Case 1:10-cv-01376-TWP-DKL Document 332 Filed 11/22/13 Page 1 of 67 PageID #: 8138
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE SOUTHERN DISTRICT OF INDIANA
`INDIANAPOLIS DIVISION
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`
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`Plaintiff,
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`v.
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`)
`ELI LILLY AND COMPANY,
`
`)
`
`
`)
`
`
` )
`
` ) Civil Action No. 1:10-cv-01376-TWP-DKL
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` )
`
`
`
` )
`TEVA PARENTERAL MEDICINES, INC.,
` )
`APP PHARMACEUTICALS, LLC,
` )
`PLIVA HRVATSKA D.O.O.,
`TEVA PHARMACEUTICALS USA, INC., and )
`BARR LABORATORIES, INC.,
` )
`
` )
`
` )
`
` )
`
`
`Defendants.
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`PLAINTIFF ELI LILLY AND COMPANY’S POST-TRIAL BRIEF
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`Lilly Ex. 2004 pg. 1
`Sandoz v. Lilly IPR2016-00318
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`Case 1:10-cv-01376-TWP-DKL Document 332 Filed 11/22/13 Page 2 of 67 PageID #: 8139
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`TABLE OF CONTENTS
`Background ......................................................................................................................... 5
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`I.
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`A.
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`B.
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`C.
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`D.
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`E.
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`F.
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`G.
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`Antifolates and Folates ............................................................................................5
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`Antifolate Drug Development as of 1999 ................................................................6
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`Pemetrexed and Dr. Niyikiza’s Invention ................................................................7
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`Experts Inside and Outside Lilly Were Hostile To Dr. Niyikiza’s Idea ..................9
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`Lilly’s Calculus Changes After a Spike in Pemetrexed-Related Deaths ...............10
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`Dr. Niyikiza’s Invention Is a Success ....................................................................11
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`The ’209 Patent and the Current Proceeding .........................................................11
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`II.
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`Defendants Have Failed To Prove by Clear and Convincing Evidence that the
`Asserted Claims of the ’209 Patent Would Have Been Obvious ...................................... 12
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`A.
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`The POSA Would Have Avoided Folic Acid Pretreatment with Pemetrexed .......16
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`1.
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`2.
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`3.
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`The POSA’s Background Understanding Would Have Been that Folic
`Acid Pretreatment Would Reduce Pemetrexed’s Efficacy ........................16
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`The Hammond and Worzalla References Would Have Reinforced the
`POSA’s Concern that Folic Acid Pretreatment Would Impair the
`Antitumor Efficacy of Pemetrexed ............................................................20
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`The Niyikiza Abstracts and Other References Cited by Defendants
`Would Not Give the POSA Reason To Pretreat with Folic Acid ..............29
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`B.
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`The POSA Would Have Avoided Vitamin B12 Pretreatment with Pemetrexed ....35
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`1.
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`2.
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`3.
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`The Use of Vitamin B12 Pretreatment with Antifolate Cancer Therapy
`Was Unprecedented as of June 1999 .........................................................35
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`Vitamin B12 Would Have Been Expected To Counteract Antifolate
`Efficacy and Aid Tumor Growth ...............................................................36
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`The POSA Would Not Have Used Vitamin B12 Pretreatment with
`Pemetrexed .................................................................................................39
`
`a.
`
`b.
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`The POSA Would Not Have Administered Vitamin B12 To
`Reduce Pemetrexed Toxicity .........................................................39
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`The POSA Would Not Have Been Concerned About a Masked
`Vitamin B12 Deficiency in Cancer Patients ....................................42
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`
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`i
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`Lilly Ex. 2004 pg. 2
`Sandoz v. Lilly IPR2016-00318
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`Case 1:10-cv-01376-TWP-DKL Document 332 Filed 11/22/13 Page 3 of 67 PageID #: 8140
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`C.
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`D.
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`Defendants Failed To Prove that the Particular Doses and Schedules of the
`Asserted Claims Would Have Been Obvious ........................................................44
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`Objective Indicia Demonstrate the Nonobviousness of the Claimed Invention ....50
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`1.
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`2.
