Paper No. 1
`Filed: July 1, 2016
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
`
`TEVA PHARMACEUTICALS USA, INC.
`
` &
`
`
`
`
`FRESENIUS KABI USA, LLC
`
`PETITIONERS
`
`V.
`
`ELI LILLY & COMPANY
`
`PATENT OWNER
`___________________
`
`CASE NO.: IPR2016-01341
`PATENT NO. 7,772,209
`FILED: JULY 11, 2007
`ISSUED: AUGUST 10, 2010
`INVENTOR: CLET NIYIKIZA
`TITLE: ANTIFOLATE COMBINATION THERAPIES
`___________________
`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 7,772,209
`
`
`
`
`
`

`

`TABLE OF CONTENTS
`
`INTRODUCTION ................................................................................... 1
`
`A.
`
`B.
`
`
`C.
`
`Real Parties-in-Interest (37 C.F.R. § 42.8(b)(1)) .......................... 2
`
`Related Judicial and Administrative Matters
`(37 C.F.R. § 42.8(b)(2)) ............................................................... 3
`
`Lead and Back-Up Counsel (37 C.F.R. § 42.8(b)(3)) and
`Service Information (37 C.F.R. § 42.8(b)(4)) .............................. 4
`
`
`I.
`
`II. OVERVIEW ............................................................................................ 1
`
`III. GROUNDS FOR STANDING (37 C.F.R. § 42.104(A)) ........................ 2
`
`IV. MANDATORY NOTICES (37 C.F.R. § 42.8) ....................................... 2
`
`
`
`
`
`V.
`
`VI.
`
`
`
`
`
`
`
`
`
`PAYMENT OF FEES (37 C.F.R. § 42.15(A) AND § 42.103) ............... 5
`
`IDENTIFICATION OF CHALLENGE .................................................. 5
`
`A. Overview of U.S. Patent No. 7,772,209 ....................................... 5
`
`The ’209 Patent Specification ............................................. 5
`
`The ’209 Patent Claims ....................................................... 7
`
`1.
`
`2.
`
`3.
`
`Claim Construction of Challenged Claims ................................. 13
`
`The ’209 Prosecution History ............................................. 8
`
`B.
`
`1.
`
`2.
`
`3.
`
`4.
`
`
`“Patient” ............................................................................ 14
`
`“Methylmalonic acid lowering agent” .............................. 14
`
`“An effective amount of pemetrexed disodium” .............. 14
`
`“An effective amount of folic acid and an effective
` amount of a methylmalonic acid lowering agent” ........... 15
`i
`
`

`

`
`5.
`
`6.
`
`“Toxicity” ......................................................................... 15
`
`“Antifolate” and “antifolate drug” .................................... 15
`
`C.
`
`
`Statement of Precise Relief Requested for Each
`Claim Challenged ........................................................................ 16
`
`1.
`
`2.
`
`Claims for Which Review is Requested ........................... 16
`
`Statutory Grounds of Challenge ....................................... 16
`
`D. Overview of the State of the Art and Motivation to Combine ... 17
`
`1.
`
`
`Summary of the Petition’s Prior Art References .............. 22
`
`a.
`
`b.
`
`c.
`
`The ’974 Patent (Ex. 1009) ..................................... 22
`
`EP 005 (Ex. 1010) .................................................. 23
`
`Niyikiza (Ex. 1008) ................................................ 25
`
`E.
`
`Level of Ordinary Skill in the Art ............................................... 26
`
`
`VII. DETAILED EXPLANATION OF THE CHALLENGE ...................... 27
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`A. Ground 1: Claims 1–22 of U.S. Patent No. 7,772,209
`
`are obvious under 35 U.S.C. § 103(a) over Niyikiza
`
`in view of the’974 Patent and in further view of
`
`EP 005 and the knowledge of one of ordinary
`
`skill in the art ..................................................................... 27
`
`1.
`
`
`
`
`2.
`
`3.
`
`Independent Claims 1 and 12 are obvious
`over Niyikiza in view of the’974 Patent and
`in further view of EP 005 and the knowledge
`of one of ordinary skill in the art. ........................... 27
`
`Dependent Claims 2–10 and 14–21 are obvious .... 42
`
`Dependent Claims 11, 13, and 22 are obvious ....... 51
`ii
`
`

`

`
`The S.D. of Indiana Decision Finding that Teva Did Not
`Establish by Clear and Convincing Evidence that Certain
`Claims of the ’209 Patent are Obvious is Not Relevant to
`this Proceeding ............................................................................ 53
`
`B.
`
`
`
`
`
`VIII. ANY SECONDARY CONSIDERATIONS ARE INSUFFICIENT
`TO OVERCOME THE OBVIOUSNESS OF CLAIMS 1–22 .............. 57
`
`
`IX. CONCLUSION ...................................................................................... 63
`
`
`
`
`
`
`
`iii
`
`

