Case 1:10-cv-01376-TWP-DKL Document 331 Filed 10/11/13 Page 1 of 63 PageID #: 8065
`
`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’ OPENING POST-TRIAL BRIEF REGARDING
`THE INVALIDITY OF U.S. PATENT NO. 7,772,209
`
`Lilly Ex. 2003 pg. 1
`Sandoz v. Lilly IPR2016-00318
`
`

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`Case 1:10-cv-01376-TWP-DKL Document 331 Filed 10/11/13 Page 2 of 63 PageID #: 8066
`
`TABLE OF CONTENTS
`
`Page
`
`TABLE OF AUTHORITIES..........................................................................................................iv
`
`TABLE OF ABBREVIATIONS...................................................................................................vii
`
`INTRODUCTION...........................................................................................................................1
`
`STATEMENT OF FACTS..............................................................................................................2
`
`I.
`
`II.
`
`The Science Of Folates And Antifolates .................................................................2
`
`The Public History Of The Development Of Antifolates With Vitamins...............3
`
`A.
`
`B.
`
`Lilly Conceives Of, Patents, And Publishes In The Prior Art The
`Idea To Use Folic Acid Supplementation With Its Antifolates In The
`1990s............................................................................................................4
`
`Dr. Niyikiza’s Research Regarding Predicting, And Finding Ways
`Of Reducing, Pemetrexed’s Toxicity Was Disclosed To The Public .........5
`
`1.
`
`2.
`
`3.
`
`Dr. Niyikiza’s Conclusions Were Published Before A Patent
`Application Was Filed.....................................................................6
`
`Preclinical And Clinical Studies Disclosed Using Folic Acid
`With Pemetrexed .............................................................................8
`
`Additional Information Was Publicly Known About
`Pemetrexed’s Promising Activity And Toxicity Profile As Of
`June 1999.......................................................................................10
`
`III.
`
`The ‘209 Patent And Litigation.............................................................................11
`
`INVALIDITY OF THE ASSERTED CLAIMS OF THE ‘209 PATENT ....................................12
`
`I.
`
`Each Of The Asserted Claims Of The ‘209 Patent Is Obvious .............................12
`
`A.
`
`B.
`
`Worzalla Or Hammond Teach The Use Of Folic Acid Pretreatment
`With Pemetrexed .......................................................................................13
`
`A POSA Would Be Motivated To Add Vitamin B12 To The Folic
`Acid Pretreatment Regimen Taught In Worzalla Or Hammond ...............14
`
`1.
`
`A POSA Would Be Motivated To Add Vitamin B12
`Pretreatment To Reduce Pemetrexed-Related Toxicity ................15
`
`i
`
`Lilly Ex. 2003 pg. 2
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`Case 1:10-cv-01376-TWP-DKL Document 331 Filed 10/11/13 Page 3 of 63 PageID #: 8067
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`2.
`
`A POSA Would Be Motivated To Add Vitamin B12
`Pretreatment For Additional Reasons............................................17
`
`C.
`
`A POSA Would Not Have Been Motivated To Remove The Folic
`Acid Pretreatment Regimen Taught In Worzalla or Hammond................18
`
`1.
`
`2.
`
`3.
`
`4.
`
`Worzalla Confirms The Benefits Of Folic Acid
`Supplementation............................................................................18
`
`Hammond Does Not Teach That Folic Acid Supplementation
`Decreases Pemetrexed’s Efficacy..................................................21
`
`The ‘974 Patent Teaches A POSA That Folic Acid
`Supplementation Is Beneficial To Pemetrexed Therapy...............24
`
`Theoretical Concerns Regarding Folic Acid’s Impact On
`Pemetrexed’s Efficacy Would Not Discourage A POSA
`From Practicing Folic Acid Pretreatment With Pemetrexed.........25
`
`The Prior Art Did Not Teach Away From Adding Vitamin B12 To
`The Folic Acid Pretreatment Regimen Of Worzalla Or Hammond ..........26
`
`The Claimed Doses And Schedules For Administering Folic Acid
`And Vitamin B12 Do Not Confer Any Novelty To The ‘209 Patent
`Claims........................................................................................................29
`
`1.
`
`2.
