`Filed: July 1, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________
`
`
`APOTEX INC. and APOTEX CORP.
`
`Petitioners
`
`V.
`
`ELI LILLY & COMPANY
`
`Patent Owner
`
`_____________________
`
`Inter Partes Review No.: IPR2016-01190
`
`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 AUTHORITIES ................................................................................... iii
`
`TABLE OF CONTENTS
`
`TABLE OF EXHIBITS .......................................................................................... vii
`
`I.
`
`II.
`
`INTRODUCTION ........................................................................................... 1
`
`GROUNDS FOR STANDING (37 C.F.R. § 42.104(a)) ................................. 1
`
`III. MANDATORY NOTICES (37 C.F.R. § 42.8) ............................................... 2
`
`A.
`
`B.
`
`C.
`
`Real Parties-in-Interest (37 C.F.R. § 42.8(b)(1)) ........................ 2
`
`Related Matters (37 C.F.R. § 42.8(b)(2)) .................................... 2
`
`Lead and Back-Up Counsel (37 C.F.R. § 42.8(b)(3)) and
`Service Information (37 C.F.R. § 42.8(b)(4)) ............................ 3
`
`IV. PAYMENT OF FEES (37 C.F.R. § 42.15(a) and § 42.103) ........................... 3
`
`V.
`
`IDENTIFICATION OF CHALLENGE .......................................................... 4
`
`A. Overview of U.S. Patent No. 7,772,209 ..................................... 4
`
`1.
`
`2.
`
`3.
`
`The ‘209 Patent Specification........................................... 4
`
`The ‘209 Patent Claims..................................................... 6
`
`The ‘209 Prosecution History ........................................... 7
`
`B.
`
`Claim Construction of Challenged Claims ............................... 12
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`“Patient” .......................................................................... 13
`
`“Methylmalonic acid lowering agent” ............................ 13
`
`“An effective amount of pemetrexed disodium” ............ 13
`
`“An effective amount of folic acid and an effective
`amount of a methylmalonic acid lowering agent” ......... 14
`
`“Toxicity” ....................................................................... 14
`
`“Antifolate” and “antifolate drug” .................................. 14
`
`i
`
`
`
`C.
`
`Statement of Precise Relief Requested for Each Claim
`Challenged ................................................................................ 15
`
`1.
`
`2.
`
`Claims for Which Review is Requested ......................... 15
`
`Statutory Grounds of Challenge ..................................... 15
`
`D. Overview of the State of the Art and Motivation to
`Combine .................................................................................... 16
`
`1.
`
`Summary of the Petition’s Prior Art References ............ 20
`
`E.
`
`Level of Ordinary Skill in the Art ............................................. 24
`
`VI. DETAILED EXPLANATION OF THE CHALLENGE .............................. 25
`
`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. .......................... 25
`
`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. ................................................... 25
`
`Dependent Claims 2–10 and 14–21 are obvious. ........... 39
`
`Dependent Claims 11, 13, and 22 are obvious. .............. 48
`
`B.