`

`
`
`
`
`TABLE OF AUTHORITIES
`
`
`Cases
`
`Abbott Labs v. Andrx Pharms., Inc.,
` 452 F.3d 1331 (Fed. Cir. 2006)..................................................................... 52
`
`Bayer Schering Pharma AG v. Barr Labs., Inc.,
` 575 F.3d 1341 (Fed. Cir. 2009)..................................................................... 41
`
`Dow Chem. Co. v. Sumitomo Chem. Co.,
` 257 F.3d 1364 (Fed. Cir. 2001)..................................................................... 33
`
`Dystar Textilfarben GmbH v. C.H. Patrick Co.,
` 464 F.3d 1356 (Fed. Cir. 2006)..................................................................... 53
`
`Ethicon, Inc. v. Quigg,
` 849 F.2d 1422 (Fed. Cir. 1988)..................................................................... 53
`
`Ex parte Gelles,
` 22 USPQ2d 1318 (Bd. Pat. App. & Inter. 1992) .............................. 57, 59, 62
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
` 737 F.3d 731 (Fed. Cir. 2013) ....................................................................... 57
`
`Geo M. Martin Co. v. Alliance Mach. Sys. Int’l LLC,
` 618 F.3d 1294 (Fed. Cir. 2010)..................................................................... 62
`
`In re Am. Acad. of Sci. Tech. Ctr.,
` 367 F.3d 1359 (Fed. Cir. 2004)..................................................................... 13
`
`In re Applied Materials, Inc.,
` 692 F.3d 1289 (Fed. Cir. 2012)......................................................... 36, 41, 48
`
`In re Cipro Cases I & II,
` 61 Cal. 4th 116 (Cal. 2015) ........................................................................... 54
`
`In re Cuozzo Speed Techs., LLC,
` 778 F.3d 1271 (Fed. Cir. 2015) .................................................................... 13
`iv
`
`

`

`In re Dill,
` 604 F.2d 1356 (CCPA 1979) ....................................................................... 60
`
`In re Glatt Air Techniques, Inc.,
` 630 F.3d 1026 (Fed. Cir. 2011)..................................................................... 33
`
`In re Graves,
` 69 F.3d 1147 (Fed. Cir. 1995) ....................................................................... 33
`
`In re Icon Health & Fitness, Inc.,
` 496 F.3d 1374 (Fed. Cir. 2007)............................................................... 27, 34
`
`In re Klosak,
` 455 F.2d 1077 (CCPA 1973) ....................................................................... 59
`
`In re Merchant,
` 575 F.2d 865 (CCPA 1978) .......................................................................... 59
`
`In re Peterson,
` 315 F.3d 1325 (Fed. Cir. 2003)................................................... 38, 45, 50, 51
`
`In re Preda,
` 401 F.2d 825 (CCPA 1968) .......................................................................... 33
`
`In re Swanson,
` 540 F.3d 1368 (Fed. Cir. 2008) .................................................................... 53
`
`KSR Int’l Co. v. Teleflex Inc.,
` 550 U.S. 398 (2007) ................................................................................ 42, 53
`
`Leapfrog Enterprises Inc. v. Fisher-Price Inc.,
` 485 F.3d 1157 (Fed. Cir. 2007) .................................................................... 58
`
`Nat’l Steel Car, Ltd. v. Canadian Pac. Ry., Ltd.,
` 357 F.3d 1319 (Fed. Cir. 2004)..................................................................... 21
`
`Newell Cos., Inc. v. Kenney, Mfg. Co.,
` 864 F.2d 757 (Fed. Cir. 1988) ...................................................................... 57
`
`
`
`
`v
`
`

