`vitamin B12. Many of the challenged claims require folic acid doses of 1000 µg or
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`less. The only prior art reference that describes folic acid pretreatment with
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`pemetrexed—which Neptune’s expert Dr. Bleyer sought in deposition to embrace
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`as a newfound centerpiece of his case—is Hammond I, which used 5000 µg doses
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`starting two days before pemetrexed. If Hammond I were as encouraging as
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`Petitioner contends, the POSA would have no reason to reduce the folic acid dose
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`or lengthen the time interval between folic acid and pemetrexed (as certain claims
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`require). And if the POSA did use a lower folic acid dose, the POSA would have
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`no reason to combine that lower dose with the “massive” dose of 1000 µg vitamin
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`B12 (or 500 µg to 1500 µg) that is recited in claims 3, 4, 12, 14, and 15, much less
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`to administer it intramuscularly (which Petitioner’s EP 005 reference teaches away
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`from doing).
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`For all of these reasons, the claimed invention is not, contrary to Neptune’s
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`arguments and the Institution Decision, a “combination of known treatments . . .
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`for their known purpose . . . to achieve a predictable result.” Paper 13 at 17. Not
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`only did it contradict the prevailing wisdom as of the critical date, but it involved
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`the counterintuitive administration of a drug after its own antidote (folic acid), a
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`totally unprecedented additional ingredient (vitamin B12) that would release an
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`unpredictable amount of antidote (folates), and specific dosages and schedules for
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`which Neptune articulates no persuasive reason.
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`The patentability of all challenged claims should be confirmed.
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`I.
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`Background
`A. Antifolates and Folates
`Folates, such as folic acid, are a class of compounds that the body needs to
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`make DNA. Ex. 2120 ¶ 34; Ex. 2118 ¶ 21. DNA is required in order for cells,
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`both normal and cancerous, to divide and grow. Ex. 2120 ¶ 34. Various enzymes
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`in the human body convert various forms of folate to other forms; this cycle or
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`pathway of folates being converted from one form to another is the folic acid
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`pathway. Ex. 2120 ¶ 34; Ex. 2118 ¶ 22. For example, one such enzyme in the
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`folic acid pathway is thymidylate synthase (“TS”), which creates thymidine, a
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`component of DNA. Ex. 2120 ¶ 35; Ex. 2118 ¶ 22.
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`Antifolates are compounds that inhibit one or more of the enzymes in the
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`folate pathway by binding to them in place of folate. Ex. 2120 ¶ 45; Ex. 2118
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`¶¶ 24-25. Pemetrexed inhibits three enzymes in the folate pathway. Its principal
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`effect is on TS; it also inhibits to some extent enzymes known as DHFR and
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`GARFT. Ex. 2120 ¶ 35, 46; Ex. 2118 ¶ 25. By interfering with the binding of
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`folates to these enzymes, antifolates like pemetrexed interfere with DNA synthesis
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`and thereby hamper cell division, ultimately killing cells that are dividing. Ex.
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`2120 ¶ 45; Ex. 2118 ¶¶ 25-26. It is this mechanism that allows antifolates to be
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`effective in treating cancer: cancer cells divide rapidly and have a high demand for
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`DNA precursors and are thus particularly susceptible to antifolates. Id.
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`Unfortunately, the same mechanism also causes antifolate toxicities in the human
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`body: other rapidly dividing cells, such as bone marrow and gastrointestinal tract
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`cells, are also killed by antifolates, causing severe side effects as neutropenia,
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`thrombocytopenia, and gastrointestinal toxicities. Ex. 2120 ¶ 49; Ex. 2118 ¶¶ 26-
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`28.
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`As of June 1999, it was well known that, because antifolates operate by
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`competing with folates to bind to specific enzymes, administering folates would
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`counteract the activity of antifolates. Ex. 2120 ¶¶ 62-65; Ex. 2118 ¶¶ 46, 57; Ex.