`
`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. ......................................................................... 51
`
`VII. ANY SECONDARY CONSIDERATIONS ARE INSUFFICIENT TO
`OVERCOME THE OBVIOUSNESS OF CLAIMS 1–22. ........................... 54
`
`VIII. CONCLUSION .............................................................................................. 60
`
`
`
`
`
`
`
`ii
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`
`
`TABLE OF AUTHORITIES
`
`FEDERAL CASES
`Abbott Labs v. Andrx Pharms., Inc.,
`452 F.3d 1331 (Fed. Cir. 2006) ............................................................................ 49
`
`Bayer Schering Pharma AG v. Barr Labs., Inc.,
`575 F.3d 1341 (Fed. Cir. 2009) ............................................................................ 39
`
`Dow Chem. Co. v. Sumitomo Chem. Co.,
`257 F.3d 1364 (Fed. Cir. 2001) ............................................................................ 31
`
`Dystar Textilfarben GmbH v. C.H. Patrick Co.,
`464 F.3d 1356 (Fed. Cir. 2006) ............................................................................ 50
`
`Ethicon, Inc. v. Quigg,
`849 F.2d 1422 (Fed. Cir. 1988) ............................................................................ 51
`
`Ex parte Gelles,
`22 USPQ2d 1318 (Bd. Pat. App. & Inter. 1992) ..................................... 54, 57, 60
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013).............................................................................. 54
`
`Geo M. Martin Co. v. Alliance Mach. Sys. Int’l LLC,
`618 F.3d 1294 (Fed. Cir. 2010) ............................................................................ 60
`
`In re Aller,
`220 F.2d 454 (CCPA 1955) .................................................................................. 34
`
`In re Am. Acad. of Sci. Tech. Ctr.,
`367 F.3d 1359 (Fed. Cir. 2004) ............................................................................. 12
`
`In re Applied Materials, Inc.,
`692 F.3d 1289 (Fed. Cir. 2012) ................................................................ 34, 39, 45
`
`In re Cipro Cases I & II,
`61 Cal. 4th 116 (Cal. 2015) .................................................................................. 51
`
`In re Cuozzo Speed Techs., LLC,
`778 F.3d 1271 (Fed. Cir. 2015) ............................................................................ 12
`
`iii
`
`
`
`In re Dill,
`604 F.2d 1356 (CCPA 1979) ............................................................................... 57
`
`In re Glatt Air Techniques, Inc.,
`630 F.3d 1026 (Fed. Cir. 2011) ............................................................................ 31
`
`In re Graves,
`69 F.3d 1147 (Fed. Cir. 1995) .............................................................................. 31
`
`In re Icon Health & Fitness, Inc.,
`496 F.3d 1374 (Fed. Cir. 2007) ...................................................................... 26, 32
`
`In re Klosak,
`455 F.2d 1077 (CCPA 1973) ............................................................................... 57
`
`In re Merchant,
`575 F.2d 865 (CCPA 1978) .................................................................................. 57
`
`In re Peterson,
`315 F.3d at 1329 ....................................................................................... 35, 43, 48
`
`In re Preda,
`401 F.2d 825 (CCPA 1968) .................................................................................. 31
`
`In re Swanson,
`540 F.3d 1368 (Fed. Cir. 2008) ........................................................................... 51
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ................................................................................. 39, 44, 50
`
`Leapfrog Enters. Inc. v. Fisher-Price Inc.,
`485 F.3d 1157 (Fed. Cir. 2007) ............................................................................ 55
`
`Nat’l Steel Car, Ltd. v. Canadian Pac. Ry., Ltd.,
`357 F.3d 1319 (Fed. Cir. 2004) ............................................................................ 20
`
`Newell Cos., Inc. v. Kenney, Mfg. Co.,
`864 F.2d 757 (Fed. Cir. 1988) .............................................................................. 55
`
`NPF Ltd. v. Smart Parts, Inc.,
`187 Fed. App’x 973 (Fed. Cir. 2006) .................................................................. 20
`
`iv
`
`
`
`Pacing Techs., LLC v. Garmin Int’l, Inc.,
`778 F.3d 1021 (Fed. Cir. 2015) ........................................................................... 13
`
`Par Pharm., Inc. v. TWi Pharms., Inc.,
`773 F.3d 1186 (2014) ........................................................................................... 33
`
`Pentec, Inc. v. Graphic Controls Corp.,
`776 F.2d 309 (Fed. Cir. 1985) .............................................................................. 31
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) ........................................................................... 38