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`Skepticism of Dr. Niyikiza’s Invention Proves Its Nonobviousness .........50
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`Unexpected Results Further Demonstrate the Nonobviousness of the
`Claimed Invention ......................................................................................52
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`III.
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`IV.
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`Defendants Failed To Prove by Clear and Convincing Evidence that the Asserted
`Claims Are Invalid For Obviousness-Type Double Patenting ......................................... 52
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`Defendants Failed To Prove by Clear and Convincing Evidence that the Asserted
`Claims Are Invalid Under 35 U.S.C. § 112 ...................................................................... 55
`
`A.
`
`B.
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`The Asserted Claims Satisfy the Written Description Requirement .....................56
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`The Asserted Claims Satisfy the Enablement Requirement ..................................58
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`CONCLUSION ............................................................................................................................. 60
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`ii
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`Lilly Ex. 2004 pg. 3
`Sandoz v. Lilly IPR2016-00318
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`Case 1:10-cv-01376-TWP-DKL Document 332 Filed 11/22/13 Page 4 of 67 PageID #: 8141
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`TABLE OF AUTHORITIES
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`FEDERAL CASES
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`Alcon, Inc. v. Teva Pharm. USA, Inc., 664 F. Supp. 2d 443 (D. Del. 2009) .................................14
`
`Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010) (en banc) ...................56, 57
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`AstraZeneca LP v. Apotex, Inc., 633 F.3d 1042 (Fed. Cir. 2010) ..................................................46
`
`Cephalon, Inc. v. Watson Pharm., Inc., 707 F.3d 1330 (Fed. Cir. 2013) ................................58, 60
`
`DatCard Sys., Inc. v. Pacsgear, Inc., No. 8:10-cv-01288, ECF No. 164
`(C.D. Cal. Apr. 1, 2013)...........................................................................................................19
`
`DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314 (Fed. Cir. 2009) ...............24
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`Eli Lilly v. Teva Parenteral Meds., Inc., 689 F.3d 1368 (Fed. Cir. 2012) ...............................15, 53
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`Epcon Gas Sys., Inc. v. Bauer Compressors, Inc., 279 F.3d 1022 (Fed. Cir. 2002) ......................56
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`Falkner v. Inglis, 448 F.3d 1357 (Fed. Cir. 2006) .........................................................................58
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`Graham v. John Deere Co., 383 U.S. 1 (1966) .............................................................................12
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`Hodosh v. Block Drug Co., 786 F.2d 1136 (Fed. Cir. 1986) .........................................................38
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`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig.,
`676 F.3d 1063 (Fed. Cir. 2012)................................................................................................12
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`In re Klein, 647 F.3d 1343 (Fed. Cir. 2011) ............................................................................34, 41
`
`In re Soni, 54 F.3d 746 (Fed. Cir. 1995) ........................................................................................52
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`In re Wands, 858 F.2d 731 (Fed. Cir. 1988) ..................................................................................58
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`In re Woodruff, 919 F.2d 1575 (Fed. Cir. 1990) ............................................................................45
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`Innogenetics, N.V. v. Abbott Labs., 512 F.3d 1363 (Fed. Cir. 2008) .............................................13
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`Kinetic Concepts, Inc. v. Smith & Nephew, Inc., 688 F.3d 1342 (Fed. Cir. 2012) ..................50, 51
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`Koito Mfg. Co. v. Turn-Key-Tech, LLC, 381 F.3d 1142 (Fed. Cir. 2004) .....................................57
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`KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007)............................................................... passim
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`Leo Pharm. Prods., Ltd. v. Rea, 726 F.3d 1346 (Fed. Cir. 2013) ............................................36, 50
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`Microsoft Corp. v. i4i Ltd., 131 S. Ct. 2238 (2011) .................................................................12, 46
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`
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`iii
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`Lilly Ex. 2004 pg. 4
`Sandoz v. Lilly IPR2016-00318
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`Case 1:10-cv-01376-TWP-DKL Document 332 Filed 11/22/13 Page 5 of 67 PageID #: 8142
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`Mintz v. Dietz & Watson, Inc., 679 F.3d 1372 (Fed. Cir. 2012) ..............................................49, 50
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`Ormco Corp. v. Align Tech., Inc., 463 F.3d 1299 (Fed. Cir. 2006) ...............................................55
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`Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc., 520 F.3d 1358 (Fed. Cir. 2008) .......................50