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`2040 at 6122. If there are more folates in the body, there are more folates to
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`compete with antifolates to bind to the relevant enzymes, and the effects of the
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`antifolates—both desirable and undesirable—are diminished. The POSA would
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`therefore have expected that administering an antifolate together with a folate, such
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`as folic acid, would have decreased the beneficial anti-proliferative effect of the
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`antifolate.
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`B. Antifolates and Vitamin B12
`Though not a folate, vitamin B12 can also interfere with an antifolate’s anti-
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`cancer efficacy by increasing folate levels. Ex. 2120 ¶¶ 37-39; Ex. 2118 ¶ 29. As
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`is relevant here, the folate cycle includes the conversion of an inactive form of
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`folate—which cannot be used by enzymes that make DNA precursors—into an
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`active form that can be used by these enzymes. Id. This conversion requires
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`vitamin B12. Id. Specifically, an enzyme called methionine synthase converts an
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`inactive form of folate, 5-methyltetrahydrofolate (“5-MTHF”) into an active form
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`of folate, tetrahydrofolate, and in the process converts the substance homocysteine
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`into another substance, methionine. Id.; Ex. 2118 ¶¶ 30-34. Vitamin B12 is
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`required for methionine synthase to be able to carry out these steps. Accordingly,
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`if a patient is deficient in vitamin B12, 5-MTHF and homocysteine will accumulate
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`in the cell, as the mechanism by which they would be converted to tetrahydrofolate
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`and methionine is impaired. Ex. 2118 ¶¶ 32, 35.
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`Scientists refer to the situation in which 5-MTHF builds up in a cell due to
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`insufficient vitamin B12 as a “methyl trap” because the folate is “trapped” in the
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`inactive 5-MTHF form. This results in a reduced amount of active folate available
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`to synthesize DNA even though the total amount of folate, including the 5-MTHF,
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`may not be low. Ex. 2120 ¶ 39; Ex. 2118 ¶¶ 30-34. Administering vitamin B12 can
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`make more folate available by converting the inactive 5-MTHF folate to active
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`folate. Ex. 2120 ¶¶ 52-56; Ex. 2118 ¶ 53. Even a small amount of vitamin B12 has
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`the potential to increase a patient’s folate level more than just administering a
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`folate, because administering vitamin B12 could convert a large pool of “trapped”
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`folate into its active form. Ex. 2120 ¶¶ 52-56; Ex. 2118 ¶ 53-56. In other words,
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`administering vitamin B12 to a patient with a vitamin B12 deficiency can have the
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`effect of increasing the available folate for various reactions in the folate pathway.
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`Ex. 2120 ¶ 123; Ex. 2118 ¶ 34. Thus, the POSA would have expected that
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`administering vitamin B12 was tantamount to administering an unpredictable and
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`potentially large amount of folate, and would have been expected to reduce an
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`antifolate’s anti-cancer properties. Ex. 2120 ¶¶ 33c, 39, 85-87, 102-03, 123, 206;
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`Ex. 2118 ¶¶ 52-56.
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`C. Homocysteine and MMA
`As explained above, homocysteine is another compound that relates to the
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`folate pathway. In a healthy human, homocysteine is constantly created and then
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`converted to methionine through, among other processes, the action of methionine
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`synthase. Ex. 2120 ¶¶ 37, 40; Ex. 2118 ¶¶ 30, 35, 42. Because this conversion
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`requires folate to proceed, if a patient has insufficient folate, methionine synthase
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`activity will be hindered, which will lead homocysteine levels to rise.
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`Accordingly, abnormally high homocysteine levels can indicate a folic acid
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`deficiency. Id. Similarly, a vitamin B12 deficiency can also cause homocysteine
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`levels to rise—as explained, vitamin B12 is necessary for homocysteine to be
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`converted into methionine; if it is lacking, homocysteine levels will rise. Id. Thus,
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`absent additional information, abnormally high homocysteine levels could indicate,
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`among other things, a folic acid deficiency, a vitamin B12 deficiency, or both.
