Case 1:10-cv-01376-TWP-DKL Document 333 Filed 12/17/13 Page 1 of 24 PageID #: 8205
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE SOUTHERN DISTRICT OF INDIANA
`INDIANAPOLIS DIVISION
`
`CASE NO. 1:10-CV-1376-TWP-DKL
`
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`
`ELI LILLY AND COMPANY,
`
`Plaintiff,
`
`v.
`TEVA PARENTERAL MEDICINES, INC.,
`APP PHARMACEUTICALS, LLC,
`PLIVA HRVATSKA D.O.O.,
`TEVA PHARMACEUTICALS USA, INC.,
`and BARR LABORATORIES, INC.,
`
`Defendants.
`
`DEFENDANTS’ REPLY POST-TRIAL BRIEF REGARDING
`THE INVALIDITY OF U.S. PATENT NO. 7,772,209
`
`Lilly Ex. 2013 pg. 1
`Sandoz v. Lilly IPR2016-00318
`
`

`
`Case 1:10-cv-01376-TWP-DKL Document 333 Filed 12/17/13 Page 2 of 24 PageID #: 8206
`
`TABLE OF CONTENTS
`
`Page
`
`I.
`
`II.
`
`III.
`
`IV.
`
`V.
`
`LILLY HAS FAILED TO REBUT DEFENDANTS’ CLEAR AND CONVINCING
`EVIDENCE THAT THE CLAIMS ARE INVALID FOR OBVIOUSNESS-TYPE
`DOUBLE PATENTING .....................................................................................................2
`
`LILLY DOES NOT ADDRESS MUCH OF THE EVIDENCE ADDUCED AT TRIAL
`ON OBVIOUSNESS...........................................................................................................4
`
`LILLY MISSTATES AND MISAPPLIES THE LAW OF OBVIOUSNESS IN
`ATTEMPTING TO DEFEND THE NON-OBVIOUSNESS OF THE ‘209 PATENT......8
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`Lilly Attempts To Improperly Create A “Lead Reference” Requirement...............8
`
`Lilly Seeks To Require An Explicit Motivation In The Prior Art But The Supreme
`Court Rejected That Standard. ................................................................................9
`
`Lilly Misapplies The Proper Meaning Of “Teaching Away”................................11
`
`Lilly Improperly Focuses On Isolated Vitamin B12 References Rather Than On
`The Prior Art As A Whole.....................................................................................12
`
`Lilly Improperly Relies On Defendants’ ANDA To Suggest That The Claimed
`Doses Of Vitamins Are Not Arbitrary...................................................................12
`
`LILLY HAS ABANDONED ALL BUT TWO SECONDARY CONSIDERATIONS,
`NEITHER OF WHICH SUPPORT THE NONOBVIOUSNEE OF THE ‘209 PATENT
`CLAIMS ............................................................................................................................13
`
`IF THE COURT AGREES WITH LILLY’S INTERPRETATION OF THE PRIOR ART,
`THEN THE ‘209 PATENT SPECIFICATION IS DEFICIENT ......................................14
`
`i
`
`Lilly Ex. 2013 pg. 2
`Sandoz v. Lilly IPR2016-00318
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`

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`Case 1:10-cv-01376-TWP-DKL Document 333 Filed 12/17/13 Page 3 of 24 PageID #: 8207
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`CASES
`
`Allergan, Inc. v. Sandoz Inc.,
`726 F.3d 1286 (Fed. Cir. 2013) ...............................................................................................10
`
`Bayer Healthcare Pharms., Inc. v. Watson Pharms., Inc.,
`713 F.3d 1369 (Fed. Cir. 2013) ...........................................................................................9, 13
`
`Daiichi Sankyo Co. v. Apotex, Inc.,
`501 F.3d 1254 (Fed. Cir. 2007) .................................................................................................9
`
`Depuy Spine, Inc. v. Medtronic Sofamor Danek, Inc.,
`567 F.3d 1314 (Fed. Cir. 2009) ...............................................................................................11
`
`Eisai Co. Ltd. v. Dr. Reddy’s Labs., Ltd.,
`533 F.3d 1353 (Fed. Cir. 2008) .................................................................................................8