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`Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280 (Fed. Cir. 2012) ................................14, 49, 53
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`Panduit Corp. v. Dennison Mfg. Co., 810 F.2d 1561 (Fed. Cir. 1987) ...................................15, 45
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`PPG Indus., Inc. v. Guardian Indus. Corp., 75 F.3d 1558 (Fed. Cir. 1996) .................................58
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`Procter & Gamble Co. v. Teva Pharm. USA, Inc., 566 F.3d 989 (Fed. Cir. 2009) .................12, 13
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`Rambus Inc. v. Rea, 731 F.3d 1248 (Fed. Cir. 2013) ....................................................................50
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`Sanofi-Synthelabo v. Apotex, Inc., 550 F.3d 1075 (Fed. Cir. 2008) ........................................15, 45
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`Santarus, Inc. v. Par Pharm., Inc., 720 F. Supp. 2d 427 (D. Del. 2010) .......................................51
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`Spectralytics, Inc. v. Cordis Corp., 649 F.3d 1336 (Fed. Cir. 2011) .......................................21, 24
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`Star Scientific, Inc. v. R.J. Reynolds Tobacco Co., 655 F.3d 1364 (Fed. Cir. 2011) .....................24
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`Tec Air, Inc. v. Denso Mfg. Mich. Inc., 192 F.3d 1353 (Fed. Cir. 1999) .......................................21
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`Transocean Offshore Deepwater Drilling, Inc. v. Maersk Contractors USA, Inc.,
`617 F.3d 1296 (Fed. Cir. 2010)................................................................................................50
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`Unigene Labs., Inc v. Apotex, Inc., 655 F.3d 1352 (Fed. Cir. 2011) .............................................14
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`OTHER AUTHORITIES
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`37 C.F.R. 1.75(e)............................................................................................................................56
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`35 U.S.C. § 103 ............................................................................................................12, 15, 45, 53
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`35 U.S.C. § 112 ..........................................................................................................................4, 55
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`35 U.S.C. § 282 ..............................................................................................................................15
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`iv
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`Lilly Ex. 2004 pg. 5
`Sandoz v. Lilly IPR2016-00318
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`Case 1:10-cv-01376-TWP-DKL Document 332 Filed 11/22/13 Page 6 of 67 PageID #: 8143
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`The central question in this case is whether the person of ordinary skill in the art (POSA)
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`would have been motivated to pretreat patients receiving pemetrexed with folic acid and vitamin
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`B12 according to the regimens recited in the asserted claims of the ’209 patent. Even if Lilly had
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`the burden of proof, the evidence demonstrated overwhelmingly that the POSA would not have
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`done so, and thus that the asserted claims would not have been obvious. The actual burden,
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`however, is Defendants’, and they have not come close to proving by clear and convincing
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`evidence that Lilly’s claims are invalid.
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`As of June 1999, the expectation of the POSA was that if pretreating patients with folic
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`acid and vitamin B12 reduced the toxicity of pemetrexed, that pretreatment would also decrease
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`the drug’s efficacy against cancer and, indeed, could cause the patient’s tumor to grow. That is
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`the last thing that a POSA—who was treating a patient with a deadly disease—would have
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`wanted to do. And none of the preclinical or clinical evidence—including Hammond and
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`Worzalla, the primary references on which Defendants base their obviousness case—rebutted the
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`conventional wisdom that folic acid and vitamin B12 pretreatment would be detrimental. Folic
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`acid pretreatment, without vitamin B12, had been tried and failed, both with pemetrexed and with
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`other antifolates. While folic acid reduced the toxicity of antifolates in those studies, critically, it
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`also reduced their efficacy against cancer.
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`That is not a trade that the POSA would have made. Indeed, the literature shows exactly
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`that. The 1999 Physician’s Desk Reference (PDR) (TX 2094), a standard medical reference,
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`recognized that patients with folic acid deficiency could be more likely to suffer toxicities from
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`methotrexate, an antifolate. Defendants use this very rationale as their basis for saying that the
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`POSA would have wanted to pretreat patients with folic acid, i.e., in order to lessen toxicity.