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`Vitamin B12 deficiencies are also evidenced by elevated levels of
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`methylmalonic acid, or MMA. Ex. 2120 ¶ 40; Ex. 2118 ¶ 43. Folic acid
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`deficiencies do not lead to elevated MMA levels. Id. Thus, knowing both a
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`patient’s homocysteine level and MMA level can allow a physician to distinguish
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`between a folate deficiency and a vitamin B12 deficiency. For instance, if a patient
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`had elevated homocysteine levels but did not have elevated MMA levels, this
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`would indicate that they have a folate deficiency but not a vitamin B12 deficiency.
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`Id.
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`D. Antifolate Research
`The story of antifolate cancer chemotherapy research is largely one of
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`failures. The first antifolates—aminopterin and methotrexate—were invented in
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`the late 1940s/early 1950s. Ex. 2120 ¶ 50. However, as of June 1999, no
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`antifolate had been approved in the United States for the treatment of cancer since
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`the approval of methotrexate, notwithstanding many others being tested. Id.
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`Virtually none of the antifolates tested during the five decades before the critical
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`date, including at least seven antifolates in clinical trials in 1999, were
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`administered to cancer patients with folic acid pretreatment (and none with vitamin
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`B12). Ex. 2120 ¶ 69 & n.9. See generally Exs. 2050, 2051.
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`In the 1990s, Lilly attempted folic acid pretreatment with two antifolates it
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`was developing, lometrexol and LY309887, but these efforts were unsuccessful.
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`Ex. 2120 ¶ 68. For example, Lilly attempted to administer folic acid with
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`lometrexol to combat lometrexol’s severe toxicities after a disastrous initial clinical
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`trial; however, a phase I clinical trial of this regimen, published by Laohavinij in
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`1996, showed that the regimen led to only one response—far fewer than had been
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`observed in trials of lometrexol unsupplemented by folic acid. Ex. 2031 at 333.
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`Clearly, folic acid had compromised lometrexol’s efficacy.
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`E. Development of the Claimed Invention
`During the 1990s, Lilly was also developing pemetrexed. As of April 1999,
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`phase II studies of pemetrexed had shown anticancer responses in six different
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`tumor types, and pemetrexed’s anti-tumor activity was considered “remarkable and
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`unusual.” Ex. 2120 ¶¶ 51-52; Ex. 2034 at 107; Ex. 2029 at 103–04; Ex. 1011 at
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`1194; Ex. 1013 at Table 3; Ex. 2022. This promising efficacy in killing cancer was
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`accompanied by toxicities that were considered tolerable, and manageable through
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`the typical means of combating antifolate toxicities—that is, adjustments to the
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`dose and schedule of pemetrexed administration. Ex. 2120 ¶¶ 33a, 53-61, 144-147.
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`In the second half of the 1990s, Dr. Niyikiza undertook a study to try to
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`determine which patients were more likely to develop toxicities from pemetrexed.
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`To do so, he statistically analyzed more than sixty variables describing patients
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`participating in pemetrexed clinical trials. Dr. Niyikiza published the results from
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`this analysis in two abstracts in 1998. Ex. 1008 (Niyikiza I) at 609P, Ex. 2015
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`(Niyikiza II) at 2139. The abstracts explained that there was a correlation between
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`pemetrexed toxicity and the level of homocysteine in the patients’ blood prior to
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`pemetrexed treatment. Id. Critically, however, he found no such correlation
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`between pemetrexed toxicity and MMA levels. Ex. 2015; see Ex. 2120 ¶ 33d, 106;
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`Ex. 2118 ¶ 70. This suggested no correlation between pemetrexed toxicity and a
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`patient’s levels of vitamin B12. Ex. 2120 ¶ 33d, 106; Ex. 2118 ¶ 70.