`
`Eli Lilly & Co. v. Teva Pharm. USA, Inc.,
`619 F.3d 1329 (Fed. Cir. 2010) .................................................................................................9
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
`No. 2013-1034, 2013 WL 6483704 (Fed. Cir. Dec. 11, 2013) .............................................8, 9
`
`In re ‘318 Patent Infringement Litig.,
`583 F.3d 1317 (Fed. Cir. 2009) ...............................................................................................15
`
`In re Gardner,
`427 F.2d 786 (C.C.P.A. 1970).................................................................................................15
`
`In re Gurley,
`27 F.3d 551 (Fed. Cir. 1994) .....................................................................................................9
`
`In re Hasse,
`2013 WL 5813645 (Fed. Cir. Oct. 30, 2013) ............................................................................3
`
`In re Napier,
`55 F.3d 610 (Fed. Cir. 1995) .............................................................................................11, 12
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................................9, 10
`
`Metso Minerals, Inc. v. Powerscreen Int’l Distrib., Ltd.,
`Nos. 2011-1572, 2012-1168, 2012-1169, 2013 WL 1969309 (Fed. Cir. May 14, 2013) .......10
`
`Mutual Pharm. Co., Inc. v. Bartlett,
`133 S. Ct. 2466 (2013) ............................................................................................................13
`
`ii
`
`Lilly Ex. 2013 pg. 3
`Sandoz v. Lilly IPR2016-00318
`
`

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`Case 1:10-cv-01376-TWP-DKL Document 333 Filed 12/17/13 Page 4 of 24 PageID #: 8208
`
`Ormco Corp. v. Align Tech. Inc.,
`463 F.3d 1299 (Fed. Cir. 2006) .................................................................................................3
`
`Pliva, Inc., v. Mensing,
`131 S. Ct. 2567 (2011) ............................................................................................................13
`
`Tyco Healthcare Grp. LP v. Mutual Pharm. Co., Inc.,
`642 F.3d 1370 (Fed. Cir. 2011) ...............................................................................................13
`
`STATUTES
`
`21 U.S.C. § 355 .............................................................................................................................12
`
`OTHER AUTHORITIES
`
`21 CFR § 314.94......................................................................................................................12, 13
`
`iii
`
`Lilly Ex. 2013 pg. 4
`Sandoz v. Lilly IPR2016-00318
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`

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`Case 1:10-cv-01376-TWP-DKL Document 333 Filed 12/17/13 Page 5 of 24 PageID #: 8209
`
`TABLE OF ABBREVIATIONS
`
`Abbreviation
`
`Document Description
`
`General
`
`“Defendants”
`
`Teva Parenteral Medicines, Inc., APP Pharmaceuticals, LLC,
`Pliva Hrvatska D.O.O., Teva Pharmaceuticals USA, Inc., and
`Barr Laboratories, Inc.,
`
`“Defs. Br.”
`
`Defendants’ Opening Post-Trial Brief Regarding The
`Invalidity of U.S. Patent No. 7,772,209 (D.I. 331)
`
`“Lilly”/”Eli Lilly”
`
`Eli Lilly and Company
`
`“Asserted Claims”
`
`Claims 9, 10, 12, 14, 15, 18, 19, and 21 of the ‘209 patent
`
`“Pl. Br.”
`
`“POSA”
`
`“TX”
`
`Plaintiff Eli Lilly And Company’s Post-Trial Brief (D.I. 332)
`
`Person of ordinary skill in the art
`
`Trial Exhibit
`
`Testimony
`
`“Ratain Tr.”
`
`“Green Tr.”
`
`Trial testimony of Dr. Mark J. Ratain
`
`Trial testimony of Dr. Ralph Green
`
`“Niyikiza Tr.”
`
`Trial testimony of Clet Niyikiza
`
`“Chabner Tr.”
`
`Trial testimony of Dr. Bruce A. Chabner
`
`“Calvert Dep. Tr.”