`

`NPF Ltd. v. Smart Parts, Inc.,
` 187 Fed. Appx. 973 (Fed. Cir. 2006) ............................................................ 21
`
`Pacing Techs., LLC v. Garmin Int’l, Inc.,
` 778 F.3d 1021 (Fed. Cir. 2015)..................................................................... 14
`
`Par Pharm., Inc. v. TWi Pharms., Inc.,
` 773 F.3d 1186 (Fed. Cir. 2014)..................................................................... 35
`
`Pentec, Inc. v. Graphic Controls Corp.,
` 776 F.2d 309 (Fed. Cir. 1985) ....................................................................... 33
`
`Pfizer, Inc. v. Apotex, Inc.,
` 480 F.3d 1348 (Fed. Cir. 2007) .................................................................... 40
`
`Rogers v. Desa Int’l, Inc.,
` 198 Fed. Appx. 918 (Fed. Cir. 2006) ............................................................ 35
`
`See Sciele Pharma, Inc. v. Lupin Ltd.,
` 684 F.3d 1253 (Fed. Cir. 2012) .................................................................... 46
`
`Trs. of Columbia Univ. v. Illumina, Inc.,
` 2015 U.S. App. LEXIS 12343 (Fed. Cir. July 17, 2015).............................. 62
`
`Tyco Healthcare Grp. LP v. Ethicon Endo-Surgery, Inc.,
` 774 F.3d 968 (Fed. Cir. 2014) ....................................................................... 29
`
`Statutes
`
`35 U.S.C. § 102(b) ......................................................................... 16, 22, 23, 25
`35 U.S.C. § 103
` ........................................................................... 1, 16, 27, 47
`35 U.S.C. § 103(a) ................................................................................ 8, 17, 54
`35 U.S.C. § 311
` ....................................................................................... 1, 16
`
`Regulations
`
`37 C.F.R. § 42.8(b)(1) ........................................................................................ 2
`37 C.F.R. § 42.15(a) ........................................................................................... 5
`37 C.F.R. § 42.103 ............................................................................................. 5
`37 C.F.R. § 42.104(a) ......................................................................................... 2
`vi
`
`
`
`

`

`37 C.F.R. § 42.8(b)(2) ........................................................................................ 3
`
`37 C.F.R. § 42.8(b)(2) .................................................... ..37 CFR. § 42.8(b)(2) ................................................
`
`33
`
`37 C.F.R. §42.8(b)(3) ...................................................................... "437 CPR. §42.8(b)(3) .................................................................... 4
`37 C.F.R. § 42.8(b)(3) ........................................................................................ 4
`
`37 C.F.R. § 42.8(b)(4)......................................................:::::::::::::::::::::::::::""" "437 CFR § 42.8(bx4)................................................IIIIIIIIIIIIIIIIIIIIIIIIIII""""""" 4
`37 C.F.R. § 42.8(b)(4) ........................................................................................ 4
`
`
`
`vii
`
`
`
`ViiVii
`
`

`

`
`
`Exhibit No.
`Exhibit 1001
`
`Exhibit 1002
`
`Exhibit 1003
`
`Exhibit 1004
`
`Exhibit 1005
`
`Exhibit 1006
`
`Exhibit 1007
`
`Exhibit 1008
`
`Exhibit 1009
`Exhibit 1010
`
`Exhibit 1011
`
`TABLE OF EXHIBITS
`
`Description
`U.S. Patent No. 7,772,209 to Clet Niyikiza,
`filed on July 11, 2007, and issued on Aug. 10,
`2010 (“the ’209 patent”)
`U.S. Patent No. 7,772,209 Prosecution History
`(“’209 prosecution history”)
`U.S. Patent No. 5,344,932 to Edward C Taylor,
`issued on Sep. 6, 1994 (“Taylor”)
`Claim Chart for Niyikiza ’209 Petition
`(Attachment 2 to Bleyer Declaration)
`Worzalla et al., “Role of Folic Acid in
`Modulating the Toxicity and Efficacy of the
`Multitargeted Antifolate, LY231514.”
`Anticancer Research 18:3235-3240 (1998)
`(“Worzalla”)
`U.S. Patent No. 4,140,707 to Cleare et al.,
`issued on Feb. 20, 1979 (“Cleare”)
`Tsao CS, “Influence of Cobalamin on the
`Survival of Mice Bearing Ascites Tumor.”
`Pathobiology 1993;61:104-108 (“Tsao”)
`Niyikiza et al., “MTA (LY231514):
`Relationship of vitamin metabolite profile,
`drug exposure, and other patient characteristics
`to toxicity.” Annals of Oncology, Vol. 9,
`Suppl. 4, 1998, Abstract 609P, pg. 126
`(“Niyikiza”)
`U.S. Patent No. 5,217,974 (“the ’974 Patent”)
`European Patent Application No. 0,595,005 A1
`(“EP 005”)
`Rusthoven et al., “Multitargeted Antifolate
`LY231514 as First-Line Chemotherapy for
`Patients with Advanced Non-Small-Cell Lung
`Cancer: A Phase II Study.” Journal of Clinical
`Oncology, Vol. 17, No. 4, (April 1999), pp.
`1194-1199 (“Rusthoven”)
`
`
`
`viii
`
`