`
`Rogers v. Desa Int’l, Inc.,
`198 Fed. App’x 918 (Fed. Cir. 2006) ................................................................... 33
`
`Sciele Pharma, Inc. v. Lupin Ltd.,
`684 F.3d 1253 (Fed. Cir. 2012) ............................................................................ 44
`
`Trs. of Columbia Univ. v. Illumina, Inc.,
`2015 U.S. App. LEXIS 12343 (Fed. Cir. July 17, 2015) .................................... 60
`
`Tyco Healthcare Grp. LP v. Ethicon Endo-Surgery, Inc.,
`774 F.3d 968 (Fed. Cir. 2014) .................................................................. 27, 33, 53
`
`FEDERAL STATUTES
`
`35 U.S.C. § 102(b) ....................................................................................... 20, 22, 23
`
`35 U.S.C. § 103 ........................................................................................................ 15
`
`35 U.S.C. § 103(a) ............................................................................................... 7, 52
`
`35 U.S.C. § 311 ........................................................................................................ 15
`
`35 U.S.C. § 315(b) ...................................................................................................... 1
`
`35 U.S.C. § 315(c) ...................................................................................................... 1
`
`35 U.S.C. §§ 311–19 .................................................................................................. 1
`
`FEDERAL REGULATIONS
`
`37 C.F.R. § 42.100(b) ............................................................................................... 12
`
`v
`
`
`
`37 C.F.R. § 42.104(a) ................................................................................................. 1
`
`37 C.F.R. § 42.104(a) ............................................................................................... ..137 CPR. § 42.104(a) ................................................................................................. 1
`
`37 C.F.R. § 42.8(b)(2) ................................................................................................ 2
`
`37 C.F.R. § 42.8(b)(2) .............................................................................................. ..237 CPR. § 42.8(b)(2) ................................................................................................ 2
`
`37 C.F.R. §§ 42.100 et seq. ........................................................................................ 1
`
`37 C.F.R. §§ 42.100 et seq....................................................................................... ..137 C.F.R. §§ 42.100 et seq......................................................................................... 1
`
`37 C.F.R. §§ 42.103(a) ............................................................................................... 3
`
`37 C.F.R. §§ 42.103(a) ............................................................................................. ..337 C.F.R. §§ 42.103(a) ............................................................................................... 3
`
`37 C.F.R. §§ 42.15(a) ................................................................................................. 3
`
`37 C.F.R. §§ 42.15(a) ............................................................................................... ..337 CPR. §§ 42.15(a) ................................................................................................. 3
`
`
`
`
`
`vi
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`
`
`ViVi
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`
`
`TABLE OF EXHIBITS
`
`Description
`Exhibit No.
`Exhibit 1001 U.S. Patent No. 7,772,209 to Clet Niyikiza, filed on July 11, 2007,
`and issued on Aug. 10, 2010 (“the ‘209 patent”)
`Exhibit 1002 U.S. Patent No. 7,772,209 Prosecution History (“‘209 prosecution
`history”)
`Exhibit 1003 U.S. Patent No. 5,344,932 to Edward C Taylor, issued on Sep. 6,
`1994 (“Taylor”)
`Exhibit 1004 Claim Chart for Niyikiza ‘209 Petition (Attachment 2 to Bleyer
`Declaration)
`Exhibit 1005 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”)
`Exhibit 1006 U.S. Patent No. 4,140,707 to Cleare et al., issued on Feb. 20, 1979
`(“Cleare”)
`Exhibit 1007 Tsao CS, “Influence of Cobalamin on the Survival of Mice
`Bearing Ascites Tumor.” Pathobiology 1993;61:104-108 (“Tsao”)
`Exhibit 1008 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”)
`Exhibit 1009 U.S. Patent No. 5,217,974 (“the ’974 Patent”)
`Exhibit 1010 European Patent Application No. 0,595,005 A1 (“EP 005”)
`Exhibit 1011 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”)
`Exhibit 1012 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”)
`Exhibit 1013 Calvert AH & Walling JM, “Clinical studies with MTA.” British
`Journal of Cancer (1998) 78 (Suppl. 3), 35-40 (“Clavert 1998”)
`
`
`
`
`vii
`
`
`
`Description
`Exhibit No.