`
`Deposition testimony of Dr. A. Hilary Calvert
`
`Patents
`
`U.S. Patent No. 7,772,209 (TX 1)
`
`“the ‘209
`patent”/”patent-in-
`suit”
`
`“the ‘974 patent”
`
`U.S. Patent No. 5,217,974 (TX 916)
`
`Compounds, Enzymes, and Conferences
`
`iv
`
`Lilly Ex. 2013 pg. 5
`Sandoz v. Lilly IPR2016-00318
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`Case 1:10-cv-01376-TWP-DKL Document 333 Filed 12/17/13 Page 6 of 24 PageID #: 8210
`
`Abbreviation
`
`Document Description
`
`“Pemetrexed”/
`“MTA”/”LY231514”
`
`Pemetrexed/Pemetrexed disodium
`
`“the ‘887
`compound”
`
`“GARFT”
`
`“Arsenyan”
`
`“Calvert”
`
`“Hammond I”/
`“Hammond”
`
`“Hammond II”/
`“Hammond”
`
`“Laohavinij”
`
`“Mendelsohn”
`
`LY309887
`
`Glycinamide ribonucleotide formyl transferase
`
`Literature
`
`Arsenyan, et al., Influence of Methylcobalamin on the
`Antineoplastic Activity of Methotrexate, PHARMACEUTICAL
`CHEMISTRY JOURNAL, 12(10): 1299-1303 (1978) (TX 1016)
`
`Calvert, An Overview of Folate Metabolism: Features relevant
`to the Action and Toxicities of Antifolate Cancer Agents,
`SEMINARS IN ONCOLOGY, 26: 3-10 (1999) (TX 401)
`
`Hammond, et al., A phase I and pharmacokinetic (PK) study
`of the multitargeted antifolate (MTA, LY231514) with folic
`acid (FA), ANNALS OF ONCOLOGY, 9: 129, Abstract 620P
`(1998) (TX 911)
`
`Hammond, et al., Phase I and pharmacokinetic (PK) study of
`the glycinamide ribonucleotide formyltransferase (GARFT)
`inhibitor LY309887 as a bolus every 3 weeks with folic acid
`(FA) (Meeting abstract) Abstract 865, AMERICAN SOCIETY OF
`CLINICAL ONCOLOGY, 17: 225a (1998) (TX 912)
`
`Laohavinij, et al., A Phase I clinical study of the antipurine
`antifolate lometrexol (DDATHF) given with oral folic acid,
`INVESTIGATIONAL NEW DRUGS, 14: 325-335 (1996) (TX 1036)
`
`Mendelsohn, et al., Preclinical and Clinical Evaluation of the
`Glycinamide Ribonucleotide Formyltransferase Inhibitors
`Lometrexol and LY306887, ANTICANCER DRUG DEVELOPMENT
`GUIDE: ANTIFOLATE DRUGS IN CANCER THERAPY, (Jackman:
`Editor) Chapter 12: 261-280 (1999) (TX 400)
`
`v
`
`Lilly Ex. 2013 pg. 6
`Sandoz v. Lilly IPR2016-00318
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`Case 1:10-cv-01376-TWP-DKL Document 333 Filed 12/17/13 Page 7 of 24 PageID #: 8211
`
`Abbreviation
`
`Document Description
`
`“Niyikiza”
`
`Niyikiza, et al., MTA (LY231514): Relationship of vitamin
`metabolite profile, drug exposure, and other patient
`characteristics to toxicity, ANNALS OF ONCOLOGY, Abstract
`609P, 9 (Suppl 4): 125-140 (1998) (TX 911)
`Niyikiza, et al., LY231514 (MTA): Relationship of vitamin
`metabolite profile to toxicity, PROCEEDINGS OF THE AMERICAN
`ASSOCIATION FOR CANCER RESEARCH, Abstract 2139, 17:
`558a (1998) (TX 910)
`
`“Methotrexate PDR” Physicians’ Desk Reference for Methotrexate (1999) (TX
`1374)
`
`“Rinaldi”
`
`“Rusthoven”
`
`“Shih”
`
`Rinaldi, et al., A phase I evaluation of LY231514, a novel
`multitargeted antifolate, administered every 21 days,
`AMERICAN SOCIETY OF CLINICAL ONCOLOGY, 15: 489,
`Abstract 1559 (TX 1303)
`
`Rusthoven, et al. Multitargeted Antifolate LY231514 as a
`First-Line Chemotherapy for Patients With Advanced Non-
`Small-Cell Lung Cancer: A Phase II Study, JOURNAL OF
`CLINICAL ONCOLOGY, 17(4): 1194-1199 (1999) (TX 78)
`
`Shih et al., Preclinical Pharmacology Studies and the Clinical
`Development of a Novel Multitargeted Antifolate, MTA
`(LY231514), ANTICANCER DRUG DEVELOPMENT GUIDE:
`ANTIFOLATE DRUGS IN CANCER THERAPY, (Jackman: Editor)
`Chapter 8:183-201 (1999) (TX 1152)
`
`“Tomudex data
`sheet”
`
`ABPI Compendium of Data Sheets and Summaries of Product
`Characteristics (1998) (TX 1035)
`
`“Vidal”
`
`“Worzalla”
`
`Vidal, The Dictionary, 74th ed. (1998) (TX 915)
`
`Worzalla, et al., Role of Folic Acid in Modulating the Toxicity
`and Efficacy of the Multitargeted Antifolate, LY231514,
`ANTICANCER RESEARCH, 18: 3235-3240 (1998) (TX 384)
`Worzalla, et al., Effects of folic acid on toxicity and antitumor
`activity of LY231514 multi-targeted antifolate (MTA),
`PROCEEDINGS OF THE AMERICAN ASSOCIATION FOR CANCER
`RESEARCH, Abstract 3198, Eighty-eighth Annual Meeting,
`April 12-16, 1997, Volume 38, March 1997 (TX 1495)
`
`vi
`
`Lilly Ex. 2013 pg. 7
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`Case 1:10-cv-01376-TWP-DKL Document 333 Filed 12/17/13 Page 8 of 24 PageID #: 8212
`
`Lilly’s post-trial arguments are insufficient to save the validity of the ‘209 patent-in-suit.
