Case No. IPR2016-00318
`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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`SANDOZ INC.,
`Petitioner,
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`v.
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`ELI LILLY AND COMPANY,
`Patent Owner.
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`Case No. IPR2016-00318
`Patent No. 7,772,209
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`PATENT OWNER’S RESPONSE
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`Case No. IPR2016-00318
`Patent 7,772,209
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`TABLE OF CONTENTS
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`I. 
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`Antifolates and Vitamin B12 .............................................................................6 
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`Homocysteine and MMA ..................................................................................7 
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`Development of the Claimed Invention ........................................................9 
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`Background ...................................................................................................... 4 
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`A.  Antifolates and Folates ......................................................................................4 
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`B. 
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`C. 
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`D.  Antifolate Research ............................................................................................8 
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`E. 
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`F. 
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`The District Court Litigation ..........................................................................12 
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`II. 
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`III.  The Person of Ordinary Skill in the Art ........................................................ 13 
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`IV.  Claim Construction – “Patient” ..................................................................... 14 
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`V. 
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`Critical Date of the ’209 Patent ..................................................................... 13 
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`Sandoz Has Failed to Demonstrate That the Challenged Claims Are
`Obvious .......................................................................................................... 17 
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`A. 
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`The POSA Would Not Have Had Reason To Use Folic Acid
`Pretreatment with Pemetrexed .......................................................................18 
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`1. 
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`2. 
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`3. 
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`The POSA Would Have Avoided Folic Acid
`Pretreatment Because It Would Have Lowered
`Pemetrexed’s Efficacy .............................................................. 19 
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`The POSA Would Have Considered Pemetrexed’s
`Toxicities to be Tolerable and Manageable .............................. 21 
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`The Hammond Abstracts, Worzalla, and the ’974 Patent
`Would Not Have Given the POSA a Reason To Pretreat
`with Folic Acid .......................................................................... 23 
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`B. 
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`C. 
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`Case No. IPR2016-00318
`Patent 7,772,209
`The POSA Would Not Had Reason To Pretreat Pemetrexed
`Patients with Vitamin B12................................................................................34 
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`1. 
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`The POSA Would Have Expected that Vitamin B12
`Pretreatment Would Decrease Pemetrexed’s Efficacy ............. 35 
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`Niyikiza I and Calvert I Do Not Support Adding Vitamin
`B12 to the Worzalla and Hammond Regimes ............................ 37 
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`The POSA Would Not Have Used Folic Acid and
`Vitamin B12 Pretreatment Based on EP 005 ............................. 42 
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`The POSA would not have been concerned about a
`“masked” vitamin B12 deficiency in cancer patients ................ 44 
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`Sandoz’s Additional References Do Not Teach Vitamin
`B12 Pretreatment ........................................................................ 46 
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`The POSA Would Not Use the Doses and Schedules Claimed
`in the ’209 Patent ..............................................................................................49 
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`1. 
`
`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 ....................................... 50 
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`2. 
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`3. 
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`4. 
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`5. 
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`2. 
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`The Additional Dosing and Scheduling Limitations
`Would Not Have Been Obvious ............................................... 51 
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`VI.  Secondary Considerations of Non-Obviousness Support Patentability ........ 57 
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`Case No. IPR2016-00318
`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) .................................................................... 12
`
`Eli Lilly & Co. v. Teva Parenteral Medicines, Inc., et al., No. 2015-
`2067 (Fed. Cir.) ................................................................................................... 13
`
`In re Applied Materials, Inc., 692 F.3d 1289 (Fed. Cir. 2012) ............................... 56
`
`Kinetic Concepts, Inc. v. Smith & Nephew, Inc., 688 F.3d 1342 (Fed.