`Exhibit 1014 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”)
`Exhibit 1015 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”)
`Exhibit 1016 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”)
`Exhibit 1017 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”)
`Exhibit 1018 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”)
`Exhibit 1019 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”)
`Exhibit 1020 Carrasco et al., “Acute megaloblastic anemia: homocysteine levels
`are useful for diagnosis and follow-up.” Haematologica, Vol.
`84(8), August 1999, 767-768 (“Carrasco”)
`Exhibit 1021 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”)
`Exhibit 1022 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”)
`
`
`
`viii
`
`
`
`
`
`Description
`Exhibit No.
`Exhibit 1023 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)
`Exhibit 1024 Curriculum Vitae of W. Archie Bleyer, M.D., FRCP[Glasg]
`(Attachment 1 to Bleyer Declaration)
`Exhibit 1025 Declaration of W. Archie Bleyer, M.D., FRCP[Glasg]
`Exhibit 1026 Eli Lilly and Company v. Teva Parental Medicines, Inc., et al.,
`INSD-1:10-cv-01376 Markman Order (June 20, 2012) (“Teva”)
`Exhibit 1027 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”)
`Exhibit 1028 Eli Lilly and Company v. Teva Parental Medicines, Inc., et al.,
`INSD-1:10-cv-01376 Decision (March 31, 2014) (“Teva
`Decision”)
`Exhibit 1029 Curriculum Vitae of Scott Bennett, Ph.D.
`Exhibit 1030 Declaration of Scott Bennett, Ph.D.
`Exhibit 1031 Copy of Niyikiza from Oxford University Press Journals
`Exhibit 1032 University of Illinois at Urbana-Champaign Library directory entry
`for Annals of Oncology
`Exhibit 1033 Statewide Illinois Library Catalog record for Annals of Oncology
`Exhibit 1034 Copy of Niyikiza from the University of Wisconsin Library
`Exhibit 1035 Online copy of Carrasco from the Highwire Press
`Exhibit 1036 University of Illinois at Urbana-Champaign Library directory entry
`for Haematologica
`Exhibit 1037 Statewide Illinois Library Catalog record for Haematologica
`Exhibit 1038 Copy of Carrasco from the University of Michigan Taubman
`Medical Library
`Exhibit 1039 Web of Science entry for Carrasco
`Exhibit 1040 Curriculum Vitae of Michael Kelley, M.D.
`
`ix
`
`
`
`Exhibit 1041 Declaration of Michael Kelley, M.D.
`
`
`
`x
`
`
`
`I.
`
`INTRODUCTION
`Apotex Inc. and Apotex Corp. (“Apotex”), request Inter Partes Review
`
`(“IPR”) of Claims 1–22 (“Challenged Claims”) of U.S. Patent No. 7,772,209 (“the
`
`‘209 Patent”) (Ex. 1001) under 35 U.S.C. §§ 311–19 and 37 C.F.R. §§ 42.100 et
`
`seq. Apotex asserts the same grounds of unpatentability directed to the same claims
`
`as IPR2016-00237 (“Neptune IPR”) that the Board already instituted. This Petition
`
`does not add to or alter any arguments, or expand the grounds of unpatentability
`
`from the Neptune IPR the Board has already instituted. Solely to preserve its right
`
`to rely on expert testimony in the event the Neptune IPR is settled, Apotex submits
`
`the Declaration of Michael Kelley, M.D. (Ex. 1041), in which Dr. Kelley adopts the
`
`opinions set forth by Dr. Bleyer in connection with the Neptune IPR. Accordingly,
`
`and as explained below, there exists a reasonable likelihood that Apotex will prevail
`
`in demonstrating unpatentability of at least one of the challenged claims.
`
`II. 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.
`
`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 Neptune IPR, and it is accompanied by a
`
`Motion for Joinder.
