UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`
`APOTEX INC., APOTEX CORP., EMCURE PHARMACEUTICALS LTD.,
`HERITAGE PHARMA LABS INC.,
`HERITAGE PHARMACEUTICALS INC., GLENMARK
`PHARMACEUTICALS INC., USA, GLENMARK HOLDING SA,GLENMARK
`PHARMACEUTICALS LTD., MYLAN LABORATORIES LIMITED
`
`Petitioners
`v .
`
`ELI LILLY AND COMPANY,
`
`
`
`
`
`Patent Owner
`
`
`
`
`U.S. Patent 7,772,209
`Issue Date: Aug. 10, 2010
`Title: Antifolate Combination Therapies
`
`
`
`Inter Partes Review No. IPR2016-01429
`
`
`
`
`
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 7,772,209 PURSUANT TO
`35 U.S.C. §§ 311-319 AND 37 C.F.R. § 42
`
`

`

`TABLE OF CONTENTS
`INTRODUCTION ......................................................................................... 13
`I.
`OVERVIEW .................................................................................................. 14
`II.
`III. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8(A)(1) ...................... 15
`A.
`Real Party-In-Interest .......................................................................... 15
`B.
`Related Matters .................................................................................... 16
`C.
`Lead and Back-Up Counsel ................................................................. 17
`D.
`Service Information ............................................................................. 18
`IV. GROUNDS FOR STANDING ...................................................................... 18
`V.
`PAYMENT OF FEES ................................................................................... 19
`VI.
`IDENTIFICATION OF CHALLENGE AND STATEMENT OF THE
`PRECISE RELIEF REQUESTED ................................................................ 19
`VII. THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW ............. 20
`VIII. STATEMENT OF REASONS FOR THE RELIEF REQUESTED ............. 20
`A.
`Summary of the Argument .................................................................. 20
`B.
`Background of the ’209 Patent ............................................................ 24
`1.
`Prior Art Administration of Pemetrexed Resulted in
`Toxicity Caused by Elevated Homocysteine Levels ................ 24
`It Was Well-Known that Elevated Baseline
`Homocysteine Levels Are Most Effectively Treated by
`Administering Both Folic Acid and Vitamin B12 ..................... 26
`The ’209 Patent ......................................................................... 27
`3.
`The Prosecution of the ’209 Patent ........................................... 28
`4.
`Person of Ordinary Skill in the Art ..................................................... 30
`Claim Construction.............................................................................. 30
`1.
`“Patient” .................................................................................... 31
`2.
`The “Effective Amount” Limitations ....................................... 34
`3.
`“Methylmalonic Acid Lowering Agent” .................................. 35
`Patents and Printed Publications Relied on in this Petition ................ 35
`
`C.
`D.
`
`2.
`
`E.
`
`i
`
`

`

`F.
`
`1.
`
`4.
`
`2.
`
`3.
`
`2.
`
`Calvert (Ex. 1007) Teaches that Elevated Baseline
`Homocysteine Levels Associated with Pemetrexed
`Toxicity Are Caused by Either Folic Acid or Vitamin B12
`Deficiencies ............................................................................... 35
`Niyikiza I (Ex. 1006) Teaches a Strong Correlation
`between Baseline Homocysteine Levels and Pemetrexed
`Toxicity ..................................................................................... 36
`3. Worzalla (Ex. 1013) Teaches Pretreating Animal Patients
`with Folic Acid before Pemetrexed Therapy ............................ 38
`Hammond I (Ex. 1015) Teaches Pretreating Human
`Patients with Folic Acid before Starting Pemetrexed
`Therapy ..................................................................................... 38
`The Challenged Claims Are Unpatentable as Obvious over the
`Prior Art ............................................................................................... 39
`1.
`Calvert and Niyikiza I Would Have Motivated a POSA to
`Add Vitamin B12 to the Folic Acid Pretreatment Regimen
`of Worzalla or Hammond I ....................................................... 40
`a.
`A POSA Would Know to Pretreat Patients with
`Vitamin B12 to Reduce High Homocysteine Levels
`Linked to Pemetrexed Toxicity ...................................... 40
`The Prior Art Taught Combining Antifolates with
`Vitamin B12 and Folic Acid ............................................ 44
`Claims 1 and 2 Are Obvious Over Calvert and Niyikiza I
`in View of Worzalla or Hammond I, and a POSA’s
`Knowledge of the Relationship between Homocysteine,
`Folic Acid and Vitamin B12 ...................................................... 46
`a.
`The POSA Would Have Had a Reasonable
`Expectation of Success ................................................... 52
`No Secondary Considerations Support Non-
`Obviousness .................................................................... 56
`The Patent Owner’s “Teaching Away” Arguments
`Lack Merit ...................................................................... 60
`Claims 3-10, 12, and 14-21 Are Obvious in Further View
`of the Known Dosages and Schedules for Administering
`Folic Acid and Vitamin B12 ..................................................... 63
`
`b.
`
`b.
`
`c.
`
`ii
`
`