`
`The Claimed Doses Of Folic Acid And Vitamin B12 Are
`Obvious..........................................................................................31
`
`The Claimed Schedules For Administering Folic Acid And
`Vitamin B12 Are Obvious.............................................................33
`
`A POSA Would Have A Reasonable Expectation Of Success That
`The Claimed Pretreatment Regimen Would Provide A Therapeutic
`Benefit .......................................................................................................33
`
`Lilly’s Argument That A POSA Would Have Used Other Methods
`Of Reducing Pemetrexed’s Toxicity In Place Of Folic Acid And
`Vitamin B12 Supplementation Is Both Factually And Legally Wrong.....35
`
`D.
`
`E.
`
`F.
`
`G.
`
`II.
`
`III.
`
`Each Asserted Claim Is Invalid For Obviousness-Type Double Patenting...........36
`
`Secondary Considerations Do Not Support The Nonobviousness Of The
`Claimed Methods Of Use ......................................................................................39
`
`A.
`
`Lilly’s Evidence Of Skepticism Is Entitled To Little, If Any, Weight......40
`
`ii
`
`Lilly Ex. 2003 pg. 3
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`Case 1:10-cv-01376-TWP-DKL Document 331 Filed 10/11/13 Page 4 of 63 PageID #: 8068
`
`1.
`
`2.
`
`3.
`
`The FDA’s Statements Regarding Lilly’s Compliance With
`Federal Regulations Is Not Relevant Evidence Of Skepticism.....40
`
`Lilly Represented To The FDA That It And Its External
`Consultants Were Not Skeptical About The Efficacy Of The
`Claimed Methods...........................................................................41
`
`Statements By Lilly’s Litigation Experts Years After The
`Relevant Date Are Not Probative Of Skepticism ..........................42
`
`B.
`
`There is No Evidence That The Asserted Claims Have Unexpected
`Results Or Properties.................................................................................43
`
`1.
`
`2.
`
`The Closest Prior Art Is The Folic Acid Regimen Disclosed
`In The Hammond Study ................................................................43
`
`The Claimed Regimen Has No Unexpected Results Or
`Properties Over The Hammond regimen.......................................44
`
`IV.
`
`The Asserted Claims Of The ‘209 Patent Do Not Meet The Requirements
`Of 35 U.S.C. § 112, First Paragraph......................................................................46
`
`A.
`
`B.
`
`The Asserted ‘209 Patent Claims Are Not Adequately Described............47
`
`The Asserted ‘209 Patent Claims Are Not Enabled ..................................48
`
`CONCLUSION .............................................................................................................................50
`
`iii
`
`Lilly Ex. 2003 pg. 4
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`Case 1:10-cv-01376-TWP-DKL Document 331 Filed 10/11/13 Page 5 of 63 PageID #: 8069
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`CASES
`
`Alcon Research, Ltd. v. Apotex Inc.,
`687 F.3d 1362 (Fed. Cir. 2012) ...............................................................................................34
`
`Allergan, Inc., v. Sandoz Inc.,
`726 F.3d 1286 (Fed. Cir. 2013) ...................................................................................12, 14, 40
`
`Allergan Inc. v. Watson Labs,
`869 F. Supp. 2d 456 (D. Del. 2012) ........................................................................................42
`
`Ariad Pharms., Inc. v. Eli Lilly & Co.,
`598 F.3d 1336 (Fed. Cir. 2010) (en banc)...............................................................................47
`
`AstraZeneca Pharms. LP v. Teva Pharms. USA, Inc.,
`583 F.3d 766 (Fed. Cir. 2009) .................................................................................................43
`
`Aventis Pharma Deutschland GmbH v. Lupin, Ltd.,
`499 F.3d 1293 (Fed. Cir. 2007) ...............................................................................................27
`
`Bayer Healthcare Pharms., Inc. v. Watson Pharms. Inc.,
`713 F.3d 1369 (Fed. Cir. 2013) .........................................................................................36, 40
`
`Bayer Schering Pharma AG v. Barr Labs., Inc.,
`575 F.3d 1341 (Fed. Cir. 2009) ...............................................................................................14
`
`Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc.,
`923 F. Supp. 2d 602 (D. Del. 2013) ..................................................................................42, 43
`
`DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc.,
`567 F.3d 1314 (Fed. Cir. 2009) ...............................................................................................21
`
`Dow Jones & Co. v. Ablaise Ltd.,
`606 F.3d 1338 (Fed. Cir. 2010) ...............................................................................................41
`
`Eli Lilly & Co. v. Barr Labs., Inc.,
`251 F.3d 955 (Fed. Cir. 2001) .................................................................................................37
`
`Fina Oil & Chem. Co. v. Ewen,
`123 F.3d 1466 (Fed. Cir. 1997) ...............................................................................................31
`
`Geneva Pharms., Inc. v. GlaxoSmithKline PLC,