`
`1
`
`
`
`III. MANDATORY NOTICES (37 C.F.R. § 42.8)
`A. Real Parties-in-Interest (37 C.F.R. § 42.8(b)(1))
`Petitioner certifies that Apotex Inc., Apotex Corp., Apotex Pharmaceuticals
`
`Holdings Inc., and Apotex Holdings, Inc. are the real parties in interest. No other
`
`party funds, directs, or controls this Petition.
`
`B. Related Matters (37 C.F.R. § 42.8(b)(2))
`Pursuant to 37 C.F.R. § 42.8(b)(2), Petitioner states the ‘209 Patent is the
`
`subject of the following proceedings: Petition for IPR by Apotex, PTAB-IPR2016-
`
`01191 (filed concurrently); Petitions for IPR by Wockhardt Bio AG, PTAB-IPR2016-
`
`01335 and PTAB-IPR2016-01337 (filed June 30, 2016); 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 & 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
`
`2
`
`
`
`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 (37 C.F.R. § 42.8(b)(3)) and Service
`Information (37 C.F.R. § 42.8(b)(4))
`
`Lead counsel is John D. Polivick (jpolivick@rmmslegal.com), Reg. No.
`
`57,926. Backup counsel are Deanne M. Mazzochi (dmazzochi@rmmslegal.com),
`
`Reg. No. 50,158, and William A. Rakoczy (wrakoczy@rmmslegal.com), pro hac
`
`vice to be filed; and Patrick C. Kilgore (pkilgore@rmmslegal.com), Reg. No.
`
`69,131—all of Rakoczy Molino Mazzochi Siwik LLP, 6 West Hubbard Street, Suite
`
`500, Chicago, Illinois 60654 (Tel. 312-527-2157; Fax. 312-527-4205).
`
`Please direct all correspondence to lead counsel and back-up counsel. Petitioner
`
`consents to electronic service at the email addresses listed above.
`
`IV. PAYMENT OF FEES (37 C.F.R. § 42.15(a) and § 42.103)
`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.
`
`3
`
`
`
`V.
`
`IDENTIFICATION OF CHALLENGE
`A. Overview of U.S. Patent No. 7,772,209
`The ‘209 Patent is titled “Antifolate Combination Therapies.” (Ex. 1001 at
`
`Front Cover.) The underlying application, U.S. Patent App. No. 11/776,329 (the
`
`“’329 Application”), was filed on July 11, 2007. The ‘209 Patent issued to Clet
`
`Niyikiza on August 10, 2010. (Id.) The earliest application to which the ‘209 Patent
`
`claims priority is U.S. Patent App. No. 60/215,310 (filed June 3, 2000).
`
`The ‘209 Patent Specification
`
`1.
`The ‘209 Patent claims “a method of administering an antifolate to a mammal
`
`in need thereof, comprising administering an effective amount of said antifolate in
`
`combination with a methylmalonic acid lowering agent and a FBP [folate binding
`
`protein] binding agent.” (Id. at 3:1–5.) “A preferred FBP binding agent is folic
`
`acid,” and a preferred methylmalonic acid (“MMA”) lowering agent is vitamin
`
`B12. (Id. at 3:5–6, 4:47–50.)
`
`The ‘209 specification admits the following with respect to the prior art:
`
`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.
`
`4
`
`
`
`(Id. at 1:19–25.) The ‘209 specification states that “life-threatening toxicity remains
`
`a major limitation to the optimal administration of antifolates,” while admitting that
`
`increased homocysteine levels have been known to cause antifolate toxicity. (Id. at
`
`1:11–13, 2:24–26.) The specification also admits that “[f]olic acid has been shown
`
`to lower homocysteine levels.” (Id. at 2:16–17.) And, it admits that “increased levels
`
`of methylmalonic acid is a predicator of toxic events in patients that receive an
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`antifolate drug,” and further admits that treatment with vitamin B12 was known to
`
`reduce those toxic events: “the treatment and prevention of cardiovascular disease
`
`with folic acid in combination with vitamin B12 is known….” (Id. at 2:41–43, 50–
`
`52.)