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`And yet the PDR taught physicians to do exactly the opposite. Despite acknowledging the role
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`1
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`Lilly Ex. 2004 pg. 6
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`folate deficiency could play in patients suffering toxicities, the PDR expressly directed
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`physicians not to administer folic acid with the antifolate chemotherapy because it could
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`interfere with the anti-cancer efficacy of the drug. That is real-world, contemporaneous evidence
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`that, despite Defendants’ hindsight-driven arguments, it was not obvious to pretreat cancer
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`patients with folic acid prior to giving them an antifolate.
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`As to vitamin B12 pretreatment, the evidence showed that this was anything but obvious.
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`In the half century that researchers had been looking for ways to safely and effectively
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`administer antifolates to cancer patients, no one had ever tried it or suggested that it would be a
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`good idea. That speaks volumes as to whether it was really obvious to do. And, indeed, the
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`evidence at trial showed that there was no reason to pretreat pemetrexed patients with vitamin
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`B12, and that in fact it would have been viewed as affirmatively detrimental.
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`The POSA would have been particularly unwilling to sacrifice the efficacy of pemetrexed
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`in an attempt to mitigate its toxicity because in June 1999, pemetrexed was viewed as an
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`extraordinarily promising anti-cancer agent whose toxicities were seen as generally manageable
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`and tolerable. Indeed, the evidence showed that this was precisely the contemporaneous reaction
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`to Dr. Niyikiza’s idea when he first proposed his invention to his colleagues, to outside experts
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`retained by Lilly, and to the FDA. The overwhelming consensus was that Dr. Niyikiza’s idea of
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`pretreating patients with folic acid and vitamin B12 posed an unacceptable risk to the efficacy of
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`the drug and that it should not be pursued.
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`That chorus of skepticism of Dr. Niyikiza’s invention is perhaps the most probative
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`evidence in this case. Unlike in most obviousness cases, the Court here has evidence of what the
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`leading experts in the field of antifolate chemotherapy actually thought of Dr. Niyikiza’s
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`invention at the time. Dr. Niyikiza described how, for years, he was a “lone wolf,” advocating
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`2
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`Lilly Ex. 2004 pg. 7
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`Case 1:10-cv-01376-TWP-DKL Document 332 Filed 11/22/13 Page 8 of 67 PageID #: 8145
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`an idea that both his colleagues at Lilly and the broader community of antifolate researchers
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`considered to be meritless, but which ultimately became an essential aspect of pemetrexed
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`therapy. Tr. 879:5-20. Dr. Hilary Calvert—one of the leading antifolate experts in the world—
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`testified that he and the rest of Lilly’s Antifolate Advisory Board were concerned that
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`administering folic acid and vitamin B12 pretreatment would hurt the efficacy of the drug, and
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`thus they recommended against pretreatment until, well after the June 1999 priority date,
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`unexpected deaths in pemetrexed clinical trials left no choice but to risk the drug’s efficacy.
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`Calvert Dep. Tr. 64:22–66:8, 69:18–70:5, 126:16–128:7. And Lilly’s expert, Dr. Bruce
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`Chabner, told the Wall Street Journal in 2004 that when he first heard of the idea of
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`administering vitamin pretreatment to patients about to receive pemetrexed, he thought it was
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`“crazy.” Tr. 1175:21–1179:4; TX 2119 at 3.
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`Faced with this evidence, Defendants attempt to change the subject. Defendants focus on
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`the undisputed question of whether the invention would have been expected to reduce
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`pemetrexed’s toxicity. The POSA, however, was not focused on toxicity alone, but rather would
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`have been concerned that using vitamins would mean reducing efficacy, and would not have had
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`reason to use vitamins given that the toxicity of pemetrexed was understood to be tolerable and
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`manageable with conventional techniques. To the extent Defendants address efficacy at all, they
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`focus on whether the claimed regimen would have been expected to provide some “therapeutic
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`benefit” to a patient. The question, though, is not whether Dr. Niyikiza’s invention would have
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`been expected to eliminate all therapeutic benefit from pemetrexed, but whether the POSA
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`would have had reason to carry out the claimed invention given the expected reduction in
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`efficacy. The evidence showed that the POSA would not have.