`
`Rather than directly addressing and responding to the strong arguments for obviousness-type
`
`double patenting (“OTDP”) and obviousness presented by Defendants, Lilly ignores much of the
`
`evidence and instead expressly attacks its own prior art published throughout the 1990s
`
`regarding the use of vitamins, including folic acid and vitamin B12, with its antifolates. Lilly
`
`first attempts this tactic in response to Defendants’ ‘974 patent OTDP argument – contending
`
`that a POSA would not even use pemetrexed with folic acid pretreatment as claimed in the ‘974
`
`patent. The evidence at trial was to the contrary: pemetrexed falls within the scope of the ‘974
`
`patent and was the most promising of all antifolates -- a POSA would have used it with the
`
`invention of the ‘974 patent.
`
`Similarly, Lilly responds to Defendants’ obviousness argument by characterizing the
`
`prior art in a manner inconsistent with its own prior art publications. For example, Lilly takes
`
`the position that pemetrexed’s toxicity was not an issue, even though it previously published
`
`ways to reduce toxicity (including with vitamins). Lilly also argues that Worzalla teaches away
`
`from folic acid supplementation with pemetrexed, despite the fact that Worzalla itself concluded
`
`that folic acid supplementation may enhance pemetrexed’s clinical profile. In addition, Lilly’s
`
`nonobviousness argument also hinges on a misapplication of the law of obviousness. Contrary
`
`to Lilly’s argument, the Federal Circuit recently reaffirmed that obviousness simply does not
`
`require a “lead reference” or starting point.
`
`Finally, Lilly responds to Defendants’ attack on the sufficiency of information regarding
`
`“effective amounts” of pemetrexed in the ‘209 patent specification by pointing to vague,
`
`unsupported statements in the ‘209 patent, prior art references without vitamins, and an
`
`antifolate regimen that does not even pertain to pemetrexed. If Lilly’s interpretation of the prior
`
`Lilly Ex. 2013 pg. 8
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`Case 1:10-cv-01376-TWP-DKL Document 333 Filed 12/17/13 Page 9 of 24 PageID #: 8213
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`art is correct (and the ‘209 patent is not obvious), then the use of an effective amount of
`
`pemetrexed with vitamins lacks written description and is not enabled.
`
`I.
`
`LILLY HAS FAILED TO REBUT DEFENDANTS’ CLEAR AND CONVINCING
`EVIDENCE THAT THE CLAIMS ARE INVALID FOR OBVIOUSNESS-TYPE
`DOUBLE PATENTING
`
`Lilly’s prior art ‘974 patent claims administering certain antifolates with folic acid
`
`pretreatment. Lilly now acknowledges that the claims of the ‘974 patent “technically” cover
`
`pemetrexed. Pl. Br. 54. There is thus no longer any dispute that claim 20 of the ‘974 patent
`
`covers the use of folic acid pretreatment with pemetrexed. The asserted claims of the ‘209 patent
`
`merely add vitamin B12 pretreatment and specify obvious doses of folic acid. The ‘209 patent
`
`claims extend the coverage of the ‘974 patent and OTDP renders it invalid.