`Cir. 2012) ...................................................................................................... 18, 41
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`KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007) .......................................... 18, 56
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`Leo Pharm. Prod., Ltd. v. Rea, 726 F.3d 1346 (Fed. Cir. 2013) ............................. 57
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`Medichem S.A. v. Rolabo, 437 F.3d 1157 (Fed. Cir. 2006) ..................................... 27
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`Phillips v. AWH Corp., 415 F.3d 1303 (Fed Cir. 2005) (en banc) .......................... 15
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`Princeton Biochemicals, Inc. v. Beckman Coulter, Inc., 411 F.3d 1332
`(Fed. Cir. 2005) ................................................................................................... 27
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`Spectralytics, Inc. v. Cordis Corp., 649 F.3d 1336 (Fed. Cir. 2011) ....................... 29
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`Syntex (U.S.A.) LLC v. Apotex, Inc., 407 F.3d 1371 (Fed. Cir. 2005) ..................... 27
`
`Thorner v. Sony Computer Entm’t Am. LLC, 669 F.3d 1362 (Fed. Cir.
`2012) ................................................................................................................... 16
`
`WBIP, LLC v. Kohler Co., —F.3d—, 2016 WL 3902668 (Fed. Cir.
`Jul. 19, 2016) ....................................................................................................... 57
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`OTHER AUTHORITIES
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`37 C.F.R. § 42.100(b) .............................................................................................. 14
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`35 U.S.C. § 103(a) ................................................................................................... 17
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`IPR2016-00237, Paper 1 .......................................................................................... 15
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`Case No. IPR2016-00318
`Patent 7,772,209
`IPR2016-00240, Paper 1 .......................................................................................... 15
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`U.S. Patent No. 7,772,209 .................................................................................passim
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`Wall Street Journal ............................................................................................... 1.58
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`Lilly’s U.S. Patent No. 7,772,209 (the ’209 patent) covers methods of
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`Case No. IPR2016-00318
`Patent 7,772,209
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`administering pemetrexed by pretreating patients with folic acid and vitamin B12,
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`which reduces the toxicities associated with pemetrexed without compromising its
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`anti-cancer efficacy. Contrary to Sandoz’s Petition, that regimen would have been
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`anything but obvious. In fact, within both Lilly and the FDA, the reaction to the
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`proposed regimen was overwhelming skepticism. Pemetrexed had shown
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`remarkable efficacy against cancer cells and “manageable and tolerable” toxicity
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`against healthy cells, and it was believed that the claimed regimen would
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`undermine the efficacy of this very promising drug. In fact, Dr. Bruce Chabner,
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`then the clinical director of the Massachusetts General Hospital Cancer Center—
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`and who is testifying as an expert in this case—told the Wall Street Journal that
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`when he heard what Lilly was doing, he “thought it was crazy.” Ex. 2091 at 3. It
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`was only after the critical date of June 1999—and after patients started dying
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`unexpectedly in a Phase III pemetrexed clinical trial—that Lilly and the FDA were
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`persuaded to use the inventive vitamin pretreatment regimen with pemetrexed,
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`which saved the drug from oblivion.
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`Sandoz’s Petition does not come close to demonstrating that the claimed
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`regimen would have been obvious.
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`As to the vitamin B12 component of the claimed regimen, vitamin B12
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`pretreatment of an antifolate cancer patient is nowhere to be found in any of the
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`Patent 7,772,209
`references Sandoz cites. In fact, it was totally unprecedented as part of an
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`antifolate chemotherapy regimen. Unable to point to a relevant prior art teaching
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`to pretreat antifolate cancer patients with vitamin B12, Sandoz focuses instead on
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`evidence that certain levels of homocysteine (still within the normal range)
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`correlated with pemetrexed toxicities. While homocysteine, in the absence of other
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`evidence, can be a marker for both folic acid and vitamin B12, Sandoz conveniently
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`ignores that the same analysis on which it relies expressly taught that there was not
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`an association between vitamin B12 and toxicity. The POSA therefore would have
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`had no reason to pretreat patients with vitamin B12. And not only was there no
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`reason to administer vitamin B12, but it would have been understood to be
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`deleterious. Sandoz’s own references demonstrate that vitamin B12 could
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`encourage cancer to grow, and its use in cancer patients was contraindicated by a
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`leading European medical reference.