`349 F.3d 1373 (Fed. Cir. 2003) ...............................................................................................36
`
`Georgia-Pacific Corp. v. U.S. Gypsum Co.,
`195 F.3d 1322 (Fed. Cir. 1999) ..........................................................................................37-38
`
`iv
`
`Lilly Ex. 2003 pg. 5
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`

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`Case 1:10-cv-01376-TWP-DKL Document 331 Filed 10/11/13 Page 6 of 63 PageID #: 8070
`
`In re Carlson,
`983 F.3d 1032 (Fed. Cir. 1992) ...............................................................................................12
`
`In re Droge,
`695 F.3d 1334 (Fed. Cir. 2012) ...............................................................................................34
`
`In re Gardner,
`427 F.2d 786 (C.C.P.A. 1970).................................................................................................50
`
`In re Gentile,
`No. 93-1086, 1993 WL 393318 (Fed. Cir. Oct. 5, 1993) ........................................................30
`
`In re Gurley,
`27 F.3d 551 (Fed. Cir. 1994) ...................................................................................................36
`
`In re Huang,
`100 F.3d 135 (Fed. Cir. 1996) .................................................................................................43
`
`In re Lonardo,
`119 F.3d 960 (Fed. Cir. 1997) .................................................................................................36
`
`In re Merchant,
`575 F.2d 865 (C.C.P.A. 1978).................................................................................................43
`
`In re Wands,
`858 F.2d 731 (Fed. Cir. 1988) .....................................................................................48, 49, 50
`
`In re Woodruff,
`919 F.2d 1575 (Fed. Cir. 1990) ...............................................................................................30
`
`In re Young,
`927 F.2d 588 (Fed. Cir. 1991) .................................................................................................29
`
`Innovention Toys, LLC v. MGA Entm’t, Inc.,
`637 F.3d 1314 (Fed. Cir. 2011) .........................................................................................18, 32
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) .........................................................................................................passim
`
`Merck & Co., Inc. v. Biocraft Labs., Inc.,
`874 F.2d 804 (Fed. Cir. 1989) .................................................................................................30
`
`Milliken Research Corp. v. Dan River, Inc.,
`739 F.2d 587 (Fed. Cir. 1984) .................................................................................................30
`
`Nartron Corp. v. Schukra U.S.A. Inc.,
`558 F.3d 1352 (Fed. Cir. 2009) ...............................................................................................31
`
`v
`
`Lilly Ex. 2003 pg. 6
`Sandoz v. Lilly IPR2016-00318
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`

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`Case 1:10-cv-01376-TWP-DKL Document 331 Filed 10/11/13 Page 7 of 63 PageID #: 8071
`
`Novo Nordisk A/S v. Caraco Pharm. Labs., Ltd.,
`719 F.3d 1346 (Fed. Cir. 2013) ...................................................................................14, 43, 48
`
`Ormco Corp. v. Align Tech. Inc.,
`463 F.3d 1299 (Fed. Cir. 2006) ...............................................................................................38
`
`Perricone v. Medicis Pharm. Corp.,
`432 F.3d 1368 (Fed. Cir. 2005) ...............................................................................................36
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .........................................................................................13, 40
`
`Pharmastem Therapeutics, Inc. v. Viacell, Inc.,
`491 F.3d 1342 (Fed. Cir. 2007) .........................................................................................30, 34
`
`Santarus, Inc. v. Par Pharm., Inc.,
`720 F.Supp.2d 427 (D. Del. 2010) ....................................................................................42, 43
`
`Tyco Healthcare Grp. LP v. Mutual Pharm. Co., Inc.,
`642 F.3d 1370 (Fed. Cir. 2011) ...............................................................................................41
`
`STATUTES
`
`35 U.S.C. § 103 ...............................................................................................................................1
`
`35 U.S.C. § 112 .........................................................................................................................2, 46
`
`vi
`
`Lilly Ex. 2003 pg. 7
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`

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`Case 1:10-cv-01376-TWP-DKL Document 331 Filed 10/11/13 Page 8 of 63 PageID #: 8072
`
`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.,
`
`“Lilly”/”Eli Lilly”
`
`Eli Lilly and Company
`
`“Asserted Claims”
`
`Claims 9, 10, 12, 14, 15, 18, 19, and 21 of the ‘209 patent
`
`“POSA”
`
`“TX”
`
`“DTX”
`
`Person of ordinary skill in the art
`
`Trial Exhibit
`
`Demonstrative
`
`Testimony
`
`“Ratain Tr.”