`

`4.
`
`5.
`
`Claim 11 Is Obvious in Further View of the POSA’s
`Knowledge of the Benefit of Combining Cisplatin with
`Pemetrexed ................................................................................ 69
`Claims 13 and 22 Are Obvious over Worzalla or
`Hammond I in View of Niyikiza I, Calvert in Further
`View of the POSA’s Knowledge of the Claimed
`Dosages, Schedules and Combination with Cisplatin .............. 71
`IX. CONCLUSION .............................................................................................. 71
`
`
`iii
`
`

`

`TABLE OF AUTHORITIES
`
`
`
`CASES
`Aventis Pharma Deutschland GmbH v. Lupin, Ltd.,
`499 F.3d 1293 (Fed. Cir. 2007) ............................................................................44
`Bayer Healthcare Pharm., Inc. v. Watson Pharm. Inc.,
`713 F.3d 1369 (Fed. Cir. 2013) ............................................................................58
`Bell Commc’ns Research, Inc. v. Vitalink Commc’ns Corp., 55 F.3d
`615, 623 (Fed. Cir. 1995) .....................................................................................45
`Bristol-Myers Squibb Co. v. Teva Pharm. USA, Inc.,
`923 F. Supp. 2d 602 (D. Del. 2013) .....................................................................59
`Dow Jones & Co., Inc. v. Ablaise Ltd.,
`606 F.3d 1338 (Fed. Cir. 2010) ............................................................................59
`In re Am. Acad. of Sci. Tech. Ctr.,
`367 F.3d 1359 (Fed. Cir. 2004) ............................................................................34
`In re Cuozzo Speed Techs., LLC,
`793 F.3d 1268 (Fed. Cir. 2015) ............................................................................31
`In re Droge,
`695 F.3d 1334 (Fed. Cir. 2012) ............................................................................52
`In re Fulton,
`391 F.3d 1195 (Fed. Cir. 2004) ............................................................................61
`In re Young,
`927 F.2d 588 (Fed. Cir. 1991) ..............................................................................63
`Key Pharm. Inc. v. Hercon Labs. Corp.,
`161 F.3d 709 (Fed. Cir. 1998) ....................................................................... 34, 35
`Medichem S.A. v. Rolabo S.L.,
`437 F.3d 1157 (Fed. Cir. 2006) ............................................................................56
`Merck & Co. v. Teva Pharm. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005) ............................................................................60
`Novo Nordisk A/S v. Eli Lilly & Co.,
`No. 98-643 WL 1094213 (D. Del. Nov. 18, 1999) ..............................................33
`
`iv
`
`

`

`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) ............................................................................57
`Santarus, Inc. v. Par Pharm., Inc.,
`720 F. Supp. 2d 427 (D. Del. 2010) .....................................................................59
`Syntex (U.S.A.) LLC v. Apotex, Inc.,
`407 F.3d 1371 (Fed. Cir. 2005) ..................................................................... 61, 63
`Tyco Healthcare Grp. LP v. Mut. Pharm. Co. Inc.,
`642 F.3d 1370 (Fed. Cir. 2011) ............................................................................58
`STATUTES
`35 U.S.C. § 102 ..................................................................................... 26, 27, 39, 70
`35 U.S.C. § 314(a) ...................................................................................................21
`35 U.S.C. § 315 (c) ...................................................................................................19
`35 U.S.C. § 315(b) ....................................................................................................19
`OTHER AUTHORITIES
`21 C.F.R. § 312.30 ...................................................................................................59
`37 C.F.R. § 42 ............................................................................................. 13, 19, 31
`37 C.F.R. § 42.104(a) ...............................................................................................19
`37 C.F.R. § 42.8(b)(2) ..............................................................................................16
`
`
`
`
`v
`
`

`

`Exhibit
`No.
`
`Exhibit
`1001:
`
`Exhibit
`1002:
`
`Exhibit
`1003:
`
`Exhibit
`1004:
`
`Exhibit
`1005:
`
`Exhibit
`1006:
`
`EXHIBIT LIST
`
`Description
`
`U.S. Patent No. 7,772,209
`
`File History of U.S. Patent Application
`No. 11/776,329, which issued as U.S. Patent
`No. 7,772,209 on August 10, 2010
`
`Findings Of Fact And Conclusions Of Law
`Following Bench Trial August 19, 2013, in
`Eli Lilly & Co. v. Teva Parenteral
`Medicines, Inc., Case No. 1:10-cv-1376,
`Dkt. 336 (S.D. Ind. March 31, 2014)
`
`Referred To In
`The Petition As
`
`“’209 patent”
`
`“’209 file history”
`
`“Teva Decision”
`
`Declaration of Ron D. Schiff, M.D., Ph.D.
`
`“Schiff Decl.”
`
`U.S. Patent No. 5,217,974
`
`C. Niyikiza, et al., MTA (LY231514):
`Relationship of vitamin metabolite profile,
`drug exposure, and other patient
`characteristics to toxicity, Annals Oncology 9
`(Suppl. 4): 125-140, Abstract 609P, (1998)
`
`“’974 patent”
`
`“Niyikiza I”
`
`Exhibit
`1007:
`
`Hilary Calvert, An Overview of Folate
`Metabolism: Features Relevant to the Action
`and Toxicities of Antifolate Anticancer
`Agents, Seminars Oncology, 26: 3-10 (1999)
`
`“Calvert”
`
`Exhibit
`1008:
`
`Textbook of Small Animal Medicine (John K.
`Dunn ed. 1999)
`
`“Animal Medicine”
`
`Exhibit
`1009:
`
`Sidney Farber, et al., Temporary Remissions in
`acute leukemia in children produced by folic
`vi
`
`“Farber”
`
`
`
`