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`As to folic acid pretreatment, it had been tried, in two references that Sandoz
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`puts at the center of its case: Hammond I (in a Phase I clinical trial) and Worzalla
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`(in laboratory mice). But the POSA would not have used these references as a
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`starting point, as they confirmed what the POSA would already have expected
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`from the relevant biochemistry and from the antifolate literature: folic acid, a
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`folate, would act as pemetrexed’s antidote. That is, folic acid pretreatment would
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`reduce pemetrexed’s effects on cancer cells and healthy cells alike. To the extent
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`Patent 7,772,209
`that pretreating patients with folic acid reduced the toxicity of pemetrexed, it also
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`would decrease the drug’s efficacy against cancer, and, worse still, it would have
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`been expected to cause the patient’s tumor to grow. Modifying the Hammond or
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`Worzalla regimens to add vitamin B12 would only have made matters worse, by
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`increasing the available folate to an unpredictable—and potentially large—degree.
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`That is the last thing that the POSA, who was treating a patient with a deadly
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`disease, would have wanted to do.
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`Finally, even if the Board concludes (contrary to the evidence) that the
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`broadest claims are invalid, Sandoz has failed to demonstrate the obviousness of
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`the claims requiring particular doses and schedules of folic acid and vitamin B12.
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`Many of the challenged claims require folic acid doses of 1000 µg or less.
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`Hammond I, the foundation of Sandoz’s case and the only prior art reference that
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`describes folic acid pretreatment with pemetrexed in a cancer patient, used 5000 µg
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`doses starting two days before pemetrexed. If Hammond I were as encouraging as
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`Sandoz contends, the POSA would have no reason to reduce the folic acid dose or
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`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 that is recited in claims 4 and 15, much less to administer it intramuscularly
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`(which Sandoz’s EP 005 reference teaches away from doing).
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`Case No. IPR2016-00318
`Patent 7,772,209
`For all of these reasons, the claimed invention is not, contrary to Sandoz’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 14 at 18-19.
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`Not only did it contradict the prevailing wisdom as of the critical date, but it
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`involved the counterintuitive administration of a drug after its own antidote (folic
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`acid), a totally unprecedented additional ingredient (vitamin B12) that would
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`release an unpredictable amount of antidote (folates), and specific dosages and
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`schedules for which Sandoz 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 for cells, both
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`normal and cancerous, to divide and grow. Ex. 2120 ¶ 34. Various enzymes in the
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`human body convert various forms of folate to other forms; this cycle of folates
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`being converted from one form to another is the folic acid pathway. Ex. 2120 ¶ 34;
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`Ex. 2118 ¶ 22. For example, one such enzyme in the folic acid pathway is
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`thymidylate synthase (“TS”), which creates thymidine, a component of DNA. Ex.
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`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 such enzymes. Its principal effect is on TS; it
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`also inhibits to some extent enzymes known as DHFR and GARFT. Ex. 2120 ¶¶
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`35, 46; Ex. 2118 ¶ 25. By interfering with the binding of folates to these enzymes,
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`antifolates like pemetrexed interfere with DNA synthesis and thereby hamper cell
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`division, ultimately killing cells that are dividing. Ex. 2120 ¶ 45; Ex. 2118 ¶¶ 25-
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`26. It is this mechanism that allows antifolates to be effective in treating cancer:
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`cancer cells divide rapidly and have a high demand for DNA precursors and are
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`thus particularly susceptible to antifolates. Id. Unfortunately, the same
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`mechanism also causes antifolate toxicities in the human body: other rapidly
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`dividing cells, such as bone marrow and gastrointestinal tract cells, are also killed
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`by antifolates, causing severe side effects as neutropenia, thrombocytopenia, and
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`gastrointestinal toxicities. Ex. 2120 ¶ 49; Ex.2118 ¶¶ 26-28.