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`Defendants argue that the asserted claims are invalid based on obviousness-type double
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`3
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`Lilly Ex. 2004 pg. 8
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`Case 1:10-cv-01376-TWP-DKL Document 332 Filed 11/22/13 Page 9 of 67 PageID #: 8146
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`patenting over the ’974 patent. This defense essentially amounts to a repeat of their erroneous
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`obviousness arguments, this time starting with a patent that has nothing to do with pemetrexed in
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`particular and suggests nothing about vitamin B12 pretreatment.
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`Defendants’ final arguments are that the asserted claims do not satisfy the written
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`description or enablement requirements of 35 U.S.C. § 112 (2006). Defendants suggest that if
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`the asserted claims are not obvious, then they must be invalid under § 112. That is wrong; there
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`is no contradiction in the claims being valid under both sections. Their theory apparently is that
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`if the prior art did not teach an amount of pemetrexed that would provide a therapeutic benefit
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`when given with folic acid and vitamin B12 pretreatment, then the patent does not describe such
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`amounts of pemetrexed and the POSA would not have been able to use such amounts of
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`pemetrexed without undue experimentation. But Defendants have posited a tension that does not
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`exist. The primary reason Dr. Niyikiza’s invention was not obvious is that the POSA would not
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`have wanted to use it because it would have been thought to reduce the efficacy of pemetrexed as
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`compared to giving the drug without vitamins. Given the results of unsupplemented pemetrexed
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`clinical trials, the POSA would not have been interested in pursuing a regimen that was merely
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`capable of providing some therapeutic benefit to some patient. Section 112, in contrast, is
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`directed to different issues from obviousness—whether the POSA, presented with the patent,
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`would have understood it to describe the claimed invention and would have been able to practice
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`the claimed invention without undue experimentation. The patent described, and the POSA
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`would have no difficulty at all in using, an “effective amount” of pemetrexed.
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` In sum, Defendants have fallen far short of proving by clear and convincing evidence
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`that Lilly’s asserted claims are invalid, and judgment should be entered in Lilly’s favor.
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`4
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`Lilly Ex. 2004 pg. 9
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`Case 1:10-cv-01376-TWP-DKL Document 332 Filed 11/22/13 Page 10 of 67 PageID #: 8147
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`I.
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`Background
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`A.
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`Antifolates and Folates
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`Pemetrexed is an antifolate cancer drug, which works by competing with folates, a class
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`of essential nutrients that includes folic acid. Tr. 1005:13–1007:5 (Chabner). Folates
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`participate in chemical reactions in the body that make chemical precursors to DNA. Id. DNA,
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`in turn, is required for division and growth of both cancer cells and normal cells. Id.; Tr. 356:8–
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`357:1. Antifolates interfere with the action of folates and deprive cancer cells of the DNA
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`precursors they need to proliferate. Tr. 1006:4–1007:5. Accordingly, whereas folates promote
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`cell growth and division, thus serving as “fuel for the cancer to grow,” antifolates do just the
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`opposite, inhibiting cell growth and causing cancer cells to die. Calvert Dep. Tr. 158:11-16; see
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`also Tr. 1006:4–1007:5; Tr. 1571:2-9 (Zeisel). Because of the competitive relationship between
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`folates and antifolates, the ability of an antifolate to fight cancer depends on the relative amount
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`of folate and antifolate in the cell. Tr. 1006:23–1007:5; Tr. 1571:7-9. Thus, as folate levels are
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`increased, greater amounts of antifolate are needed to achieve an antiproliferative effect. Tr.
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`1099:2-11 (Chabner); Tr. 447:16–448:7 (Green).
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`Cancer cells are fast-growing and thus have a high demand for DNA precursors, making
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`them particularly susceptible to the effects of antifolates. Tr. 1025:21–1026:13 (Chabner); Tr.