`

`Exhibit 1012
`
`Exhibit 1013
`
`Exhibit 1014
`
`Exhibit 1015
`
`Exhibit 1016
`
`Exhibit 1017
`
`Exhibit 1018
`
`Exhibit 1019
`
`Exhibit 1020
`
`
`
`Refsum H & Ueland PM, “Clinical
`significance of pharmacological modulation of
`homocysteine metabolism.” Trends in
`Pharmacol. Sci., Vol. 11, No. 10, 1990, pp.
`411-416 (“Refsum”)
`Calvert AH & Walling JM, “Clinical studies
`with MTA.” British Journal of Cancer (1998)
`78 (Suppl. 3), 35-40 (“Calvert 1998”)
`Calvert H, “An Overview of Folate
`Metabolism: Features Relevant to the Action
`and Toxicities of Antifolate Anticancer
`Agents,” Seminars in Oncology, Vol. 26, No.
`2, Suppl 6 (April), 1999, pp. 3-10 (“Calvert
`1999”)
`O’Dwyer et al., “Overview of Phase II Trials of
`MTA in Solid Tumors.” Seminars in Oncology,
`Vol. 26, No. 2, Suppl 6 (April), 1999, pp. 99-
`104 (“O’Dwyer”)
`Zervos et al., “Functional folate status as a
`prognostic indicator of toxicity in clinical trials
`of the multitargeted antifolate LY231514.”
`Proceedings of ASCO, Vol. 16, 1997, pg. 256a
`(“Zervos”)
`Allen et al., “Diagnosis of Cobalamin
`Deficiency I: Usefulness of Serum
`Methylmalonic Acid and Total Homocysteine
`Concentrations.” American Journal of
`Hematology, 34, 1990, 90-98 (“Allen”)
`Savage et al., “Sensitivity of Serum
`Methylmalonic Acid and Total Homocysteine
`Determinations for Diagnosing Cobalamin and
`Folate Deficiencies. The American Journal of
`Medicine, 96: 1994, 239-246 (“Savage”)
`Brönstrup et al., “Effects of folic acid and
`combinations of folic acid and vitamin B-12 on
`plasma homocysteine concentrations in
`healthy, young women.” Am. J. Clin. Nutr.
`Vol. 68, 1998, 1104-10 (“Bronstrup”)
`Carrasco et al., “Acute megaloblastic anemia:
`
`ix
`
`

`

`Exhibit 1021
`
`Exhibit 1022
`
`Exhibit 1023
`
`Exhibit 1024
`
`Exhibit 1025
`
`Exhibit 1026
`
`Exhibit 1027
`
`Exhibit 1028
`
`Exhibit 1029
`Exhibit 1030
`Exhibit 1031
`
`
`
`homocysteine levels are useful for diagnosis
`and follow-up.” Haematologica, Vol. 84(8),
`August 1999, 767-768 (“Carrasco”)
`Thödtmann et al., “Phase I study of different
`sequences of MTA (LY231514) in
`combination with cisplatin in patients with
`solid tumours.” Annals of Oncology, Vol. 9,
`Suppl. 4, 1998, Abstract 618P, pg. 129
`(“Thodtmann”)
`Hammond et al., “A Phase I and
`pharmacokinetic (PK) study of the
`multitargeted antifolate (MTA, LY231514)
`with folic acid (FA).” Annals of Oncology,
`Vol. 9, Suppl. 4, 1998, Abstract 620P, pg. 129
`(“Hammond”)
`Morgan et al., “The Effect of Folic Acid
`Supplementation on the Toxicity of Low-Dose
`Methotrexate in Patients with Rheumatoid
`Arthritis.” Arthritis and Rheumatism, Vol. 33,
`No. 1, January 1990, pp. 9-18 (“Morgan”) (Ex.
`1023)
`Curriculum Vitae of W. Archie Bleyer, M.D.,
`FRCP[Glasg] (Attachment 1 to Bleyer
`Declaration)
`Declaration of W. Archie Bleyer, M.D.,
`FRCP[Glasg]
`Eli Lilly and Company v. Teva Parental
`Medicines, Inc., et al., INSD-1:10-cv-01376
`Markman Order (June 20, 2012) (“Teva”)
`Eli Lilly and Company v. Teva Parental
`Medicines, Inc., et al., INSD-1:10-cv-01376
`Joint Claim Construction Brief (April 19,
`2012) (“Teva Claim Construction”)
`Eli Lilly and Company v. Teva Parental
`Medicines, Inc., et al., INSD-1:10-cv-01376
`Decision (March 31, 2014) (“Teva Decision”)
`Curriculum Vitae of Scott Bennett, Ph.D.
`Declaration of Scott Bennett, Ph.D.
`Copy of Niyikiza from Oxford University Press
`
`x
`
`