`
`The ‘209 Patent’s purported invention was designed “to lower cytotoxic
`
`activity” associated with antifolate treatment. (Id. at 2:29–37.) The patent states
`
`that “we have discovered that the combination of a methylmalonic acid lowering
`
`agent and folic acid synergistically reduces the toxic events associated with the
`
`administration of antifolate drugs.” (Id. at 2:47–50.)
`
`The ‘209 Patent’s invention can be summarized as: (1) administration of
`
`pemetrexed disodium to a patient in combination with an effective amount of folic
`
`acid and an effective amount of MMA lowering agent, such as vitamin B12; (2)
`
`pretreatment with folic acid prior to pemetrexed disodium treatment; (3)
`
`pretreatment with folic acid and vitamin B12 prior to pemetrexed disodium
`
`5
`
`
`
`treatment; (4) repetition of vitamin B12 administration; and (5) administering
`
`cisplatin with pemetrexed disodium to the patient. (Id. at 10:56–12:29.)
`
`The patent also states that a physician determines the amount of MMA
`
`lowering agent to be administered based on “the relevant circumstances, including
`
`the condition to be treated, the chosen route of administration, the actual agent
`
`administered, the age, weight, and response of the individual patient, and the
`
`severity of the patient’s symptoms….” (Id. at 5:37–50; 6:41–52.)
`
`The ‘209 Patent Claims
`
`2.
`The ‘209 Patent has two independent claims (Claims 1 and 12) and 20
`
`dependent claims. Claim 1 provides:
`
`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- 10-
`chlorocobalamin, aquocobalamin perchlorate, aquo-10-cobalamin
`perchlorate,
`azidocobalamin,
`cobalamin,
`cyanocobalamin,
`or
`chlorocobalamin.
`(Id. at 10:56–65.)
`
`Claim 12 provides:
`
`6
`
`
`
`An improved method for administering pemetrexed disodium to a
`patient
`in need of chemotherapeutic
`treatment, wherein
`the
`improvement comprises:
`administration of between about 350 µg and about 1000 µg of
`a)
`folic acid prior to the first administration of pemetrexed disodium;
`administration of about 500 µg to about 1500 µg of vitamin B12,
`b)
`prior to the first administration of pemetrexed disodium; and
`administration of pemetrexed disodium.
`c)
`(Id. at 11:25–12:4.)
`The ‘209 Prosecution History
`3.
`During prosecution of the ’329 Application, the Examiner initially rejected
`
`all claims as obvious under 35 U.S.C. § 103(a) over Taylor (Ex. 1003) in view of
`
`Poydock, and in further view of Worzalla (Ex. 1005) and Cleare (Ex. 1006). (Ex.
`
`1002 at 310.) At the time of this rejection, Claims 40–52 were pending. (Id. at 307.)
`
`Claim 40, the only independent claim, recited “[a] method for administering
`
`pemetrexed disodium to a patient in need thereof comprising administering an
`
`effective amount of pemetrexed disodium in combination with a methylmalonic
`
`acid lowering agent….” (Id. at 345.)
`
`The Examiner rejected Claims 40–52, stating that Taylor taught “N-
`
`(pyrrolo(2,3-D)pyrimidin-3-ylacyl)-glutamic acid derivatives,” including
`
`pemetrexed (LY 231514) and pemetrexed disodium, as effective antineoplastic
`
`agents for inhibition of tumor growth, where other antineoplastic agents could be
`
`7
`
`
`
`combined with pemetrexed, while Poydock taught “a methylmalonic acid lowering
`
`agent such as hydroxocobalamin” for inhibition of tumors implanted in mice. (Id. at
`
`310–11.) The Examiner further stated that Worzalla taught “the supplementation of
`
`folic acid with LY 231514 to enhance LY 231514 antitumor activity,” while Cleare
`
`taught “malonato platinum anti-tumor compounds such as cisplatin to treat
`
`malignant tumors.” (Id. at 311.) The Examiner concluded that “one skilled in the
`
`art would have assumed the combination of three antineoplastic agents into a single
`
`composition would give an additive effect in the absence of evidence to the
`
`contrary.” (Id.) The Examiner further stated that although the cited references do
`
`not teach the dosage range for the MMA lowering agent, “those skilled in the art
`
`would have [] readily optimized effective dosages and concurrent administration
`
`dosage forms as determined by good medical practice and the clinical condition of
`
`the individual patient.” (Id. at 311.)