`

`Exhibit
`No.
`
`Description
`
`Referred To In
`The Petition As
`
`Exhibit
`1010:
`
`Exhibit
`1011:
`
`Exhibit
`1012:
`
`Exhibit
`1013
`
`Exhibit
`1014
`
`Exhibit
`1015
`
`acid antagonist, 4-aminopteroylglutamic acid
`(aminopterin), New Eng. J. Med., 238(23):
`787-793
`
`Sarah L. Morgan, et al., Supplementation with
`Folic Acid during Methotrexate Therapy for
`Rheumatoid Arthritis, Annals Internal Med.,
`121: 833-841 (1994)
`
`G.B. Grindey, et al., Reversal of the toxicity but
`not the antitumor activity of Lometrexol by folic
`acid, Am. Ass’n Cancer Res., 32: 324, Abstract
`1921 (1991)
`
`Laurane G. Mendelsohn, et al., Preclinical and
`Clinical Evaluation of the Glycinamide
`Ribonucleotide Formyltransferase Inhibitors
`Lometrexol and LY309887, in Anticancer Drug
`Dev. Guide: Antifolate Drugs Cancer Therapy,
`(Ann L. Jackman, ed.) Ch. 12: 261-80 (1999)
`
`John F. Worzalla, et al., Role of Folic Acid in
`Modulating the Toxicity and Efficacy of the
`Multitargeted Antifolate, LY231514, Anticancer
`Res., 18: 3235-3240 (1998)
`
`L. Hammond, et al., A Phase I and
`Pharmacokinetic (PK) Study of the
`Multitargeted Antifol (MTA) LY231514 with
`Folic Acid, Proc. Am. Soc’y Clinical
`Oncology, 17: Abstract 866 (1998)
`
`L. Hammond, et al., A phase I and
`pharmacokinetic (PK) study of the multitargeted
`antifolate (MTA, LY231514) with folic acid
`(FA), Annals Oncology, 9: 129, Abstract 620P
`(1998)
`
`“Morgan”
`
`“Grindey”
`
`“Mendelsohn”
`
`“Worzalla”
`
`“Hammond II”
`
`“Hammond I”
`
`
`
`vii
`
`

`

`Exhibit
`No.
`
`Exhibit
`1016
`
`Exhibit
`1017
`
`Exhibit
`1018
`
`Exhibit
`1019
`
`Exhibit
`1020
`
`Exhibit
`1021
`
`Exhibit
`1022
`
`Description
`
`C. Niyikiza, et al., LY231514 (MTA):
`Relationship of vitamin metabolite profile to
`toxicity, Proc. Am. Ass’n Cancer Res., 17: 558a,
`Abstract 2139 (1998)
`
`R. Thödtmann, et al., Preliminary Results of a
`Phase I Study with MTA (LY231415) in
`Combination with Cisplatin in Patients with
`Solid Tumors, Seminars Oncology, 26 (2, Suppl.
`6): 89-93 (1999)
`
`Referred To In
`The Petition As
`
`“Niyikiza II”
`
`“Thödtmann I”
`
`U.S. Patent No. 5,563,126
`
`“’126 patent”
`
`Ernest Beutler & James K. Weick, Blood and
`Neoplastic Disorders, in Current Clinical
`Practice (Messerli, ed., 1987), Ch. 1: 291-302
`
`“Beutler”
`
`“Brattström”
`
`“Shih”
`
`“Westerhof”
`
`Lars Brattström, Vitamins as Homocysteine-
`Lowering Agents, J. Nutrition, 126: 1276S-
`1280S (1996)
`
`Chuan Shih, et al., LY231514, a Pyrrolo[2,3-
`d]pyrimidine-based Antifolate That Inhibits
`Multiple Folate-requiring Enzymes, Cancer
`Res., 57, 1116- 1123 (1997)
`
`G. Robbin Westerhof, et al., Carrier- and
`Receptor-Mediated Transport of Folate
`Antagonists Targeting Folate-Dependent
`Enzymes: Correlates of Molecular-Structure
`and Biological Activity, Am. Soc’y
`Pharmacology Experimental Therapeutics, 48:
`459-471 (1995)
`
`Exhibit
`1023
`
`F. G. Arsenyan, et al., Influence of
`Methylcobalamin on the Antineoplastic Activity
`of Methotrexate, Pharmaceutical Chemistry J.,
`
`“Arsenyan”
`
`
`
`viii
`
`