`
`Lilly’s argument that a POSA would not select pemetrexed from among the compounds
`
`covered by claim 20 of the ‘974 patent lacks support in both the law and the facts. Lilly fails to
`
`cite a single case that stands for the proposition that Defendants must establish that the POSA
`
`would select pemetrexed as the best of the claimed compounds for the method of use claimed in
`
`the ‘974 patent in the context of OTDP. Regardless, as a matter of fact, Defendants did establish
`
`that by the critical date a POSA would have focused on pemetrexed. Defs. Br. 38. All parties
`
`agree that by June 1999, pemetrexed was the single most promising antifolate in the literature.1
`
`Lilly’s argument that a POSA, even if interested in pemetrexed, would not use it with
`
`folic acid because of the Hammond study, Pl. Br. 54, must be rejected. As explained below,
`
`Lilly’s interpretations of its own publications are simply wrong; the results of Hammond would
`
`have been viewed favorably by a POSA in June 1999. Defs. Br. 21-23; infra, p. 6. Moreover,
`
`Lilly’s argument would require the court to conclude that a POSA would read the ‘974 patent;
`
`1 Lilly’s argument that a POSA would still have focused on lometrexol, Pl. Br. at 55, is
`inconsistent with Lilly’s simultaneous position that a POSA would have thought that this
`compound had been abandoned by June 1999. Tr. 66-67; Chabner Tr. 1304-05.
`
`2
`
`Lilly Ex. 2013 pg. 9
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`Case 1:10-cv-01376-TWP-DKL Document 333 Filed 12/17/13 Page 10 of 24 PageID #: 8214
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`understand that the claims cover the administration of pemetrexed with folic acid pretreatment;
`
`and further understand that the ‘974 patent states that toxic effects of the covered compounds
`
`(including pemetrexed) “can be significantly reduced by the presence of [folic acid], without
`
`adversely affecting therapeutic efficacy,” (TX 916 at 1:46-58)(emphasis added); but, despite this,
`
`still conclude that the POSA would refuse to use the claimed regimen for fear it “would hurt
`
`pemetrexed’s efficacy.” Pl. Br. 54. The evidence taught that a POSA would have reason to use
`
`folic acid pretreatment with pemetrexed in the ‘974 patent claims. Defs. Br. 18-26. Adding
`
`vitamin B12 does not render the claims patentably distinct from the ‘974 patent. Id. at 38.
`
`The specific doses and schedules also do not save the asserted claims from OTDP. The
`
`doses and schedules for administering folic acid and vitamin B12 were among the most
`
`commonly used ones as of June 1999.2 Defs. Br. 31-32. Moreover, with respect to folic acid
`
`specifically, Lilly does not dispute that both the claims and the specification of the ‘974 patent
`
`can be used for OTDP. Pl. Br. 53; Defs. Br. 38. The claimed schedule for administering folic
`
`acid in the ‘209 patent is obvious because it is explicitly disclosed in the ‘974 patent. Defs. Br.
`
`39. And there is no dispute that the doses of folic acid in claim 20 of the ‘974 patent overlap
`
`with those claimed in the asserted ‘209 patent claims – 350 to 600 µg and 350 to 1000 µg. Thus,
`
`the claimed dose range in the ‘209 patent is obvious. Ormco Corp. v. Align Tech. Inc., 463 F.3d
`
`1299, 1311 (Fed. Cir. 2006) (“[W]here a claimed range overlaps with a range disclosed in the
`
`prior art, there is a presumption of obviousness.”). As there is no patentable distinction between
`
`the asserted claims and claim 20 of the ‘974 patent, the asserted claims are invalid for OTDP.
`
`
`2 Lilly attempts to rebut the presumption of obviousness as to the doses of folic acid by arguing
`“unexpected results.” Pl. Br. 55, n.14. As discussed in Defendants’ opening brief, there is
`nothing critical, let alone “unexpectedly” critical, about the folic acid dose and schedule claimed
`in the ‘209 patent. Defs. Br. 44-46. Moreover, there is nothing unexpected in optimizing the
`ranges of folic acid doses. In re Hasse, 2013 WL 5813645, at *4 (Fed. Cir. Oct. 30, 2013)
`(“[E]ven a slight overlap in range establishes a prima facie case of obviousness.”).
`
`3
`
`Lilly Ex. 2013 pg. 10
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`II.
`
`LILLY DOES NOT ADDRESS MUCH OF THE EVIDENCE ADDUCED AT
`TRIAL ON OBVIOUSNESS
`
`The evidence at trial established that a POSA would understand that chemotherapy agents
`
`in general, and antifolates in particular, are about balance – about finding a way to hit the cancer
`
`cells hard while sparing the healthy cells. Defs. Br. 2-3, 21; see also Ratain Tr. 1730-32. While
`
`doctors would understand that, in theory, it is the same antifolate effect that results in both
`
`anticancer activity (killing cancer cells) and toxicity (killing healthy cells), the goal is to find a
`
`way to increase the activity in cancer cells while reducing or limiting the impact on healthy cells.