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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. The more folates in the body, the more folates there are to compete
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`with antifolates to bind to the relevant enzymes, and the effects of the antifolates—
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`both desirable and undesirable—are diminished. The POSA would therefore have
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`Patent 7,772,209
`expected that administering an antifolate together with a folate, such as folic acid,
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`would have decreased the beneficial anti-proliferative effect of the 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. The
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`folate cycle includes the conversion of a form of folate which cannot be used by
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`enzymes that make DNA precursors into an active form that can be used by these
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`enzymes. Id. This conversion requires vitamin B12. Id. Specifically, an enzyme
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`called methionine synthase converts an inactive form of folate, 5-
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`methyltetrahydrofolate (“5-MTHF”) into an active form of folate, tetrahydrofolate,
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`and in the process converts the substance homocysteine into another substance,
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`methionine. Id.; Ex. 2118 ¶¶ 30-34. Vitamin B12 is required for methionine
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`synthase to be able to carry out these steps. Accordingly, if a patient is deficient in
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`vitamin B12, 5-MTHF and homocysteine will accumulate in the cell, as the
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`mechanism by which they would be converted to tetrahydrofolate and methionine
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`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 5-MTHF,
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`Patent 7,772,209
`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 administering a folate,
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`because administering vitamin B12 could convert a large pool of “trapped” folate
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`into its active form. Ex. 2120 ¶¶ 52-56; Ex. 2118 ¶ 53-56. In other words, as
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`Sandoz’s expert admitted, administering vitamin B12 to a patient with a vitamin B12
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`deficiency can have the effect of increasing the available folate for various
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`reactions in the folate pathway. Ex. 2026 at 85-87. Thus, the POSA would have
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`expected that administering vitamin B12 was tantamount to administering an
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`unpredictable and potentially large amount of folate, and would have been
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`expected to reduce an antifolate’s anti-cancer properties. Ex. 2120 ¶¶ 33c, 39, 85-
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`87, 102-03, 123, 206; 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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`Patent 7,772,209
`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 another
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`substance, methylmalonic acid, or MMA. Ex. 2120 ¶ 40; Ex. 2118 ¶ 43. Folic
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`acid 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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`indicates that they have a folate deficiency but not a vitamin B12 deficiency. 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. As of June 1999, no other antifolate
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`had been approved in the United States for the treatment of cancer since
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`methotrexate, notwithstanding many others being tested. Id. As Dr. Schiff
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`admitted, the toxicities of antifolates led to the abandonment of some antifolates
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`Case No. IPR2016-00318
`Patent 7,772,209
`and complicated the development of others, such as lometrexol and raltitrexed. Ex.
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`2026 at 59. Despite this longstanding toxicity problem, virtually none of the
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`antifolates tested during the five decades before the critical date, including at least
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`seven antifolates in clinical trials in 1999, were administered to cancer patients
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`with folic acid pretreatment (and none with vitamin B12). Ex. 2120 ¶ 69 & n.9; see
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`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. A phase I clinical trial of this regimen, however, published by Laohavinij in
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`1996, showed that it led to only one response—far fewer than had been observed in
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`trials of lometrexol unsupplemented by folic acid. Ex. 2031 at 333. Clearly, folic
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`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 anti-cancer 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. 1045 at 107; Ex. 2029 at 103-04; Ex. 1052 at
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`1194; Ex. 1047 at Table 3; Ex. 2022. This promising efficacy in killing cancer was
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`Case No. IPR2016-00318
`Patent 7,772,209
`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. See infra § IV.A.2.