`

`Exhibit
`No.
`
`Description
`
`12(10): 1299-1303 (1978)
`
`Referred To In
`The Petition As
`
`Exhibit
`1024
`
`File History of U.S. Patent Application
`No. 11/288,807, Abandoned
`
`“’807 File History”
`
`Exhibit
`1025
`
`Exhibit
`1026
`
`Exhibit
`1027
`
`Exhibit
`1028
`
`Exhibit
`1029
`
`Exhibit
`1030
`
`Exhibit
`1031
`
`U.S. Food & Drug Administration, Approved
`Drug Products with Therapeutic Equivalents
`Evaluations (30th ed. 2010)
`
`“Orange Book
`Listing for
`Alimta®”
`
`Z.P. Sofyina, et al., Possibility to Increase the
`Antitumor Effect of Folic Acid Antagonist with
`the Help of Methylcobalamine Analogs, Sci.
`Center Oncology 1:72-78 (1979)
`
`Victor Herbert, The Role of Vitamin B12 and
`Folate in Carcinogenesis, Advances
`Experimental Med. Biology, 206: 293-311
`(1986)
`
`“Sofyina”
`
`“Herbert”
`
`Glenn Tisman, et al., Overcoming Colon Cancer
`Resistance to Hepatic Artery Infusional 5FUdR
`Chemotherapy with Folinic Acid, Clinical Res.,
`33(2): 459A (1985)
`
`“Tisman”
`
`J.D. Kinloch, Maintenance Treatment of
`Pernicious Anaemia by Massive Parenteral
`Doses of Vitamin B12 at Intervals of Twelve
`Weeks, Brit. Med. J., 1:99-100 (1960)
`
`“Kinloch”
`
`D. Wray, et al., Recurrent Aphthae: Treatment
`with Vitamin B12, Folic Acid, and Iron, Brit.
`Med. J., 2:490-93 (1975)
`
`“Wray”
`
`J. Tamura, et al., Immunomodulation by Vitamin
`B12: Augmentation of CD8+ T Lymphocytes and
`Natural Killer (NK) Cell Activity in Vitamin
`B12-Deficient Patients by Methyl-B12
`Treatment, Clin. Experimental Immunology,
`
`“Tamura”
`
`
`
`ix
`
`

`

`Exhibit
`No.
`
`Exhibit
`1032
`
`Exhibit
`1033
`
`Exhibit
`1034
`
`Exhibit
`1035
`
`Exhibit
`1036
`
`Exhibit
`1037
`
`Exhibit
`1038
`
`Exhibit
`1039
`
`Description
`
`Referred To In
`The Petition As
`
`116:28-32 (1999)
`
`Carrasco et al., Acute Megaloblastic Anemia:
`Homocysteine Levels Are Useful for Diagnosis
`and Follow-Up, Haematologica, 84: 767- 768
`(1999)
`
`“Carrasco”
`
`European Patent Application No. 0 595 005
`
`“EP005”
`
`U.S. Patent No. 5,344,932
`
`Amended Joint Claim Construction Statement
`in Eli Lilly & Co. v. Teva Parenteral
`Medicines, Inc. et al., No. 1:10-cv-1376 (S.D.
`Ind.), filed April 19, 2012 (Dkt. 110)
`
`Excerpts from transcript of the trial on
`invalidity held between August 19 and August
`29, 2013 in Eli Lilly & Co. v. Teva Parenteral
`Medicines, Inc., Case No. 1:10-cv-1376 (S.D.
`Ind.)
`
`E. Bajetta et al., Phase II study of pemetrexed
`disodium (Alimta®) administered with oral
`folic acid in patients with advanced gastric
`cancer, Annals of Oncology 14:1543-48
`(2003).
`
`“’932 patent”
`
`“Joint Claim
`Construction
`Statement”
`
`“Teva Litigation
`Trial Tr.”
`
`“Bajetta”
`
`Letter dated February 4, 2004 from Robert
`Temple to John Worzalla concerning NDA 21-
`462
`
`“Alimta®
`Approval Letter”
`
`Johan B. Ubbink et al., Vitamin Requirements
`for the Treatment of Hyperhomocysteinemia in
`Humans, J. Nutrition 124:1927-1933 (1994)
`
`“Ubbink I”
`
`Exhibit Anja Brönstrup et al., Effects of folic acid and
`
`“Brönstrup”
`
`
`
`x
`
`