`

`Exhibit 1032
`
`Exhibit 1033
`
`Exhibit 1034
`
`Exhibit 1035
`
`Exhibit 1036
`
`Exhibit 1037
`
`Exhibit 1038
`
`Exhibit 1039
`Exhibit 1040
`Exhibit 1041
`
`
`
`
`
`
`
`Journals
`University of Illinois at Urbana-Champaign
`Library directory entry for Annals of Oncology
`Statewide Illinois Library Catalog record for
`Annals of Oncology
`Copy of Niyikiza from the University of
`Wisconsin Library
`Online copy of Carrasco from the Highwire
`Press
`University of Illinois at Urbana-Champaign
`Library directory entry for Haematologica
`Statewide Illinois Library Catalog record for
`Haematologica
`Copy of Carrasco from the University of
`Michigan Taubman Medical Library
`Web of Science entry for Carrasco
`Declaration of Mark J. Ratain
`Curriculum Vitae of Mark J. Ratain
`
`xi
`
`

`

`I.
`
`
`
`INTRODUCTION
`
`Teva Pharmaceuticals USA, Inc. (“Teva”) and Fresenius Kabi USA, LLC
`
`(“Fresenius”) (collectively, “Petitioner”), request an Inter Partes Review (“IPR”)
`
`of Claims 1–22 (collectively, the “Challenged Claims”) of U.S. Patent No.
`
`7,772,209 (the “’209 Patent”) (Ex. 1001) in accordance with 35 U.S.C. §§ 311–19
`
`and 37 C.F.R. §§ 42.100 et seq.
`
`II. OVERVIEW
`
`
`The Board has already issued its Decision Instituting Inter Partes Review
`
`(“Decision”) on all challenged claims of the ’209 patent on the same grounds
`
`raised herein. Neptune Generics, LLC vs. Eli Lilly and Company, Case IPR2016-
`
`00237 (the “Neptune IPR” or “IPR 237”) (Paper 13). In its Decision, the Board
`
`found that Petitioner Neptune Generics, LLC (“Neptune”) 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 ground:
`
`Ground 1: Claims 1-22 are obvious in view of Niyikiza, U.S. 5,217,974, and
`
`EP 0 595 005.
`
`IPR2016-00237 (Paper 13). Petitioner Teva/Fresenius hereby files its own petition
`
`on the same grounds and concurrently seeks joinder of this IPR to the instituted
`
`IPR proceedings on these challenged claims.
`
`
`
`1
`
`

`

`
`
`For the sake of completeness and efficiency, the present Petition is a
`
`practical copy of the petition in the Neptune IPR. Specifically, the present Petition
`
`is narrowly-tailored to the same claims, prior art, and grounds of unpatentability
`
`that are the subject of the Neptune IPR. A motion for Joinder with the Neptune IPR
`
`is being filed concurrently with this Petition.
`
`III. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a))
`
`Pursuant to 37 C.F.R. § 42.104(a), Petitioner certifies that the ’209 Patent is
`
`available for IPR and that Petitioner is not barred or estopped from requesting IPR
`
`challenging the claims of the ’209 Patent on the grounds identified in this Petition.
`
`IV. MANDATORY NOTICES (37 C.F.R. § 42.8)
`
`
`
`A. Real Parties-in-Interest (37 C.F.R. § 42.8(b)(1))
`
`For Teva, the real parties-in-interest are Teva Pharmaceuticals USA, Inc.,
`
`Teva Parenteral Medicines, Inc., Pliva Hrvatska D.O.O., and Barr Laboratories,
`
`Inc.1
`
`
`1
`The following entities are parent corporations and/or publicly-held
`
`companies that own 10 percent or more of the stock of the Teva real parties-in-
`
`interest: Sicor Inc.; Teva Pharmaceuticals Holdings Cooperatieve, U.A.; IVAX
`
`LLC; Orvet UK; Teva Pharmaceuticals Europe B.V.; Teva Pharmaceuticals
`
`Industries Ltd.; Barr Pharmaceuticals, LLC; Ivax International B.V.; IVAX
`
`
`
`2
`
`