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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. 1006 (Niyikiza I) at 609P; Ex. 1016
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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. 1016; see Ex. 2120 ¶¶ 33d,
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`106; Ex. 2118 ¶ 70. This suggested no correlation between pemetrexed toxicity and
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`a 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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`vitamin B12 status might in fact play a role, although he did not yet have sufficient
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`data to show this. Ex. 2116 at 733-734, 742-748. He suggested within Lilly that
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`pretreating patients with low doses of folic acid and vitamin B12 could help to
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`reduce pemetrexed’s toxicities. Id. The proposal was rejected, however, given
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`concerns that supplementation with folic acid and vitamin B12 would interfere with
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`pemetrexed’s efficacy. Indeed, when Lilly proposed vitamin pretreatment to the
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`FDA in 1998, the agency expressed concern that pretreating pemetrexed patients
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`with vitamins would reduce pemetrexed’s ability to kill cancer, after which Lilly
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`dropped the idea. 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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`Given the high rate of deaths, and further analysis by Dr. Niyikiza, Lilly
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`decided to administer low levels of folic acid and vitamin B12 to patients prior to
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`pemetrexed, which was considered a risk worth taking under the circumstances.
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`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 that “[t]he Medical
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`Officer does not support adding vitamins to your ongoing pivotal, randomized trial
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`in mesothelioma.” Ex. 2104 at 1; see also Ex. 2106. In March 2000,
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`representatives from Lilly, including Dr. Niyikiza, met with FDA representatives
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`to discuss Dr. Niyikiza’s supplementation proposal. Ex. 2108 at 2. The FDA
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`Case No. IPR2016-00318
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`continued to be skeptical, writing that “[t]he addition of vitamins to the pivotal
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`trial(s) is at Lilly’s risk.” Id. at 2, 5. The FDA emphasized its concern over the
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`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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`F.
`The District Court Litigation
`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 Sandoz 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.1 Ex. 1003. Having heard live testimony over the course of a nine-
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`1 Similarly, the JPO and EPO have rejected validity challenges to foreign
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`counterparts of the ’209 patent.
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`day bench trial, the 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.
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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. Critical Date of the ’209 Patent
`The relevant date for analyzing Sandoz’s obviousness arguments is June 29,
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`1999, which is more than one year before the earliest U.S. filing date to which the
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`’209 patent claims priority. Ex. 1001. Dr. Niyikiza conceived of the invention and
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`presented his idea of folic acid and vitamin B12 pretreatment at meetings in 1997
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`and 1998 with Lilly employees and outside consultants employed by Lilly. Ex.
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`2111; Ex. 2112 at 7; Ex. 2113 at 10. Lilly further presented Dr. Niyikiza's vitamin-
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`supplementation idea to the FDA in 1998 and 1999. Ex. 2100 at 8044, 8046; Ex,
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`2103; Ex. 2105. Consistent with these facts, Sandoz and both sides’ experts apply
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`a date of June 1999 as the critical date for analyzing obviousness. See generally
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`Ex. 1004; Ex. 2120 ¶ 22; see also Ex. 1003 (applying same date).
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`III. The Person of Ordinary Skill in the Art
`As Dr. Chabner has opined, the POSA to whom the ’209 patent is directed is
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`a “medical doctor who specializes in oncology, specifically medical oncology,”
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`and “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.” Ex. 2120 ¶ 23. The POSA also would have an “understanding of how
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`nutritional issues relate to the use of chemotherapy agents,” as well as “an
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`understanding of the interrelationships between antifolates, the folic acid pathway,
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`and pathways related to vitamin B12.” Id. ¶ 25; see also Ex. 2118 (Zeisel) ¶¶ 4-10.
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`The definition applied by Dr. Schiff is generally consistent with Dr. Chabner’s
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`definition. Ex. 2120 ¶ 25; Ex. 1004 ¶ 13; Ex. 2026 at 43-44.
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`IV. Claim Construction – “Patient”
`A claim subject to inter partes review is given its “broadest reasonable
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`construction in light of the specification in which it appears.” 37 C.F.R.
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`§ 42.100(b). The claim constructions adopted in this Patent Owner Response are
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`consistent with the broadest reasonable interpretation standard, the specification,
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`the terms’ ordinary meanings, and the guideposts for claim construction set forth in
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`Phillips v. AWH Corp., 415 F.3d 1303 (Fed Cir. 2005) (en banc).