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`Upon reviewing his unpublished data, however, Dr. Niyikiza believed that
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`he had discerned that vitamin B12 status might in fact play a role, although he did
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`not yet have sufficient data to show this. Ex. 2116 at 733-34, 742-48. He
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`suggested within Lilly that pretreating patients with low doses of folic acid and
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`vitamin B12 could help to reduce pemetrexed’s toxicities. Id. The proposal was
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`rejected, however, given concerns that supplementation with folic acid and vitamin
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`B12 would interfere with pemetrexed’s efficacy. Indeed, when Lilly proposed the
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`vitamin pretreatment regimen to the FDA in 1998, the agency expressed concern
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`that pretreating pemetrexed patients with vitamins would reduce pemetrexed’s
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`ability to kill cancer. Ex. 2116 at 787-88.
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`In late 1999, after the critical date for the ’209 patent, the calculus changed.
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`Until that point, pemetrexed’s toxicities appeared manageable and tolerable. But
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`then, in an ongoing phase III pemetrexed trial, an alarming 7% of patients died,
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`apparently due to severe pemetrexed toxicities. Ex. 2103 at 2. This threatened to
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`halt development of pemetrexed altogether. Ex. 2107 at 16.
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`The high rate of deaths during the pemetrexed phase III trial, and further
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`analysis by Dr. Niyikiza, convinced Lilly to administer low levels of folic acid and
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`vitamin B12 to patients prior to pemetrexed, which was considered to be a risk
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`worth taking under the circumstances. Ex. 2107 at 17; Ex. 2116 at 798-99.
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`Even then, the FDA was skeptical of folic acid and vitamin B12 pretreatment
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`because they feared a reduction of pemetrexed’s efficacy. Ex. 2116 at 821-22. In
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`response to Lilly’s supplementation proposal, the FDA wrote Lilly that “[t]he
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`Medical Officer does not support adding vitamins to your ongoing pivotal,
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`randomized trial in mesothelioma.” Ex. 2104 at 1; see also Ex. 2106. In March
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`2000, representatives from Lilly, including Dr. Niyikiza, met with FDA
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`representatives to discuss Dr. Niyikiza’s supplementation proposal. Ex. 2108 at 2.
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`The FDA continued to be skeptical, writing that “[t]he addition of vitamins to the
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`pivotal trial(s) is at Lilly’s risk.” Id. at 2, 5. The FDA emphasized its concern over
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`the proposal’s risk of reducing pemetrexed’s efficacy, asking Lilly “[w]hat is the
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`evidence that folate/ B12 repletion will not stimulate tumor growth prior to the
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`administration of chemotherapy?” Id. at 5.
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`Despite the FDA’s skepticism, Lilly implemented Dr. Niyikiza’s vitamin-
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`supplementation proposal in the ongoing trial, and it was a resounding success.
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`Ex. 2116 at 824; Ex. 2110 (Niyikiza 2002) at 551. Pretreatment with folic acid and
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`vitamin B12 “result[ed] in significant reduction of toxicity associated with
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`pemetrexed therapy, while maintaining, or possibly improving, efficacy.” Ex.
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`2110 at 551.
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`The District Court Litigation
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`F.
`In Eli Lilly & Co. v. Teva Parenteral Medicines, et al., Case No. 1:10-cv-
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`1376-TWP-DKL (S.D. Indiana), defendants raised invalidity arguments that are
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`nearly identical to the ones Neptune raises here. Ex. 2004. In March 2014, the
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`District Court rejected these arguments and upheld the validity of the asserted ’209
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`patent claims.2 Ex. 1028. Having heard live testimony over the course of a nine-
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`day bench trial, District Court specifically found credible the opinions of the
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`experts whose testimony Lilly presents again here, Dr. Chabner and Dr. Zeisel. Id.
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`at 14.