`
`“Green Tr.”
`
`Trial testimony of Dr. Mark J. Ratain
`
`Trial testimony of Dr. Ralph Green
`
`“Morgan Tr.”
`
`Trial testimony of Dr. Sarah L. Morgan
`
`“Schulz Tr.”
`
`Trial testimony of Thomas K. Schulz
`
`“Niyikiza Tr.”
`
`Trial testimony of Clet Niyikiza
`
`“Chabner Tr.”
`
`Trial testimony of Dr. Bruce A. Chabner
`
`“O’Dwyer Tr.”
`
`Trial testimony of Dr. Peter O’Dwyer
`
`“Cupps Tr.”
`
`“Zeisel Tr.”
`
`Trial testimony of Dr. Thomas R. Cupps
`
`Trial testimony of Dr. Steven H. Zeisel
`
`“Calvert Dep. Tr.”
`
`Deposition testimony of Dr. A. Hilary Calvert
`
`“Dorr Dep. Tr.”
`
`Deposition testimony of Dr. F. Andrew Dorr
`
`“Rusthoven Dep.
`Tr.”
`
`Deposition testimony of Dr. James Rusthoven
`
`vii
`
`Lilly Ex. 2003 pg. 8
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`Case 1:10-cv-01376-TWP-DKL Document 331 Filed 10/11/13 Page 9 of 63 PageID #: 8073
`
`Abbreviation
`
`Document Description
`
`“Stuglik Dep. Tr.”
`
`30(b)(1) Deposition testimony of Mr. Brian Stuglik
`
`“Thornton Dep. Tr.” Deposition testimony of Dr. Donald Thornton
`
`“Worzalla 2010 Dep.
`Tr.”
`
`March 19, 2012 deposition testimony of Mr. John Worzalla
`(Case No. 08-CV-335-GMS (D. Del))
`
`“Worzalla 2012 Dep.
`Tr.”
`
`November 8, 2012 deposition testimony of Mr. John Worzalla
`(Case No. 10-CV-1376-TWP-DML)
`
`Patents
`
`U.S. Patent No. 7,772,209 (TX 1)
`
`“the ‘209
`patent”/”patent-in-
`suit”
`
`“the ‘126 patent”
`
`U.S. Patent No. 5,563,126 (TX 15)
`
`“the ‘974 patent”
`
`U.S. Patent No. 5,217,974 (TX 916)
`
`Compounds, Enzymes, and Conferences
`
`“Pemetrexed”/
`“MTA”/“LY231514”
`
`Pemetrexed/Pemetrexed disodium
`
`“the ‘887
`compound”
`
`“FBP”
`
`“GARFT”
`
`“MMA”
`
`“MVA”
`
`“TS”
`
`“Arsenyan”
`
`LY309887
`
`Folate binding protein
`
`Glycinamide ribonucleotide formyl transferase
`
`Methylmalonic acid
`
`Multivariate analysis
`
`Thymidylate synthase
`
`Literature
`
`Arsenyan, et al., Influence of Methylcobalamin on the
`Antineoplastic Activity of Methotrexate, PHARMACEUTICAL
`CHEMISTRY JOURNAL, 12(10): 1299-1303 (1978) (TX 1016)
`
`viii
`
`Lilly Ex. 2003 pg. 9
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`Case 1:10-cv-01376-TWP-DKL Document 331 Filed 10/11/13 Page 10 of 63 PageID #: 8074
`
`Abbreviation
`
`Document Description
`
`“Bastrup-Madsen”
`
`“Calvert”
`
`“Hammond I”/
`“Hammond”
`
`“Hammond II”/
`“Hammond”
`
`“Laohavinij”
`
`“Linnell”
`
`“Mendelsohn”
`
`“Niyikiza”
`
`Bastrup-Madsen, et al., Long term therapy of pernicious
`anaemia with the depot cobalamin preparation Betolvex®,
`SCANDINAVIAN JOURNAL OF HAEMATOLOGY, 31: 57-62 (1983)
`(TX 1320)
`
`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)
`
`Linnell, et al., Tissue Distribution of Methylcobalamin in Rats
`Fed Amino Acid-Defined, Methyl-Deficient Diets, THE
`JOURNAL OF NUTRITION , 113: 124-30 (1983) (TX 1032)
`
`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)
`
`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 912)
`
`“PDR”
`
`Physicians’ Desk Reference (TX 1374)
`
`ix
`
`Lilly Ex. 2003 pg. 10
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`Case 1:10-cv-01376-TWP-DKL Document 331 Filed 10/11/13 Page 11 of 63 PageID #: 8075
`
`Abbreviation
`
`Document Description
`
`“Rinaldi”
`
`“Rusthoven”
`
`“Shih”
`
`“Steinberg”
`
`“Takimoto”
`
`“Worzalla”
`
`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)
`
`Steinberg, Megaloblastic Anemia in Beutler & Weick, Blood
`and Neoplastic Disorders, in CURRENT CLINICAL PRACTICE,
`Chapter 1: 291-302 (1987) (TX 1323)
`
`Takimoto, et al., Phase I and Pharmacokinetic Study of
`Pemetrexed with High-Dose Folic Acid Supplementation or