`

`Exhibit
`No.
`1040
`
`Exhibit
`1041
`
`Exhibit
`1042
`
`Exhibit
`1043
`
`Exhibit
`1044
`
`Exhibit
`1045
`
`Exhibit
`1046
`
`Exhibit
`1047
`
`Exhibit
`1048
`
`Description
`
`Referred To In
`The Petition As
`
`combinations of folic acid on plasma
`homocysteine concentrations in healthy, young
`women, Am. J. Clin. Nutr. 1998:68:1104-10
`(1998)
`
`J. B. Ubbink, The role of vitamins in the
`pathogenesis and treatment of
`hyperhomocyst(e)inaemia, J. Inherited
`Metabolic Disease, 20:316-25 (1997)
`
`“Ubbink II”
`
`S. Sörenson et al., A systematic overview of
`chemotherapy effects in non-small cell lung
`cancer, Acta Oncologica 40(2-3):327-29 (2001)
`
`“Sörenson”
`
`R. Thödtmann et al., Phase I study of different
`sequences of MTA (LY231514) in combinaition
`with cisplatin in patients with solid tumours,
`Annals Oncology, 9: 129, 618P (Abstract)
`(1998)
`
`“Thödtmann II”
`
`Complaint filed in Eli Lilly & Co. v. Teva
`Parenteral Medicines, Inc., No. 1:08-cv-335 (D.
`Del.) on June 5, 2008
`
`“Delaware Teva
`Litigation
`Complaint”
`
`Calvert, MTA: Summary and Conclusions,
`Seminars in Oncology, 26 (2, Suppl. 6): 105-08
`(1999)
`
`“MTA: Summary
`& Conclusions”
`
`Center for Drug Evaluation and Research,
`Product Development under the Animal Rule:
`Guidance for the Industry (October 2015)
`
`“FDA Animal
`Rule Guidance”
`
`A.H. Calvert & J.M. Walling, Clinical Studies
`with MTA, British J. Cancer (1998) 78 (Suppl.
`3): 35-40
`
`“Calvert &
`Walling”
`
`Center for Drug Evaluation and Research,
`Guidance for Industry: Single Dose Acute
`Toxicity Testing for Pharmaceuticals (August
`xi
`
`“FDA Single Dose
`Guidance”
`
`
`
`

`

`Exhibit
`No.
`
`Exhibit
`1049
`
`Exhibit
`1050
`
`Description
`
`Referred To In
`The Petition As
`
`1996)
`
`Center for Drug Evaluation and Research, E6
`Good Clinical Practice: Consolidated Guidance
`(April 1996)
`
`“FDA E6
`Guidance”
`
`Robert H. Allen et al., Diagnosis of Cobalamin
`Deficiency I: Usefulness of Serum
`Methylmalonic Acid and Total Homocysteine
`Concentrations, Am. J. Hematology 34:90-98
`(1990)
`
`Allen
`
`Exhibit
`1051
`
`Eli Lilly & Company, Alimta® Labeling
`(Revised Sept. 2013)
`
`Rusthoven et al., Multitargeted Antifolate
`LY231514 as First-Line Chemotherapy for
`Patients with Advanced Non-Small-Cell Lung
`Cancer: A Phase II Study, J. Clin. Oncology, 17
`(4) 1194-99 (April 1999)
`
`“Alimta Labeling”
`
`“Rusthoven”
`
`Exhibit
`1052
`
`Exhibit
`1053
`
`Exhibit
`1054
`
`
`
`
`
`Return of Service, Eli Lilly & Co. v. Sandoz
`Inc., Case No. 1:14-cv-2008 (S.D. Ind. Dec. 29,
`2014)
`
`“Return of
`Service”
`
`FDA, Electronic Orange Book: Approved Drug
`Products and Therapeutic Equivalence
`Evaluations Entry for Alimta®, available at
`http://www.accessdata.fda.gov/scripts/cder/ob/d
`ocs/patexclnew.cfm?Appl_No=021462&Produc
`t_No=001&table1=OB_Rx (last accessed Dec.
`14, 2015)
`
`“2015 Alimta®
`Orange Book
`Listing”
`
`xii
`
`

`

`I.
`
`INTRODUCTION
`
`Pursuant to 35 U.S.C. §§ 311-319 and 37 C.F.R. § 42, Apotex Inc. and
`
`Apotex Corp. (“Apotex”), Emcure Pharmaceuticals Ltd., Heritage Pharma Labs
`
`Inc., and Heritage Pharmaceuticals Inc. (“Emcure”), Glenmark Pharmaceuticals,
`
`Inc., USA, Glenmark Holding SA, and Glenmark Pharmaceuticals, Ltd.
`
`(“Glenmark”), and Mylan Laboratories Limited (“Mylan”) (collectively
`
`“Petitioners”) respectfully request Inter Partes Review (“IPR”) of claims 1-22 of
`
`U.S. Patent No. 7,772,209 to Niyikiza, titled “Antifolate Combination Therapies”
`
`(“’209 patent,” Ex. 1001), which is currently assigned to Eli Lilly and Company
`
`(“Lilly” or “Patent Owner”).
`
`The Board has already issued its Decision Instituting Inter Partes Review
`
`(“Decision”) on claims 1-22 of the ’209 patent on the same grounds raised herein.
`
`Sandoz Inc. v. Eli Lilly and Company, IPR2016-00318 (the “Sandoz IPR” or “IPR
`
`318”) (Paper 14). In its Decision, the Board found that Petitioner Sandoz Inc.
`
`(“Sandoz”) had demonstrated a reasonable likelihood that claims 1-22 of the ‘209
`
`patent are unpatentable for failing to satisfy the nonobviousness requirement of 35
`
`U.S.C. § 103. Id. The Board instituted IPR of the challenged claims on the
`
`following grounds:
`
`Ground 1: Claims 1-22 are obvious over Calvert in view of Niyikiza I,
`
`Worzalla, EP 005 and the ’974 Patent.
`
`13
`
`