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`1365:2-14 (Cupps). But antifolates’ effects are not limited to cancer cells. Tr. 1025:21–1026:13.
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`Fast-growing normal cells, such as cells that line the gastrointestinal tract and cells of the bone
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`marrow, also divide rapidly and are also particularly susceptible to the effects of antifolates. Id.
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`Accordingly, the same mechanisms by which antifolates kill cancer cells also kill fast-growing
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`normal cells, causing antifolate-related side effects, or “toxicities,” that can be severe and even
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`life-threatening. Tr. 1571:2-6 (Zeisel); Tr. 447:7-15 (Green).
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`5
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`Lilly Ex. 2004 pg. 10
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`Case 1:10-cv-01376-TWP-DKL Document 332 Filed 11/22/13 Page 11 of 67 PageID #: 8148
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`B.
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`Antifolate Drug Development as of 1999
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`Antifolate research began in 1948 with the observation by Farber that giving folic acid to
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`children with leukemia caused tumor growth to accelerate. See Tr. 1019:13-21, 1041:14–
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`1042:17 (Chabner); Calvert Dep. Tr. 158:11-16. Based on that finding, Farber administered an
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`experimental antifolate called aminopterin, which caused some of his patients to go into
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`remission. Tr. 1018:23–1020:5 (Chabner); Tr. 132:18–133:10, 265:11-21 (Ratain). Following
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`Farber’s work, many companies and researchers worked to develop antifolates for treating
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`cancer. Tr. 268:15-18 (Ratain). In the early 1950s, the FDA approved the antifolate drug
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`methotrexate. Tr. 269:5-9 (Ratain). After that, numerous companies and researchers tried to
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`find additional antifolates that could be useful in the treatment of cancer. Tr. 1020:11-20
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`(Chabner). Between 1950 and 1999, a great many antifolates were made and tested, but as of
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`1999, methotrexate remained the only one approved by the FDA for treating cancer. Tr. 268:15–
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`269:9 (Ratain). Virtually none of these experimental antifolates—including at least seven that
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`were in clinical trials as of 1999—were administered to cancer patients with folic acid
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`pretreatment. Tr. 1049:18–1050:4 (Chabner); Tr. 308:5–310:7 (Ratain).
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`Defendants focused their attention at trial on the small handful of instances where
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`someone had tried the idea of using folic acid pretreatment with an antifolate. For instance,
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`among the many antifolates in clinical trials in the 1990s was a compound being developed by
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`Lilly called lometrexol. Tr. 722:16-22 (Niyikiza). Initial clinical trials of lometrexol without
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`folic acid supplementation were a “complete disaster,” with patients exhibiting “appalling
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`toxicities.” Calvert Dep. Tr. 92:8-14. In an effort to address these severe and cumulative
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`toxicities, researchers tried administering lometrexol with folic acid. Tr. 723:7-16 (Niyikiza). A
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`clinical trial published by Laohavinij involved administering a daily oral dose of 5 mg of folic
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`acid 7 days before and 7 days after lometrexol administration. Tr. 311:9-12 (Ratain); TX 1036.
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`6
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`Lilly Ex. 2004 pg. 11
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`Case 1:10-cv-01376-TWP-DKL Document 332 Filed 11/22/13 Page 12 of 67 PageID #: 8149
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`By 1999, however, the lometrexol experience was known to have ended in failure, as the use of
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`folic acid pretreatment had been shown to compromise the efficacy of the drug. Tr. 1045:5–
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`1046:13 (Chabner); Tr. 307:11-17 (Ratain). The Laohavinij study of lometrexol and folic acid
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`reported “only one” response among folic acid supplemented patients—far fewer than had been
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`observed in earlier unsupplemented patients. TX 1036 at 333; see also Tr. 723:7-16 (Niyikiza);
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`Tr. 311:18–312:4 (Ratain); Tr. 1045:9–1046:13 (Ratain). As of 1999, Lilly had also pursued
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`clinical development of a related antifolate, LY309887 (“the ’887 compound”), which was also
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`tested with folic acid pretreatment for the same reasons as lometrexol. Calvert Dep. Tr. 130:18-
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`24; Tr. 723:18–724:3 (Niyikiza). As with lometrexol, however, those studies proved
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`unsuccessful. Tr. 1048:13–1049:3 (Chabner).