`
`In response, Applicant amended Claim 45 by disclosing a “specific folic-
`
`binding-protein binding agent species recited in the specification,” and amended
`
`Claim 40 by adding, among other limitations, “lowering agent.” (Id. at 188.)
`
`Applicant also argued that Poydock was “discredited prior to the present
`
`application’s priority date” because, shortly after publication, it was discovered that
`
`MMA lowering agent did not possess antitumor activity. (Id. at 188–89.)
`
`8
`
`
`
`In response, the Examiner rejected the claims as obvious over Taylor in view
`
`of Tsao (Ex. 1007), and in further view of Worzalla and Cleare. (Ex. 1002 at 108.)
`
`The Examiner stated Tsao teaches “a methylmalonic acid lowering agent such as
`
`cobalamin (vitamin B12) is effective as having antitumor activity,” and maintained
`
`rejections with respect to Taylor, Worzalla, and Cleare. (Id. at 108–09.)
`
`Applicant then canceled Claims 45–46, added new Claims 53–63, and
`
`amended Claim 40 by adding, among other limitations, “administering an effective
`
`amount of folic acid and an effective amount of a methylmalonic acid lowering
`
`agent followed by.” (Id. at 82–85.) Applicant argued that the Examiner
`
`misinterpreted “the art concerning vitamin B12 antineoplastic activity and the
`
`teachings of [Taylor].” (Id. at 86.) Applicant also argued that the Examiner
`
`overstated Tsao’s teachings because Tsao disclosed results from hospital surveys
`
`and animal studies with conflicting results on the effectiveness of vitamin B12
`
`therapy alone or in combination with chemotherapeutic agents and “cyanocobalamin
`
`‘did not affect cell growth at a daily dose as high as 1,000 mg/kg body weight.’” (Id.
`
`at 86–87.) Thus, “a person of ordinary skill in the art reading Tsao, would not have
`
`perceived a reasonable expectation of success in making Applicant’s invention in
`
`view of the scientific uncertainty concerning vitamin B12 and its use as an
`
`antitumor agent.” (Id. at 87.)
`
`9
`
`
`
`Applicant further submitted “that the activity of B12 as a potential antitumor
`
`therapeutic is still inconclusive even as of today.” (Id.) Applicant argued that
`
`pemetrexed disodium, a folate analog, as a multitargeted antifolate with specific
`
`activity at three enzymes in the biosynthesis of nucleic acids—“dihydrofolate
`
`reductase (DHFR), thymidine synthase (TS), and GAR formyltransferase
`
`(GARFT)”—competes with folate at each of the enzymes’ folate binding sites. (Id.
`
`at 88.) Applicant additionally argued that “[i]f there is an excess of the natural
`
`ligand (the natural folate source) for the three enzymes then the effectiveness of
`
`pemetrexed disodium is reduced.” (Id.)
`
`Applicant also argued that “[a]t the time of the invention, the skilled artisan
`
`would have been aware it was standard of care to avoid vitamins in patients
`
`undergoing chemotherapy, because the usage of vitamins could decrease the
`
`effectiveness of the chemotherapy.” (Id.) Applicant then stated that AstraZeneca’s
`
`compound Tomudex® (TS inhibitor), if administered with folic or folinic acid, may
`
`impair its cytotoxic action; “[v]itamin preparations containing folic acid or its
`
`derivatives may decrease responses to systemically administered methotrexate”
`
`(DHFR inhibitor); and fluorouracil (5-F