`

`Ground 2: Claims 1-22 are obvious over Calvert in view of Niyikiza I,
`
`Hammond I, EP 005 and the ’974 Patent.
`
`Decision at 21. Petitioners hereby file their own petition on the same grounds and
`
`concurrently seek joinder of this IPR to the instituted IPR proceedings on these
`
`challenged claims.
`
`For the sake of completeness and efficiency, the present Petition is a
`
`substantively identical copy of the petition in the Sandoz IPR. Specifically, the
`
`present Petition is narrowly-tailored to the same claims, prior art, and grounds of
`
`unpatentability that are the subject of the Sandoz IPR, and, in addition, relies on
`
`the same expert as the Sandoz IPR. A motion for joinder with the Sandoz IPR is
`
`being filed concurrently with this Petition.
`
`II. OVERVIEW
`This Petition demonstrates a reasonable likelihood that claims 1-22 of the
`
`’209 patent are unpatentable. The claims of the ’209 patent are generally directed
`
`to a method of pretreating a patient with folic acid and a methylmalonic acid
`
`(“MMA”) lowering agent (e.g., vitamin B12) prior to administering pemetrexed.
`
`But this pretreatment regimen was obvious more than a year before the earliest
`
`claimed priority date for the ’209 patent (June 2000).
`
`The case for obviousness is straightforward. Prior to June 1999, the patentee
`
`(Niyikiza) published studies linking pemetrexed toxicity with elevated baseline
`
`14
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`

`

`homocysteine levels. Ex. 1006, Niyikiza I; see also Ex. 1016, Niyikiza II. Calvert
`
`pointed to this known link and further explained that the elevated homocysteine
`
`levels associated with pemetrexed toxicity are caused by a folic acid and/or
`
`vitamin B12 deficiency. Ex. 1007, Calvert. Thus, based on Calvert and Niyikiza I,
`
`it was known that sufficient amounts of both folic acid and vitamin B12 are
`
`necessary to lower homocysteine levels. In view of the teachings of Calvert and
`
`Niyikiza I, it would have been obvious to add vitamin B12 to the folic acid
`
`pretreatment regimens for pemetrexed of Worzalla or Hammond I, which had
`
`previously been published by the Patent Owner. See Ex. 1013, Worzalla;
`
`Ex. 1015, Hammond I. The reasonably expected result: the lowering of baseline
`
`homocysteine levels with a corresponding reduction in the prevalence and/or
`
`severity of pemetrexed toxicity.
`
`III. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8(a)(1)
`A. Real Party-In-Interest
`Petitioners certify that Apotex Inc., Apotex Corp., Apotex Pharmaceuticals
`
`Holdings Inc., Apotex Holdings, Inc., Glenmark Pharmaceuticals, Inc., USA,
`
`Glenmark Holding SA, Glenmark Pharmaceuticals, Ltd., Emcure Pharmaceuticals
`
`Ltd., Heritage Pharma Labs Inc. (f/k/a Emcure Pharmaceuticals USA, Inc.),
`
`Heritage Pharmaceuticals Inc., Heritage Pharma Holdings, Inc., Mylan
`
`Laboratories Limited, Mylan Inc., Mylan N.V., and Mylan Pharmaceuticals Inc.
`
`15
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`