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`C.
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`Pemetrexed and Dr. Niyikiza’s Invention
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`In the late 1990s, pemetrexed was viewed as an extraordinarily promising anticancer
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`drug. Tr. 321:2-5 (Ratain). By 1999, the literature reported that pemetrexed had “remarkable
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`and unusual” anticancer activity across a broad range of tumor types—most notably in
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`mesothelioma, an invariably fatal and notoriously difficult-to-treat cancer. TX 907 at 107; see
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`also Calvert Dep. Tr. 137:12–138:13, 114:4-21; Tr. 1022:7–1024:25 (Chabner); Tr. 749:21–
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`750:8 (Niyikiza); Tr. 321:2-5 (Ratain); Tr. 456:21–457:19 (Green). At the same time, the
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`literature indicated that pemetrexed’s toxicities were “tolerable and manageable” with routine
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`dose and schedule adjustments. Tr. 1022:7-18, 1025:4-18 (Chabner); see also Calvert Dep. Tr.
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`138:14–139:25; Tr. 131:23–132:7 (Ratain); TX 78 at 1198; TX 1006 at 39; TX 907 at 107.
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`Internally at Lilly, however, Dr. Niyikiza—a mathematician employed by Lilly to help
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`with the clinical development of cancer compounds—set out to better understand which patients
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`were likely to develop the sporadic toxicities observed. Tr. 713:12-25 (Niyikiza). In early 1997,
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`Dr. Niyikiza performed a series of statistical analyses, known as multivariate analyses, on more
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`than 60 variables in each patient. Tr. 739:13-19, 740:6-13 (Niyikiza); TX 2058.
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`Dr. Niyikiza’s multivariate analyses, results of which he published in two abstracts in
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`1998, pointed to a correlation between the incidence of pemetrexed toxicities and patients’ levels
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`of a substance called homocysteine. Tr. 742:21–743:1 (Niyikiza); TX 910 at abstract 2139; TX
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`911 at abstract 609P. Dr. Niyikiza reported that homocysteine levels of at least 10 micromolar
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`(μM) correlated with specific pemetrexed toxicities. Id.; see also Tr. 1613:2-13 (Zeisel).
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`Elevated homocysteine levels can be a marker for either folic acid or vitamin B12
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`deficiencies, among other conditions. Tr. 173:17-20 (Ratain). Another substance,
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`methylmalonic acid (“MMA”), is a predictor of vitamin B12 deficiency, but not folate deficiency.
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`Tr. 388:7-10 (Green); Tr. 1014:21–1015:19 (Chabner). Accordingly, whereas high
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`homocysteine levels (without information about a patient’s MMA levels) can indicate either a
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`folate deficiency or a vitamin B12 deficiency, high homocysteine and high MMA levels together
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`indicate that the patient at least has a vitamin B12 deficiency. Tr. 1014:8–1015:19 (Chabner).
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`On the other hand, high homocysteine without high MMA indicates that the patient does not
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`have a B12 deficiency. Id.; see also Tr. 290:23–291:6 (Ratain). What Dr. Niyikiza found in his
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`initial analyses, and published in his abstracts, was that there was no correlation between toxicity
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`and a host of other variables he measured, including MMA. Tr. 1609:21–1610:2 (Zeisel); Tr.
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`1134:6-24, 1346:9-18 (Chabner); Tr. 547:14–548:6 (Green); Tr. 631:10-17 (Morgan). This
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`suggested that there was no connection between toxicity and patients’ vitamin B12 levels. Tr.
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`1610:3-8 (Zeisel); Tr. 1134:18–1135:12 (Chabner); Tr. 292:9-13 (Ratain).
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`Dr. Niyikiza, however, suspected there was a link between the two. And in early 1997,
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`he had the idea that pretreating patients with a combination of vitamin B12 and low levels of folic
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`acid would help to fix the problem of the sporadic toxicities observed by Lilly in its pemetrexed
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`clinical trials. Tr. 757:6-15, 763:4-12 (Niyikiza).