`Multivitamin Supplementation in Patients with Locally
`Advanced or Metastatic Cancer, CLINICAL CANCER
`RESEARCH, 13(9): 2675-2683 (2007) (TX 905)
`
`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)
`
`x
`
`Lilly Ex. 2003 pg. 11
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`Case 1:10-cv-01376-TWP-DKL Document 331 Filed 10/11/13 Page 12 of 63 PageID #: 8076
`
`INTRODUCTION
`
`Defendants established at trial that each asserted claim of the ‘209 patent was invalid for
`
`obviousness, obviousness-type double patenting or the failure to comply with the disclosure
`
`requirements of the patent statute. More than a year before Eli Lilly filed the earliest patent
`
`application that resulted in the issuance of the ‘209 patent, extensive publications were available
`
`to a person of ordinary skill in the art (“POSA”) concerning pemetrexed, including concerns
`
`about toxicity associated with pemetrexed and reducing those toxicities by vitamin
`
`supplementation. Lilly’s own publications taught a POSA that while pemetrexed was a very
`
`promising antifolate chemotherapy agent, there were significant toxicities associated with its use.
`
`Dr. Niyikiza, the sole named inventor, published a statistical analysis demonstrating a correlation
`
`between toxicity and elevated levels of homocysteine in patients’ blood, a marker for a
`
`deficiency in folate or vitamin B12. Numerous authors made the connection between Dr.
`
`Niyikiza’s correlation of high homocysteine and toxicity with the idea of treating pemetrexed
`
`patients with folic acid and vitamin B12. Although Lilly took the position at trial that a POSA
`
`would be so concerned with the theoretical risk of undermining the activity of pemetrexed with
`
`vitamin supplementation that she or he would not use these vitamins, Lilly took the opposite
`
`position for years in peer-reviewed publications. In the Worzalla and Hammond references,
`
`Lilly scientists reached favorable conclusions about the addition of folic acid to pemetrexed to
`
`reduce toxicity. Clear and convincing evidence established that a POSA would add vitamin B12
`
`to these prior art disclosures. And the undisputed evidence was that the claimed doses and
`
`schedules of folic acid and vitamin B12 were simply standard, commonly used doses to reduce
`
`homocysteine levels. Each of the asserted claims is thus obvious under 35 U.S.C. § 103.
`
`The asserted claims are also invalid for obviousness-type double patenting. Not only had
`
`Lilly published about pemetrexed, they had also patented the combination of certain antifolates
`
`Lilly Ex. 2003 pg. 12
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`Case 1:10-cv-01376-TWP-DKL Document 331 Filed 10/11/13 Page 13 of 63 PageID #: 8077
`
`with folic acid pretreatment in the ‘974 patent. There is no dispute that the ‘974 patent covers
`
`administering pemetrexed with folic acid. Instead, at trial, Lilly argued that even though
`
`pemetrexed is covered by the ‘974 patent, a POSA would focus on another compound,
`
`lometrexol. This argument ignores that by 1999, lometrexol was a low priority compound and
`
`pemetrexed was the most promising antifolate being developed. Contrary to Lilly’s assertion, by
`
`1999 a POSA would have focused on pemetrexed as the antifolate to administer in the ‘974
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`patented regimen. A POSA would then have added vitamin B12 to the folic acid, resulting in the
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`claims in suit, and rendering them invalid for obviousness-type double patenting.