`

`are the real parties-in-interest for the instant petition. No other party funds, directs,
`
`or controls this Petition.
`
`B. Related Matters
`Pursuant to 37 C.F.R. § 42.8(b)(2), Petitioners state the ‘209 Patent is the
`
`subject of the following proceedings: Petition for IPR by Wockhardt Bio AG,
`
`PTAB-IPR2016-01393 (filed July 8, 2016); Petitions for IPR by Teva
`
`Pharmaceuticals USA, Inc., PTAB-IPR2016-01340, PTAB-IPR2016-01341, and
`
`PTAB-IPR2016-01343 (filed July 1, 2016); Petitions for IPR by Apotex Inc.,
`
`PTAB-IPR2016-01190 and PTAB-IPR2016-01190 (filed July 1, 2016); Petitions
`
`for IPR by Wockhardt Bio AG, PTAB-IPR2016-01335 and PTAB-IPR2016-01337
`
`(filed June 30, 2016); Apotex Eli Lilly & Co. v. Biocon Ltd., INSD-1:16-cv-00469
`
`(filed Feb. 26, 2016); Eli Lilly & Co. v. Dr. Reddy’s Labs., Ltd., INSD-1:16-cv-
`
`00308 (filed Feb. 5, 2016); Petition for IPR by Sandoz Inc., PTAB-IPR201600318
`
`(filed Dec. 14, 2015); Petitions for IPR by Neptune Generics, Inc., PTAB-IPR2016-
`
`00240 and PTAB-IPR2016-00237 (filed Nov. 24, 2015); Eli Lilly & Co. v. Emcure
`
`Pharmaceuticals Ltd., INSD-1:15-cv-01244 (filed Aug. 7, 2015); Eli Lilly & Co. v.
`
`Mylan Labs. Ltd, INSD-1:15-cv-01083 (filed July 10, 2015); Eli Lilly & Co. v.
`
`Fresenius Kabi USA, LLC, INSD-1:15-cv-00096 (filed Jan. 23, 2015); Eli Lilly &
`
`Co. v. Sandoz Inc., INSD-1:14-cv-02008 (filed Dec. 5, 2014); Eli Lilly & Co. v.
`
`Nang Kuang Pharm. Co., Ltd., INSD-1:14-cv-01647 (filed Oct. 8, 2014); Eli Lilly
`
`16
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`

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`& Co. v. Glenmark Pharm. Ltd., INSD-1:14-cv- 00104 (filed Jan. 23, 2014); Eli
`
`Lilly & Co. v. Sun Pharm. Global FZE, INSD-1:13-cv-01469 (filed Sept. 13,
`
`2013); Petition for IPR by Accord Healthcare, Inc., PTAB-IPR2013-00356 (filed
`
`June 14, 2013); Eli Lilly & Co. v. Accord Healthcare, Inc., USA, INSD-1:13-cv-
`
`00335 (filed Feb. 28, 2013); Eli Lilly & Co. v. Apotex, Inc., INSD-1:12-cv-00499
`
`(filed Apr. 17, 2012); Eli Lilly & Co. v. Accord Healthcare, Inc., USA, INSD-
`
`1:12-cv-00086 (filed Jan. 20, 2012); Eli Lilly & Co. v. App Pharm., LLC, INSD-
`
`1:11-cv-00942 (filed Jul. 15, 2011); and Eli Lilly & Co. v. Teva Parental
`
`Medicines, Inc., INSD-1:10-cv-01376 (filed Oct. 29, 2010).
`
`C. Lead and Back-Up Counsel
`Lead Counsel
`Back-Up Counsel
` Deanne M. Mazzochi
`William A. Rakoczy
`Pro hac vice to be filed
` Reg. No. 50,158
`wrakoczy@rmmslegal.com
` dmazzochi@rmmslegal.com
`jpolivick@rmmslegal.com
` Rakoczy Molino Mazzochi Siwik LLP
` 6 West Hubbard Street, Suite 500,
` Rakoczy Molino Mazzochi Siwik LLP
` Chicago, Illinois 60654
` 6 West Hubbard Street, Suite 500,
` Tel.: 312-527-2157
` Chicago, Illinois 60654
`
` Tel.: 312-527-2157
` Counsel for Apotex
`
` Counsel for Apotex
`
`
`Back-Up Counsel
` Thomas J. Parker
` Reg. No. 42,062
` thomas.parker@alston.com
` Alston & Bird LLP
` 90 Park Avenue, 15th Floor
` New York, NY 10016
`
`Back-Up Counsel
`John D. Polivick
` Reg. No. 57,926
`jpolivick@rmmslegal.com
`Rakoczy Molino Mazzochi Siwik LLP
` 6 West Hubbard Street, Suite 500
`Chicago, Illinois 60654
`
`17
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`

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` Tel.: 312-527-2157
`
` Counsel for Apotex
`
`
` T: (212) 210-9529
` F: (212) 210-9444
`
`Counsel for Mylan Laboratories
`Limited
`
`Back-Up Counsel
`Paul M. Zagar
`Reg. No. 52,392
`PZagar@BlankRome.com
`Blank Rome LLP
`The Chrysler Building
`405 Lexington Ave.
`New York, NY 10174
`T: 212-885-5290
`F: 917-332-3063
`
`Counsel for Emcure
`
`
`
`Back-Up Counsel
`Gerard A. Haddad
`Reg. No. 41,811
`GHaddad@BlankRome.com
`Blank Rome LLP
`
`The Chrysler Building
`405 Lexington Ave.
`New York, NY 10174
`T: 212-885-5135
` F: 917-591-6921
`
`Counsel for Glenmark
`Service Information
`D.
`Petitioners consent to electronic service to the lead and backup counsel at
`
`the email addresses listed above.
`
`IV. GROUNDS FOR STANDING
`Pursuant to 37 C.F.R. § 42.104(a), Petitioners certify that the ‘209 Patent is
`
`available for IPR and that Petitioners are not barred or estopped from requesting
`
`IPR challenging the claims of the ‘209 Patent on the grounds identified in this
`
`Petition. This Petition is timely and proper under 35 U.S.C. § 315(b) and (c),
`
`because it is filed within one month of the institution of the Sandoz IPR, and it is
`
`accompanied by a Motion for Joinder.
`
`18
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`