`

`For Fresenius, the real party-in-interest is Fresenius Kabi USA, LLC.
`
`B. Related Judicial and Administrative Matters (37 C.F.R.
`§ 42.8(b)(2))
`
`Pursuant to 37 C.F.R. § 42.8(b)(2), Petitioner states that the ’209 Patent has
`
`
`
`
`been the subject of the following lawsuits: Eli Lilly and Company v. Fresenius
`
`Kabi USA, LLC, INSD-1:15-cv-00096 (filed Jan. 23, 2015); Eli Lilly and Company
`
`v. Sandoz Inc., INSD-1:14-cv-02008 (filed Dec. 5, 2014); Eli Lilly and Company et
`
`al. v. Nang Kuang Pharm. Co., Ltd. et al., INSD-1:14-cv-01647 (filed Oct. 8,
`
`2014); Eli Lilly and Company v. Glenmark Pharm. Ltd. et al., INSD-1:14-cv-
`
`00104 (filed Jan. 23, 2014); Eli Lilly and Company v. Sun Pharm. Global FZE et
`
`al., INSD-1:13-cv-01469 (filed Sept. 13, 2013); Petition for Inter Partes Review by
`
`Accord Healthcare, Inc., PTAB-IPR2013-00356 (filed June 14, 2013); Eli Lilly
`
`and Company v. Accord Healthcare, Inc., USA, INSD-1:13-cv-00335 (filed Feb.
`
`28, 2013); Eli Lilly and Company v. Apotex, Inc. et al., INSD-1:12-cv-00499 (filed
`
`Apr. 17, 2012); Eli Lilly and Company v. Accord Healthcare, Inc., USA, INSD-
`
`1:12-cv-00086 (filed Jan. 20, 2012); Eli Lilly and Company v. App Pharm., LLC,
`
`INSD-1:11-cv-00942 (filed Jul. 15, 2011); and Eli Lilly and Company v. Teva
`
`Parental Medicines, Inc., et al., INSD-1:10-cv-01376 (filed Oct. 29, 2010);
`
`
`International GmbH; Ivax International (Luxembourg) S.a.r.l.;and IVAX Holdings
`
`GmbH.
`
`
`
`3
`
`

`

`Petition for Inter Partes Review by Sandoz, Inc., IPR2016-00318 (filed June 16,
`
`2016) (“Sandoz IPR”); Petition for Inter Partes Review by Neptune Generics, LLC,
`
`IPR2016-00237 (filed June 3, 2016) (“Neptune IPR 1”); Petition for Inter Partes
`
`Review by Neptune Generics, LLC, IPR2016-00240 (filed June 3, 2016) (“Neptune
`
`IPR 2”).2
`
`Teva and Fresenius were previously sued by Eli Lilly with respect to the
`
`‘209 patent. Eli Lilly and Company v. Teva Parental Medicines, Inc., et al., INSD-
`
`1:10-cv-01376 (filed Oct. 29, 2010) (the “Teva Litigation”). That suit is currently
`
`on appeal at the Federal Circuit. Eli Lilly and Company v. Teva Parenteral
`
`Medicines, No. 15-2067 (Fed. Cir.) (filed Sept. 21, 2015).
`
`C.
`
`Lead and Back-Up Counsel (37 C.F.R. § 42.8(b)(3)) and Service
`Information (37 C.F.R. § 42.8(b)(4))
`
`Lead counsel is Gary J. Speier, Reg. No. 45,458,
`
`
`
`gspeier@carlsoncaspers.com of Carlson, Caspers, Vandenburgh, Lindquist &
`
`Schuman, 225 South Sixth Street, Suite 4200, Minneapolis, MN 55402, P: (612)
`
`436-9600; F: (612) 436-9605. Back-up counsel are: Mark D. Schuman, Reg. No.
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`31,197, mschuman@carlsoncaspers.com, also of Carlson Caspers; Cynthia
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`Lambert Hardman, Reg. No. 53,179, chardman@goodwinprocter.com of Goodwin
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`2 In addition to the instant petition, Petitioner is also filing petitions and motions
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`for joinder relating to the Sandoz IPR and Neptune IPR 2.
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`4
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`