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`Finally, and in the alternative, the patents are invalid for failing to disclose any dose or
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`schedule for the administration of pemetrexed with folic acid and vitamin B12. At trial, Lilly
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`contended that concerns over the effect of vitamin pretreatment on the efficacy of pemetrexed
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`render the asserted claims nonobvious. If Lilly is correct, and such concerns would have led a
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`POSA to conclude that vitamin supplementation would so undermine the efficacy of pemetrexed,
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`then the patent fails to provide a disclosure sufficient to overcome those doubts and describe or
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`enable an effective dose and schedule of pemetrexed with folic acid and vitamin B12. The only
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`dose and schedule disclosed for an “antifolate” in the ‘209 patent is a mere fraction of the
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`amount of pemetrexed now approved by the FDA, and a dose and schedule that were never used
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`with pemetrexed. If the claims are not obvious, then the patent does not describe the invention,
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`or teach how to make and use the full scope of the invention, and each of the asserted claims is
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`invalid for failure to comply with 35 U.S.C. § 112.
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`I.
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`The Science Of Folates And Antifolates
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`STATEMENT OF FACTS
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`The ‘209 patent describes a method of using an antifolate, pemetrexed, with vitamins.
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`Antifolates interrupt the normal function of folates. Folates play a role in normal DNA
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`2
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`replication and therefore in cell growth and replication in all cells, by interacting with enzymes
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`such as TS and GARFT, in both healthy and cancer cells. Antifolates exert their anticancer
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`effect by disrupting the function of folates in cancer cells, but create toxicity by disrupting the
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`function of folates in healthy cells. Antifolates are generally useful as chemotherapy agents
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`when they disrupt cancer cells more than healthy cells. Ratain Tr. 100-03, 1730-32; Green Tr.
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`356-58.
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`It is undisputed that a deficiency in either folate or vitamin B12 leads to an elevation of a
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`chemical in the blood known as homocysteine, which is thus a marker for low levels of folate
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`and/or vitamin B12. Without sufficient levels of folates and vitamin B12, the folate pathway
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`cannot function to support the production of DNA necessary for cells to reproduce. Green Tr.
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`348-53, 367-71; TX 401 at 8-9.
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`II.
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`The Public History Of The Development Of Antifolates With Vitamins
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`Researchers in the 1990s were actively developing antifolate drugs, and by the end of the
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`decade antifolates were established as treatments for cancer and rheumatoid arthritis. Ratain Tr.
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`108-09, 137-39; Chabner Tr. 993-94; Morgan Tr. 610. Antifolates were not new – they had been
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`in clinical development since the 1940s, when Dr. Farber gave aminopterin to children with
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`leukemia. TX 1443. And in the 1990s multiple other antifolates were in clinical use or
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`development, including pemetrexed, raltitrexed, methotrexate, lometrexol, and the ‘887
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`compound. Ratain Tr. 108-09. All cancer chemotherapy drugs, including these antifolates, are
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`toxic. Ratain Tr. 100-03; Chabner Tr. 1002, 1033; Niyikiza Tr. 830-31. But by June 1999,
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`researchers had documented the benefits of using folic acid pretreatment with many of these
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`antifolates to reduce their toxicity. In the early 1990s, Dr. Morgan demonstrated that folic acid
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`pretreatment decreased methotrexate’s toxicity in rheumatoid arthritis patients without impacting
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`its efficacy. Morgan Tr. 591-97; TX 508; TX 1204; TX 1350.
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`3
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`Lilly helped pioneer folic acid pretreatment to reduce antifolate-related toxicity and
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`repeatedly used it. In the 1990s, a number of antifolates were in clinical development by Lilly.
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`Ratain Tr. 108-09. Lilly did not keep its antifolate program a secret, but rather published about it
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`extensively in the prior art.1 Lilly’s publications in the 1990s of preclinical and clinical studies
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`made clear that the use of folic acid pretreatment was a feasible approach. Ratain Tr. 134-35.
`
`A.