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`A. The term “patient” appears in both of the independent claims of the
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`’209 patent, which recite “administering pemetrexed disodium” to “a patient in
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`need thereof” (claim 1) and to “a patient in need of chemotherapeutic treatment”
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`(claim 12). “Patient” should be given its ordinary and customary meaning as
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`understood by the POSA: a “human undergoing medical treatment.” Ex. 2120
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`¶¶ 28-29.
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`As Lilly’s expert, Dr. Chabner, opines, Lilly’s definition is how an
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`oncologist would ordinarily understand the term. Ex. 2120 ¶¶ 28-29. It also is the
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`standard dictionary definition of the term, even outside the field of oncology. Ex
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`2016 at 3 (“A person receiving or registered to receive medical treatment; a sick
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`person, esp. one staying in a hospital.”); Ex. 2017 at 3 (“a person who is under
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`medical care or treatment”).
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`Sandoz argues that “patient” should be construed to mean “mammal.” That
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`is wrong. Lilly’s definition is not only the ordinary meaning of the term in
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`oncology, but it has been adopted by the District Court and by the Petitioner in the
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`co-pending IPRs (Neptune Generics, LLC). See Ex. 2014; IPR2016-00237, Paper
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`1 at 12; IPR2016-00240, Paper 1 at 13. It even has been adopted by Sandoz’s own
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`expert, who agreed both that “patient” is a “subset” of “human” and that “patient”
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`refers to being under medical treatment. Ex. 2026 at 345-47, 349. Sandoz’s
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`citations to a veterinary reference and to a court decision about a different patent,
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`neither of which bears on the relevant question of the ordinary meaning in medical
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`oncology (to which the ’209 patent undisputedly pertains), are simply beside the
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`point.
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`B. Unable to argue that “patient” ordinarily means “mammal” in
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`oncology, Sandoz focuses on the specification of the ’209 patent, and argues that
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`because the specification uses “patient” and “mammal” interchangeably, the terms
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`must mean the same thing. The passages Sandoz cites fall far short of a clear
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`redefinition of the term that could rebut the presumption that it has its ordinary
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`meaning. See Ex. 2014 at 4; Thorner v. Sony Computer Entm’t Am. LLC, 669 F.3d
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`1362, 1365 (Fed. Cir. 2012).
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`In fact, the specification of the ’209 patent supports Lilly’s construction, not
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`Sandoz’s, by making clear that “patient” is narrower than “mammal,” and drawing
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`a distinction between the two. The specification contains an extensive discussion
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`of pre-clinical experiments with laboratory mice. Ex. 1001 at 6:57-67. In
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`discussing these experiments, it refers to the mice as “animals,” never as
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`“patients.” Id. at 6:63; 7:1, 41-42, 46-47, 66; 8:15. In contrast, when the
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`specification discusses clinical studies—which by definition involve humans—the
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`specification consistently refers to “patients.” Ex. 1001 at 8:39, 42-45, 49, 55-58;
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`9:14-17, 21-55; 10:17-28. Other uses of “patient” in the specification are likewise
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`consistent with the understanding that the term means a human undergoing medical
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`treatment. Id. at 1:62-64; 2:41-46; 3:59-67; 5:38-46; 6:41-49. In short, the
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`specification fails to support Sandoz’s argument.
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`Sandoz also argues that the prosecution history supports its
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`C.
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`construction. Lilly, it argues, amended the claims to recite “patient” instead of
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`“human,” and thus “patient” must include non-human mammals. Paper 2 at 19-20.
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`That is exactly backwards. In fact, Lilly amended the claim language from
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`“mammal,” then to “human,” then to “patient,” progressively narrowing the claim.
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`Ex. 1024 at 38; Ex. 1002 at 3. That understanding is entirely consistent with the
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`testimony of Dr. Schiff, who explained that in ordinary usage “patient” is a subset
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`of “human” denoting someone receiving medical treatment. Ex. 2026 at 349. The
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`prosecution history thus supports Lilly’s construction, not Sandoz’s.
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`D.
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`Finally, the obvious motive for Sandoz’s claim construction—to make
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`Worzalla, which involved laboratory mice, more relevant—was fatally unde