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`Procter LLP, The New York Times Building, 620 Eighth Avenue, New York, NY
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`10018-1405, P: (212) 813-8800; F: (212) 355-3333. Petitioner consents to
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`electronic service.
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`V.
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`
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`PAYMENT OF FEES (37 C.F.R. § 42.15(a) and § 42.103)
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`The Petitioner authorizes the Patent and Trademark Office to charge Deposit
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`Account No. 502880 for this Petition for IPR, and further authorizes payment of
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`any additional fees to be charged to this Deposit Account. Any overpayment or
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`refund of fees may also be deposited in this Deposit Account.
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`VI.
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`
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`IDENTIFICATION OF CHALLENGE
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`A. Overview of U.S. Patent No. 7,772,209
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`The ’209 Patent is titled “Antifolate Combination Therapies.” (Ex. 1001 at
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`Front Cover.) The underlying application, U.S. Patent App. No. 11/776,329 (the
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`“’329 Application”), was filed on July 11, 2007. The ’209 Patent issued to Clet
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`Niyikiza on August 10, 2010. (Id.) The earliest application to which the ’209
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`Patent claims priority is U.S. Patent App. No. 60/215,310 (filed June 3, 2000).
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`
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`
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`1.
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`The ’209 Patent Specification
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`The ’209 Patent claims “a method of administering an antifolate to a
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`mammal in need thereof, comprising administering an effective amount of said
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`antifolate in combination with a methylmalonic acid lowering agent and a FBP
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`[folate binding protein] binding agent.” (Id. at 3:1–5.) “A preferred FBP binding
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`5
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`agent is folic acid,” and a preferred methylmalonic acid (“MMA”) lowering agent
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`is vitamin B12. (Id. at 3:5–6, 4:47–50.)
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`
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`The ’209 specification admits the following with respect to the prior art:
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`Antifolates represent one of the most thoroughly studied classes of
`antineoplastic agents, with aminopterin initially demonstrating clinical
`activity approximately 50 years ago. Methotrexate was developed
`shortly thereafter, and today is a standard component of effective
`chemotherapeutic regimens for malignancies such as lymphoma,
`breast cancer, and head and neck cancer.
`
`
`(Id. at 1:19–25.) The ’209 specification states that “life-threatening toxicity
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`remains a major limitation to the optimal administration of antifolates,” while
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`admitting that increased homocysteine levels have been known to cause antifolate
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`toxicity. (Id. at 1:11–13, 2:24–26.) The specification also admits that “[f]olic acid
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`has been shown to lower homocysteine levels.” (Id. at 2:16–17.) And, it admits that
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`“increased levels of methylmalonic acid is a predicator of toxic events in patients
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`that receive an antifolate drug,” and further admits that treatment with vitamin B12
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`was known to reduce those toxic events: “the treatment and prevention of
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`cardiovascular disease with folic acid in combination with vitamin B12 is
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`known….” (Id. at 2:41–43, 50–52.)
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`
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`The ’209 Patent’s purported invention was designed “to lower cytotoxic
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`activity” associated with antifolate treatment. (Id. at 2:29–37.) The patent states
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`that “we have discovered that the combination of a methylmalonic acid lowering
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`6
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`

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`agent and folic acid synergistically reduces the toxic events associated with the
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`administration of antifolate drugs.” (Id. at 2:47–50.)
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`
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`The ’209 Patent’s invention can be summarized as: (1) administration of
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`pemetrexed disodium to a patient in combination with an effective amount of folic
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`acid and an effective amount of MMA lowering agent, such as vitamin B12;
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`(2) pretreatment with folic acid prior to pemetrexed disodium treatment;
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`(3) pretreatment with folic acid and vitamin B12 prior to pemetrexed disodium
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`treatment; (4) repetition of vitamin B12 administration; and (5) administering
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`cisplatin with pemetrexed disodium to the patient. (Id. at 10:56–12:29.)
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`
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`The patent also states that a physician determines the amount of MMA
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`lowering agent to be administered based on “the relevant circumstances, including
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`the condition to be treated, the chosen route of administration, the actual agent
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`administered, the age, weight, and response of the individual patient, and the
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`severity of the patient’s symptoms….” (Id. at 5:37–50; 6:41–52.)
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`
`
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`
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`2.
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` The ’209 Patent Claims
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`The ’209 Patent has two independent claims (Claims 1 and 12) and 20
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`dependent claims. Claim 1 provides:
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`A method for administering pemetrexed disodium to a patient in need
`thereof comprising administering an effective amount of folic acid
`and an effective amount of a methylmalonic acid lowering agent
`followed by administering an effective amount of pemetrexed
`disodium, wherein the methylmalonic acid lowering agent is selected
`from the group consisting of vitamin B12, hydroxycobalamin, cyano-
`7
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`