`
`Defs. Br. 3-5, 25-26. This concept underlies the entire idea of chemotherapy – the reason
`
`chemotherapy drugs work to treat cancer is that they have more of an impact on cancer cells than
`
`healthy cells. When analyzing the prior art as a whole, a POSA would have a reason to combine
`
`the already disclosed pemetrexed–folic acid pretreatment regimen, as taught by Hammond and
`
`Worzalla, with vitamin B12 pretreatment, and the POSA would reasonably expect some
`
`therapeutic benefit from that combination. Id. at 12-35. The preclinical and clinical results Lilly
`
`published in the prior art support that folic acid pretreatment could reduce pemetrexed’s toxicity,
`
`without compromising its efficacy. Id. at 18-26. There was ample evidence that vitamin B12
`
`pretreatment could further reduce the toxicity of pemetrexed, while preserving pemetrexed’s
`
`efficacy. Id. at 14-18, 26-29. And once a POSA arrived at the decision to give both vitamins
`
`with pemetrexed, it would have been obvious to select the claimed doses and schedules for
`
`administering folic acid and vitamin B12 – all of which were widely published. Id. at 29-33.
`
`Lilly’s brief clarifies that many of the factual issues on which the Court heard evidence
`
`are no longer in dispute. For example, Lilly no longer takes issue with the definition of a POSA
`
`previously adopted by the Court: a POSA can be a medical doctor with expertise in nutrition,
`
`who is working with an oncologist. Defs. Br. 12, n. 4. Therefore, the testimony of Dr. Morgan
`
`4
`
`Lilly Ex. 2013 pg. 11
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`and her work can be relied on in the Court’s obviousness analysis. See id. at 17-18. Moreover,
`
`although Lilly asks the Court to ignore nutritional literature regarding the use of vitamin B12 and
`
`specific doses and schedules for administering folic acid and vitamin B12 to reduce
`
`homocysteine levels (Pl. Br. 40-41), the relevance of this literature should no longer be in
`
`dispute. Lilly also does not disagree that a POSA would have a reasonable expectation of
`
`success: a POSA would expect that administering pemetrexed, folic acid, and vitamin B12 as
`
`claimed would result in some therapeutic benefit to a patient. Defs. Br. 33-35; see Pl. Br. 13-14.
`
`Lilly’s response to Defendants’ obviousness position is built on a foundation of sand
`
`focused on the question of motivation. Pl. Br. 1. Lilly’s argument relies on the following
`
`incorrect factual conclusions: (1) that a POSA would have been focused solely on pemetrexed’s
`
`efficacy; (2) that a POSA would begin with the assumption that adding folic acid to an antifolate
`
`will irreparably damage the activity of all antifolates, including pemetrexed; (3) that the
`
`comparison of the Hammond and Rinaldi references confirms this assumption; (4) that the
`
`conclusion of Worzalla is not to the contrary; and (5) that a POSA will question the conclusions
`
`Lilly actually published in the 1990s. The Court should reject each of these proposed findings.
`
`1.
`
`Lilly’s suggestion that the only thing that a POSA would have been concerned
`
`with was an antifolate’s efficacy, but not its toxicity (Pl. Br. 16), is contradicted by Lilly’s
`
`repeated publications. Lilly itself sought to reduce the toxicity of not only the ‘887 compound
`
`and lometrexol, but also pemetrexed itself. Defs. Br. 4-11. Whether or not pemetrexed was
`
`“safe and tolerable” without vitamins, a POSA would have recognized that Lilly’s prior art
`
`encouraged the use of vitamins to further reduce the toxicity associated with pemetrexed.3 Id.