`

`V.
`
`PAYMENT OF FEES
`
`The required fees are submitted herewith in accordance with 37 C.F.R. §§
`
`42.103(a) and 42.15(a). Please charge any fees or credit overpayment to Deposit
`
`Account 503626.
`
`VI.
`
`IDENTIFICATION OF CHALLENGE AND STATEMENT OF THE
`PRECISE RELIEF REQUESTED
`Petitioners request inter partes review and cancellation of claims 1-22 of the
`
`’209 patent on one or more of grounds pursuant to 35 U.S.C. § 103 as set forth
`
`herein. The ’209 patent is to be reviewed under pre-AIA § 103. Petitioners’
`
`detailed statement of the reasons for the relief requested is set forth below in the
`
`section titled “Statement of Reasons for the Relief Requested.” In accordance with
`
`37 C.F.R. § 42.6(c), copies of the exhibits are filed herewith. In addition, the
`
`Petition is accompanied by the declaration of Dr. Ron D. Schiff. Ex. 1004.
`
`Claims 1-22 of the ’209 patent are unpatentable based upon the following
`
`grounds:
`
`Ground 1: Claims 1-22 are obvious over Calvert in view of Niyikiza I,
`
`Worzalla, and the knowledge of a person of ordinary skill.
`
`Ground 2: Claims 1-22 are obvious over Calvert in view of Niyikiza I,
`
`Hammond I, and the knowledge of a person of ordinary skill.
`
`The addition of limitations directed to specific dosages, dosing schedules,
`
`and the combination of the known chemotherapy drug cisplatin add nothing
`
`19
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`

`

`patentable to independent claims 1 and 12 because these parameters were well
`
`known to the person of ordinary skill in the art (“POSA”).
`
`There is no redundancy in Grounds 1 and 2. Ground 1 (which is directed to
`
`claims 1-22) relies on Calvert, Niyikiza I, and Worzalla as primary references.
`
`Worzalla expressly discloses folic acid pretreatment in mice. Ground 2 (which is
`
`also directed to claims 1-22) differs because it relies on Hammond I as the third
`
`primary reference. Hammond I expressly discloses folic acid pretreatment in
`
`humans.
`
`VII. THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW
`This petition meets the threshold requirement for inter partes review
`
`because it establishes “a reasonable likelihood that the petitioners would prevail
`
`with respect to at least 1 of the claims challenged in the petition.” 35 U.S.C.
`
`§ 314(a). As explained below, for each of the grounds of unpatentability proposed
`
`below, there is a reasonable likelihood that Petitioners will prevail with respect to
`
`at least one of the challenged claims.
`
`VIII. STATEMENT OF REASONS FOR THE RELIEF REQUESTED
`Summary of the Argument
`A.
`Pemetrexed is the active pharmaceutical ingredient in Lilly’s Alimta®
`
`chemotherapy product, which was approved by the U.S. Food & Drug
`
`Administration (“FDA”) in February 2004. Ex. 1038, Alimta® Approval Letter.
`
`20
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`

`

`In the early 1990s, Lilly obtained patent coverage for pemetrexed with the issuance
`
`of U.S. Patent Nos. 5,217,974 (“’974 patent”) and 5,344,932 (“’932 patent”). The
`
`’974 patent expired in 2012 and patent exclusivity for the ’932 patent will expire in
`
`2017. Ex. 1025, Orange Book Listing for Alimta® at 1025-0003; Ex. 1054, 2015
`
`Alimta® Orange Book Listing. The ’209 patent, which expires in 2022, is Lilly’s
`
`effort to extend its patent monopoly for pemetrexed for an additional 5 years
`
`beyond the 2017-expiration date of Lilly’s ’932 patent. But the claims of the ’209
`
`patent are directed to an obvious method for administering the known drug
`
`pemetrexed disodium. As such, the claims of the ’209 patent should be canceled,
`
`and Lilly’s patent monopoly over pemetrexed should end with the expiration of the
`
`’932 patent in 2017, which will clear the way for Petitioners’ lower-priced generic
`
`product.
`
`In the late 1990s, pemetrexed was one of several known antifolates, which
`
`are a class of antitumor drugs. Antifolates interfere with the growth and
`
`proliferation of cancer cells by disrupting DNA synthesis. Ex. 1004, Schiff Decl.
`
`¶ 28. Antifolates disrupt DNA synthesis by competing with folic acid (actually the
`
`metabolic derivatives of folic acid) for binding sites on certain enzymes. Id. ¶ 30.
`
`Unfortunately, antifolates also interfere with the growth and proliferation of
`
`healthy cells, which leads to “toxicity.” Id. ¶ 29. In order to maintain suf