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`The District Court’s decision is currently on appeal to the Federal Circuit,
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`which held oral argument on September 7, 2016. Eli Lilly & Co. v. Teva
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`Parenteral Medicines, Inc., et al., No. 2015-2067 (Fed. Cir.).
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`II. The Critical Date of the ’209 Patent
`The relevant date for analyzing Neptune’s obviousness arguments is June
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`29, 1999, which is more than one year before the earliest U.S. filing date to which
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`2 Similarly, the JPO and EPO have rejected validity challenges to foreign
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`counterparts of the ’209 patent.
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`13
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`Case No. IPR2016-00237
`Patent 7,772,209
`the ’209 patent claims priority. Ex. 1001. Dr. Niyikiza conceived of the invention
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`and presented his idea of folic acid and vitamin B12 pretreatment at meetings in
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`1997 and 1998 with Lilly employees and outside consultants employed by Lilly.
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`Ex. 2111; Ex. 2112 at 7; Ex. 2113 at 10. Lilly further presented Dr. Niyikiza's
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`vitamin-supplementation idea to the FDA in 1998 and 1999. Ex. 2100 at 8044,
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`8046; Ex, 2103; Ex. 2105. Consistent with these facts, both sides’ experts apply a
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`date of June 1999 as the critical date for analyzing obviousness. See Ex. 1025 ¶ 3;
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`Ex. 2120 ¶ 22; see also Ex. 1028 (District Court applying same date).
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`III. The Person of Ordinary Skill in the Art
`Lilly is submitting a declaration from Dr. Bruce Chabner, one of the world’s
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`leading medical oncologists who has over 40 years’ experience working with
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`antifolates, both in the clinic and in the laboratory. Ex. 2120 ¶¶ 7-20. As Dr.
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`Chabner explains, the POSA to whom the ’209 patent is directed would be a
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`“medical doctor who specializes in oncology, specifically medical oncology,” and
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`“would have knowledge and experience concerning the use of chemotherapy
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`agents, including antifolates, in the treatment of cancer, as well as knowledge and
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`experience regarding the management of toxicities associated with such
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`treatment.” Id. ¶ 23. Dr. Chabner added that the POSA would have an
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`“understanding of how nutritional issues relate to the use of chemotherapy agents,”
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`as well as “an understanding of the interrelationships between antifolates, the folic
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`14
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`Case No. IPR2016-00237
`Patent 7,772,209
`acid pathway, and pathways related to vitamin B12.” Id. ¶ 25. Dr. Chabner’s
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`declaration addresses the issues in this proceeding from that perspective.
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`Lilly is also submitting a declaration from Dr. Steve Zeisel. Although not an
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`oncologist, Dr. Zeisel’s background has involved research on both nutritional
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`issues and cancer, as well as one-carbon metabolism (which relates to both the
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`folic acid pathway and pathways involving vitamin B12). Ex. 2118 ¶¶ 4-10. He
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`will therefore address the aspect of the POSA’s knowledge that involves how
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`nutritional issues relates to the use of chemotherapy agents, as well as the
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`interrelationships between antifolates, the folic acid pathway, and pathways related
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`to vitamin B12. Ex. 2118 ¶ 18.
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`Dr. Bleyer’s definition of the POSA includes a medical oncologist. Ex.
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`1025 ¶¶ 20-21. However, at his deposition, Dr. Bleyer indicated that he would
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`defer to a nutritionist on whether to pretreat a cancer patient with vitamins. Ex.
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`2027 at 117-21, 270-72, 289-90. Both Dr. Chabner and Dr. Zeisel disagree with
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`such a broad definition of the POSA. Ex. 2120 ¶ 24; Ex. 2118 ¶ 17. Pemetrexed is
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`cancer chemotherapy, and decisions concerning the administration of such
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`chemotherapy and management of any toxicities are made by the medical
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`oncologist. Id. Nevertheless, even if Dr. Bleyer’s definition were used, it should
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`not change Dr. Chabner’s opinions, as the definition still includes a medical
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`oncologist. Ex. 2120 ¶ 26.