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`10-chlorocobalamin, aquocobalamin perchlorate, aquo-10-cobalamin
`perchlorate, azidocobalamin, cobalamin, cyanocobalamin, or
`chlorocobalamin.
`
`
`(Id. at 10:56–65.)
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`Claim 12 provides:
`
`
`An improved method for administering pemetrexed disodium to a
`patient in need of chemotherapeutic treatment, wherein the
`improvement comprises:
`a) administration of between about 350 μg and about 1000 μg of folic
`acid prior to the first administration of pemetrexed disodium;
`b) administration of about 500 μg to about 1500 μg of vitamin B12,
`prior to the first administration of pemetrexed disodium; and
`c) administration of pemetrexed disodium.
`(Id. at 11:25–12:4.)
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`
`
`
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`
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`3.
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` The ’209 Prosecution History
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`During prosecution of the ’329 Application, the Examiner initially rejected
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`all claims as obvious under 35 U.S.C. § 103(a) over Taylor (Ex. 1003) in view of
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`Poydock, and in further view of Worzalla (Ex. 1005) and Cleare (Ex. 1006). (Ex.
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`1002 at 310.) At the time of this rejection, Claims 40–52 were pending. (Id. at
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`307.) Claim 40, the only independent claim, recited “[a] method for administering
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`pemetrexed disodium to a patient in need thereof comprising administering an
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`effective amount of pemetrexed disodium in combination with a methylmalonic
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`acid lowering agent….” (Id. at 345.)
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`
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`8
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`
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`The Examiner rejected Claims 40–52, stating that Taylor taught “N-
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`(pyrrolo(2,3-D)pyrimidin-3-ylacyl)-glutamic acid derivatives,” including
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`pemetrexed (LY 231514) and pemetrexed disodium, as effective antineoplastic
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`agents for inhibition of tumor growth, where other antineoplastic agents could be
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`combined with pemetrexed, while Poydock taught “a methylmalonic acid lowering
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`agent such as hydroxocobalamin” for inhibition of tumors implanted in mice. (Id.
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`at 310–11.) The Examiner further stated that Worzalla taught “the supplementation
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`of folic acid with LY 231514 to enhance LY 231514 antitumor activity,” while
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`Cleare taught “malonato platinum anti-tumor compounds such as cisplatin to treat
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`malignant tumors.” (Id. at 311.) The Examiner concluded that “one skilled in the
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`art would have assumed the combination of three antineoplastic agents into a
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`single composition would give an additive effect in the absence of evidence to the
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`contrary.” (Id.) The Examiner further stated that although the cited references do
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`not teach the dosage range for the MMA lowering agent, “those skilled in the art
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`would have [] readily optimized effective dosages and concurrent administration
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`dosage forms as determined by good medical practice and the clinical condition of
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`the individual patient.” (Id. at 311.)
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`
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`In response, Applicant amended Claim 45 by disclosing a “specific folic-
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`binding-protein binding agent species recited in the specification,” and amended
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`Claim 40 by adding, among other limitations, “lowering agent.” (Id. at 188.)
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`9
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`Applicant also argued that Poydock was “discredited prior to the present
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`application’s priority date” because, shortly after publication, it was discovered
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`that MMA lowering agent did not possess antitumor activity. (Id. at 188–89.)
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`
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`In response, the Examiner rejected the claims as obvious over Taylor in view
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`of Tsao (Ex. 1007), and in further view of Worzalla and Cleare. (Ex. 1002 at 108.)
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`The Examiner stated Tsao teaches “a methylmalonic acid lowering agent such as
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`cobalamin (vitamin B12) is effective as having antitumor activity,” and maintained
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`rejections with respect to Taylor, Worzalla, and Cleare. (Id. at 108–09.)
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`
`
`Applicant then canceled Claims 45–46, added new Claims 53–63, and
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`amended Claim 40 by adding, among other limitations, “administering an effective
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`amount of folic acid and an effective amount of a methylmalonic acid lowering
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`agent followed by.” (Id. at 82–85.) Applicant argued that the Examiner
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`misinterpreted “the art concerning vitamin B12 antineoplastic activity and the
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`teachings of [Taylor].” (Id. at 86.) Applicant also argued that the Examiner
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`overstated Tsao’s teachings because Tsao disclosed results from hospital surveys
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`and animal studies with conflicting results on the effectiveness of vitamin B12
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`therapy alone or in combination with chemotherapeutic agents and
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`“cyanocobalamin ‘did not affect cell growth at a daily dose as high as 1,000 mg/kg
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`body weight.’” (Id. at 86–87.) Thus, “a person of ordinary skill in the art reading
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`Tsao, would not have perceived a reasonable expectation of success in making
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`10
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`Applicant’s invention in view of the scientific uncertainty concerning vitamin B12
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`and its use as an antitumor agent.” (Id. at 87.)
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`
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`Applicant further submitted “that the activity of B12 as a potential antitumor
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`therapeutic is still inconclusive even as of today.” (Id.) Applicant argued that
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`pemetrexed disodium, a folate analog, as a multitargeted antifolate with specific
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`activity at three enzymes in the biosynthesis of nucleic acids—“dihydrofolate
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`reductase (DHF