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`Lilly Conceives Of, Patents, And Publishes In The Prior Art The Idea To Use
`Folic Acid Supplementation With Its Antifolates In The 1990s
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`Lilly’s commitment to the use of folic acid pretreatment was known in the prior art as
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`early as 1991, when Dr. Grindey and others at Lilly published an abstract on the use of folic acid
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`with lometrexol in preclinical mouse models. Chabner Tr. 1238, 1241-43; TX 1036 at 326
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`(reference 10). The authors concluded that their data “support[ed] the use of low doses of oral
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`folic acid to reduce toxicity of [lometrexol] in clinical trials.” TX 1036 at 326; Chabner Tr.
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`1241-43. Prompted by this, Lilly later published the Laohavinij paper in 1996 on the clinical use
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`of lometrexol with folic acid pretreatment in a human phase I study. Ratain Tr. 135-37; TX 1036
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`at 326. Laohavinij demonstrated that toxicity could be modulated by folic acid supplementation
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`and identified for the first time a safe and acceptable clinical schedule for the administration of
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`lometrexol in humans. TX 1036 at 333-34; Ratain Tr. 135-37, 321-23. In that study, one patient
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`had a partial response, a sign that lometrexol was therapeutically effective even with the folic
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`acid pretreatment. Ratain Tr. 311-13; TX 1036 at 333. The paper concludes that “the
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`information obtained from this study will facilitate the future development and evaluation of this
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`class of compounds in the treatment of human cancer.” TX 1036 at 333-34; Ratain Tr. 321-23.
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`Shortly before June 1999, Dr. Mendelsohn and other Lilly employees also published their
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`research using folic acid pretreatment with lometrexol in humans, as well as the use of such
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`1 The prior art discussed in this section of this brief are stipulated to be prior art by the parties.
`D.I. 298 at 3-23.
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`4
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`pretreatment with the ‘887 compound. TX 400 at 261; Ratain Tr. 137-41. Mendelsohn
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`discussed research on folic acid pretreatment in mouse studies with lometrexol and the ‘887
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`compound, and explained that folic acid pretreatment improved their therapeutic index.2 TX 400
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`at 267-78; Ratain Tr. 138-40. Mendelsohn also described the positive results of the phase I
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`clinical studies reported in Laohavinij, and explained that patients in a phase I clinical trial would
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`receive daily folic acid pretreatment on the same schedule as lometrexol prior to their ‘887
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`compound therapy. TX 400 at 273, 277; Ratain Tr. 140; see Chabner Tr. 1247-49
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`(acknowledging that his own papers interpreted Lilly’s work as yielding positive results).
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`The concept of using folic acid pretreatment with antifolates was so promising that Lilly
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`applied for patent protection long before filing the application for the patent-in-suit. See TX 916.
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`In 1994, Lilly obtained the prior art ‘974 patent claiming the use of folic acid pretreatment with a
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`class of antifolates. Ratain Tr. 141-46; TX 916 at cl. 16. Contrary to Lilly’s position at trial, in
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`order to get this prior art patent, Lilly disclosed that the toxicity of antifolates could be
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`“significantly reduced . . . without adversely affecting therapeutic efficacy,” through
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`pretreatment with folic acid. TX 916 at 1:47-54, 5:12-13; Ratain Tr. 141-44. The ‘974 patent
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`also provides varying doses and schedules of folic acid. TX 916 at 5:43-48 (folic acid dose from
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`“about 0.5 mg to about 30 mg/day”); id. at 6:22-48 (folic acid given “for periods up to weeks
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`before treatment” with an antifolate); Ratain Tr. 241-42; Green Tr. 429-30.
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`B.
`
`Dr. Niyikiza’s Research Regarding Predicting, And Finding Ways Of
`Reducing, Pemetrexed’s Toxicity Was Disclosed To The Public
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`Pemetrexed, like lometrexol and the ‘887 compound, was part of Lilly’s armament of
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`antifolates in clinical development in the 1990s. Ratain Tr. 108-09, 134. Like every antifolate,
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`2 Therapeutic index is a measure of the efficacy of a drug relative to its toxicity. A higher
`therapeutic index is desirable, as it indicates that the benefits of a drug relative to its risk have
`improved. Ratain Tr. 139.
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`5
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`pemetrexed was toxic. Ratain Tr. 126-27; Chabner Tr. 1228; TX 78 at 1196. Dr. Clet Niyikiza,
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`a Lilly employee at the time, was charged with co