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`15
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`Case No. IPR2016-00237
`Patent 7,772,209
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`IV. Claim Construction
`Neptune and Lilly agree that the term “patient” means “a human undergoing
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`medical treatment,” which is a contested term in the co-pending Sandoz v. Lilly
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`proceeding, IPR2016-00318. Paper 1 at 13.
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`None of the remaining claim terms cited by Neptune requires construction,
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`as the Board correctly observed in its Institution Decision. Paper 13 at 10;
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`Wellman, Inc. v. Eastman Chem. Co., 642 F.3d 1355, 1361 (Fed. Cir. 2011)
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`(“[C]laim terms need only be construed to the extent necessary to resolve the
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`controversy.”). “Antifolate” and “antifolate drug” likewise should not be
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`construed, as they are not claim terms. See Paper 1 at 14 (requesting
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`constructions).
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`V. Neptune Has Failed to Demonstrate That the Challenged Claims Are
`Obvious
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`To establish obviousness, Neptune must show that “the difference between
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`the subject matter [of the claims] and the prior art are such that the subject matter
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`as a whole would have been obvious at the time the invention was made to a
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`person having ordinary skill in the art to which said subject matter pertains.” 35
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`U.S.C. § 103(a). For a claim to be obvious, the POSA would have needed a reason
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`to combine all of the elements of the claim in the particular way the claims recite.
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`KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418-419 (2007). Where, as here,
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`“hindsight provides the only discernable reason to combine the prior art
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`
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`16
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`Patent 7,772,209
`references” so as to arrive at the claimed invention, the invention is nonobvious.
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`Kinetic Concepts, Inc. v. Smith & Nephew, Inc., 688 F.3d 1342, 1369 (Fed. Cir.
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`2012).
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`The Petition falls far short of proving obviousness. The instituted ground
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`does not include any prior art teaching to administer folic acid or vitamin B12
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`pretreatment to a patient receiving antifolate chemotherapy. Neptune’s
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`obviousness case hinges instead on the premise that because homocysteine
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`correlates with pemetrexed toxicity, the POSA would be motivated to take a
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`homocysteine-lowering regimen from the EP 005 reference, outside the oncology
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`field, and administer it to patients receiving pemetrexed. Even if the EP 005
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`regimen literally met the particular limitations of the challenged claims—it does
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`not—that would not have been an obvious thing to do. Neptune completely
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`ignores the fact that the EP 005 regimen—unlike other ways of lowering
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`homocysteine that were known in the art—would have been expected to reduce
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`pemetrexed’s efficacy and encourage the patient’s cancer to grow. It also ignores
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`the prior art teaching that vitamin B12 was not correlated with pemetrexed-induced
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`toxicity, meaning that the POSA would not have had any reason to administer
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`vitamin B12 even as part of a homocysteine-lowering regimen. Thus, not only does
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`Neptune fail to explain why the POSA would have accepted the tradeoff of
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`administering a regimen that would have been expected to exacerbate the patient’s
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`17
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`Case No. IPR2016-00237
`Patent 7,772,209
`disease, it fails on its own terms—the POSA would not have had reason to practice
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`the claimed invention even if the goal were to lower homocysteine, as Neptune
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`contends. Ex. 2120 ¶¶ 95, 169; Ex. 2118 ¶¶ 45-47.
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`A. The POSA Would Have Avoided Folic Acid and Vitamin B12
`Pretreatment Because Doing So Would Have Been Expected to
`Lower Pemetrexed’s Efficacy
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`The initial flaw in Neptune’s obviousness case is their myopic focus on
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`lowering toxicity. As Neptune’s expert Dr. Bleyer acknowledged in deposition,
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`the POSA would not simply have attempted to lower toxicity at all costs, but
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`would have balanced the “benefit of red
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