`
`
`3 Moreover, the evidence at trial did establish that, like all antifolates, pemetrexed had significant
`toxicity issues that motivated a POSA to use vitamins. Ratain Tr. 121, 126-27; Green Tr. 464,
`468, 555-56; Chabner Tr. 1225-29; 1236. Rusthoven, for example, teaches a POSA that 30% of
`
`5
`
`Lilly Ex. 2013 pg. 12
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`Case 1:10-cv-01376-TWP-DKL Document 333 Filed 12/17/13 Page 13 of 24 PageID #: 8217
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`2 & 3. Lilly concludes that Hammond demonstrates that folic acid pretreatment reduces
`
`pemetrexed’s efficacy, and that a POSA would therefore never pursue this regimen. Pl. Br. 20-
`
`25. This conclusion is based on a scientifically improper comparison between the Hammond and
`
`Rinaldi abstracts. Defs. Br. 21-24. As Dr. Ratain explained, a POSA does not numerically
`
`compare the results in Phase I clinical trials because many differences, other than for example
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`the administration of folic acid, could explain the differences in these trials. Ratain Tr. 111-13,
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`172-73, 1689. Dr. Ratain gave a specific example of a potential difference between the
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`Hammond and Rinaldi studies – because the studies were conducted years apart, the subjects
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`may have been subjected to different pretreatments. Id. 1692-95 (explaining that it was likely
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`that more patients in Hammond received irenotecan pretreatment). Moreover, Lilly’s tortured
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`reading of Hammond’s results as negative is inconsistent with the fact that (1) Lilly continued to
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`pursue the Hammond regimen after Hammond was published (Chabner Tr. 1051-53; TX 912);
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`(2) Hammond itself does not suggest that pemetrexed reduced efficacy; and (3) Lilly’s own
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`expert Dr. Chabner volunteered that even the single response seen in Hammond was promising,
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`based on the published research of Dr. von Hoff. Chabner Tr. 1185-89.
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`4.
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`Lilly also asks the Court to misread the Worzalla reference. Lilly’s position that
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`Worzalla would have confirmed a POSA’s concerns that folic acid pretreatment could have a
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`deleterious effect on pemetrexed’s efficacy, and that the data in Worzalla is otherwise flawed, is
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`flatly contradicted by Worzalla itself. Defs. Br. 18-21. Worzalla concluded that “folate intake
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`can be manipulated to achieve greater therapeutic effects,” that “[f]olic acid supplementation was
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`the patients dropped out of the clinical trial due to the severity of toxicity associated with
`pemetrexed alone even after the dose was reduced. TX 78 at 1198. Calvert and Walling
`conclude their paper by informing the public that studies are also underway “to investigate the
`effect of folate on the toxicities seen with MTA, based on the observation that animals given
`folate supplements were better able to tolerate treatment with MTA, with fewer side-effects
`(Worzalla et al, 1997).” TX 1006 at 39.
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`6
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`demonstrated to preserve the antitumor activity of [pemetrexed] while reducing toxicity,” and
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`that “[t]he combination of folic acid with [pemetrexed] may provide a mechanism for enhanced
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`clinical antitumor selectivity.” TX 384 at 3235, 3238. Worzalla was repeatedly cited for these
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`propositions by a number of prior art publications. Defs. Br. 18-21. Moreover, Lilly’s
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`interpretation of Worzalla is flawed and incomplete because it refuses to consider all of the data
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`in Worzalla – particularly, the data concerning the standard diet mice (Pl. Br. 28), which shows
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`that pemetrexed’s efficacy did not change while its toxicity was reduced in mice with the highest
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`levels of folate compared to those on the standard diet. Defs. Br. 19. Lilly’s request that the
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`Court ignore the findings and conclusions in Worzalla should be dismissed.
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`5.
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`Lilly even treats the findings in Dr. Niyikiza’s prior art abstracts (that provided
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`the idea to use vitamins with pemetrexed) as meaningless. Pl. Br. 31, 39-40. Lilly argues for
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`example that Dr. Niyikiza’s abstracts do not support the use of folic acid and vitamin B12
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`pretreatment with pemetrexed.4 Pl. Br. 29-30. These arguments ignore prior art citing Dr.
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`Niyikiza’s abstracts, including literature published by Dr. Calvert and Dr. O’Dwyer for the
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`proposition that nutritional deficiencies, including folate5 and vitamin B12 deficiencies, could
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`impact pemetrexed’s toxicity. Defs. Br. 7-8, 16; TX 401 at 8-9; TX 1151 at 103. Lilly also
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`ignores that the logic of Dr. Niyikiza’s results extends to Mendelsohn, which states that in
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`addition to requiring folic acid, “[t]he biochemical pathways that utilize folate cofactors also
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`require adequate amounts of vitamins B12 and B6,” and that “the status of all three vitamins in
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`patients may significantly influence the severity of toxicity observed during chemotherapy.”
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`4 Lilly even goes so far as to argue that these abstracts teach that folic acid pretreatment would be
`expected to reduce pemetrexed’s efficacy. Pl. Br. 29-32. But no references that discuss Dr.