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`D.
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`Experts Inside and Outside Lilly Were Hostile To Dr. Niyikiza’s Idea
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`At every turn, Dr. Niyikiza faced skepticism of and resistance to his idea. As will be
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`discussed below, some of the most probative evidence in this case regarding how the invention
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`would have been perceived by the POSA is how it was actually perceived by experts in the field.
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`See infra Part II.D.1. Based on the well-known relationships between folates and antifolates,
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`experts inside and outside Lilly were concerned that pretreating patients with folic acid and
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`vitamin B12 would reduce pemetrexed’s efficacy. Tr. 749:17–750:8 (Niyikiza); Calvert Dep. Tr.
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`124:7–125:20. For instance, Dr. Niyikiza presented his idea at meetings of Lilly’s Antifolate
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`Advisory Panel, a group of worldwide experts in the field of antifolate research assembled by
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`Lilly to provide advice on a confidential basis concerning Lilly’s antifolate development
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`program. These outside experts consistently rejected his idea. Tr. 750:9–751:9,764:23–765:5,
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`768:11-17,773:5–774:7, 774:24–775:10 (Niyikiza); Calvert Dep. Tr. 62:8-23, 124:7–125:20,
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`126:16–128:7, 132:13–133:18, 138:14–139:25, 183:19–184:23, 185:23–187:21. They warned
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`that intervening with vitamin supplementation would abrogate the efficacy of pemetrexed, and
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`that in view of pemetrexed’s promising efficacy across multiple tumor types, it was not worth
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`taking the risk of damaging its efficacy with vitamin supplementation. Tr. 764:23–765:5.
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`The FDA likewise resisted the idea of vitamin supplementation. For example, in
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`September 1998, when the FDA considered Lilly’s proposal to include vitamin pretreatment in a
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`planned clinical trial, it echoed the concerns that Lilly’s outside experts had raised that
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`pretreating patients with vitamins would reduce pemetrexed’s efficacy. Tr. 787:13-16, 788:19-
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`23, 790:17-25 (Niyikiza); TX 326 at 8044. Following this reaction from the FDA, Lilly did not
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`implement vitamin supplementation in the trial. Tr. 788:24–789:3, 792:20-21.
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`E.
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`Lilly’s Calculus Changes After a Spike in Pemetrexed-Related Deaths
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`In late 1999, after the relevant priority date of the ’209 patent, circumstances changed.
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`Until that point, pemetrexed’s toxicity generally appeared to be manageable and tolerable. In
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`late 1999, however, clinicians in the ongoing phase 3 registration trial in mesothelioma
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`witnessed a “very, very alarming” increase in drug-related patient deaths. Tr. 795:16-25
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`(Niyikiza). Faced with this new, still-confidential information, as well as further analyses of
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`additional data by Dr. Niyikiza, Lilly decided to implement Dr. Niyikiza’s invention in the
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`ongoing registration trial. Tr. 796:12–797:5, 798:19–799:14. Although the experts on the
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`Antifolate Advisory Panel remained concerned that vitamin supplementation would reduce the
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`efficacy of pemetrexed, they now viewed it as a “risk worth taking” in view of the high number
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`of pemetrexed-related deaths. Tr. 798:21–799:14. Dr. Calvert, who served on the Antifolate
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`Advisory Panel at the time of the toxicity crisis, testified that although the risk remained that
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`vitamin supplementation would compromise pemetrexed’s efficacy, “it was clear that the drug
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`would get ditched” if no change was made. Calvert Dep. Tr. 65:10–66:8; see also id. 126:16–
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`128:7, 201:11–202:18, 209:12–211:15.
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`Even then, however, the FDA’s oncology experts opposed the use of vitamin
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`pretreatment. In January 2000, the FDA informed Lilly that “[t]he medical officer does not
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`support adding vitamins to the ongoing mesothelioma registration trial.” Tr. 814:8-12
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`(Niyikiza); see also TX 2100. Even after Lilly submitted a briefing document to the FDA that
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`was specifically written to justify Lilly’s decision to use vitamin supplementation, the FDA
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`remained skeptical, responding that “[t]he addition of vitamins to the p