`Niyikiza’s abstracts ever interprets the data to disfavor supplementation.
`5 Lilly’s own consultant testified that once the correlation published by Niyikiza was known,
`supplementation with folic acid was one “fairly obvious” approach to “probably everyone who
`saw the data [showing the homocysteine correlation].” Calvert Dep. Tr. 40-41.
`
`7
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`TX 400 at 270. The prior art provides motivation to use vitamin B12 with the pemetrexed-folic
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`acid pretreatment disclosed in the prior art – once the correlation of homocysteine levels and
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`pemetrexed toxicity was disclosed, a POSA would administer folic acid and vitamin B12.
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`III.
`
`LILLY MISSTATES AND MISAPPLIES THE LAW OF OBVIOUSNESS IN
`ATTEMPTING TO DEFEND THE NON-OBVIOUSNESS OF THE ‘209 PATENT
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`Lilly not only asks the Court to reach incorrect factual conclusions, it also repeatedly
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`relies upon misstatements of the law of obviousness. Lilly devises a new “lead reference”
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`argument in which Defendants need to provide a reason to start with Worzalla and Hammond –
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`the use of folic acid pretreatment with pemetrexed. But the Federal Circuit has recently
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`reaffirmed that Defendants need not do so. See Galderma Labs., L.P. v. Tolmar, Inc., No. 2013-
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`1034, 2013 WL 6483704, *4 (Fed. Cir. Dec. 11, 2013). And Lilly asks the Court to make other
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`legal errors, such as applying an outdated explicit “teaching, suggesting, motivation” (“TSM”)
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`standard for motivation to combine the prior art, incorrectly addressing the question of whether
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`there has been any “teaching away,” and failing to consider the prior art as a whole.
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`A.
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`Lilly Attempts To Improperly Create A “Lead Reference” Requirement
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`Defendants’ obviousness defense starts with Hammond or Worzalla, which disclose the
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`use of folic acid pretreatment with pemetrexed. Lilly proposes that Defendants have the burden
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`to establish a motivation for selecting a “lead reference” for the claims to be obvious. Pl. Br. 14.
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`That is wrong. The Federal Circuit has applied such a standard only in very limited
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`circumstances, when a party argues that a claim to a new chemical compound is obvious based
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`upon the structure of the molecule itself. See Pl. Br. 14-15; Eisai Co. Ltd. v. Dr. Reddy’s Labs.,
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`Ltd., 533 F.3d 1353, 1359 (Fed. Cir. 2008) (“[P]ost-KSR, a prima facie case of obviousness for a
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`chemical compound still, in general, begins with the reasoned identification of a lead
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`compound.”) (emphasis added). Cases analyzing the obviousness of a method of use patent do
`
`8
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`Lilly Ex. 2013 pg. 15
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`not require evidence concerning a starting point. See Daiichi Sankyo Co. v. Apotex, Inc., 501
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`F.3d 1254, 1257-59 (Fed. Cir. 2007); Eli Lilly & Co. v. Teva Pharm. USA, Inc., 619 F.3d 1329,
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`1333-37 (Fed. Cir. 2010). The Federal Circuit recently reiterated that alleged infringers must
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`show that “the differences between the claimed invention and the prior art are such that the
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`claimed invention as a whole would have been obvious,” but that this does not include the
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`additional burden that Lilly proposes. Galderma, 2013 WL 6483704 at *4.
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`Building on the incorrect premise that Defendants must prove a reason to start with
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`Worzalla or Hammond, Lilly again divorces its arguments from the law by arguing that a POSA
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`would have started with pemetrexed alone “because that is what the POSA would have preferred
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`to use.” Pl. Br. 15. As Defendants already explained, the obviousness inquiry is not confined to
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`what a POSA “preferred,” but rather includes all potential solutions to related problems. Defs.
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`Br. 36; see also Galderma, 2013 WL 6483704 at *6 (“A teaching that a composition may be
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`optimal or standard does not criticize, discredit, or otherwise discourage investigation into other
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`compositions.”); Bayer Healthcare Pharms., Inc. v. Watson Pharms., Inc., 713 F.3d 1369, 1376
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`(Fed. Cir. 2013); In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994). If vitamin supplementation
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`was one of a few potential solutions for addressing pemetrexed’s toxicity, a POSA would have
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`been motivated to use that solution. See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007).
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`Clear and convincing evidence establishes that a POSA would have been motivated to use the