Paper No. 1
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`Filed: November 24, 2015
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
`
`
`NEPTUNE GENERICS, LLC
`
`PETITIONER
`
`V.
`
`ELI LILLY & COMPANY
`
`PATENT OWNER
`
`___________________
`
`CASE NO.: UNASSIGNED
`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
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`I.
`
`II.
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`
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`Patent No. 7,772,209
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`TABLE OF CONTENTS
`INTRODUCTION ........................................................................................... 1
`
`GROUNDS FOR STANDING (37 C.F.R. § 42.104(A)) ................................ 1
`
`III. MANDATORY NOTICES (37 C.F.R. § 42.8) ............................................... 1
`
`A.
`
`B.
`
`C.
`
`Real Parties-in-Interest (37 C.F.R. § 42.8(b)(1)) ........................ 1
`
`Related Judicial and Administrative 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.
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`2.
`
`3.
`
`4.
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`“Patient” ..........................................................................13
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`“Methylmalonic acid lowering agent” ............................13
`
`“An effective amount of pemetrexed
`disodium” ........................................................................13
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`“An effective amount of folic acid and an
`effective amount of a methylmalonic acid
`lowering agent” ...............................................................14
`
`5.
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`“Toxicity” .......................................................................14
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`Patent No. 7,772,209
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`6.
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`“Antifolate” and “antifolate drug” ..................................14
`
`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 .......................................................................21
`
`E.
`
`Level of Ordinary Skill in the Art .............................................23
`
`VI. DETAILED EXPLANATION OF THE CHALLENGE ..............................24
`
`A. Ground 1: Claims 1–22 of U.S. Patent No. 7,772,209
`are obvious under 35 U.S.C. § 103(a) over Rusthoven
`in view of EP 005 and the knowledge of one of
`ordinary skill in the art. .............................................................24
`
`1.
`
`2.
`
`3.
`
`Claims 1 and 12 are obvious over Rusthoven in
`view of EP 005 and the knowledge of one of
`ordinary skill in the art. ...................................................24
`
`Dependent Claims 2–10 and 14–21 are
`obvious. ...........................................................................37
`
`Dependent Claims 11, 13, and 22 are obvious. ..............45
`
`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. .....................................................48
`
`VII. ANY SECONDARY CONSIDERATIONS ARE INSUFFICIENT
`TO OVERCOME THE OBVIOUSNESS OF CLAIMS 1–22. .....................49
`
`VIII. CONCLUSION ..............................................................................................55
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`Cases
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`Patent No. 7,772,209
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`TABLE OF AUTHORITIES
`
`
`Abbott Labs v. Andrx Pharms., Inc.,
`452 F.3d 1331 (Fed. Cir. 2006) .....................................................................46
`
`Bayer Schering Pharma AG v. Barr Labs., Inc.,
`575 F.3d 1341 (Fed. Cir. 2009) .....................................................................37
`
`Concrete Appliances Co. v. Gomery,
`269 U.S. 177 (1925).......................................................................................20
`
`Dow Chem. Co. v. Sumitomo Chem. Co.,
`257 F.3d 1364 (Fed. Cir. 2001) .....................................................................29
`
`Dystar Textilfarben GmbH v. C.H. Patrick Co.,
`464 F.3d 1356 (Fed. Cir. 2006) .....................................................................47
`
`Ecolochem, Inc. v. S. Cal. Edison Co.,
`227 F.3d 1361 (Fed. Cir. 2000) .....................................................................20
`
`Ethicon, Inc. v. Quigg,
`849 F.2d 1422 (Fed. Cir. 1988) .....................................................................48
`
`Ex parte Gelles,
`22 USPQ2d 1318 (Bd. Pat. App. & Inter. 1992) .............................. 48, 50, 53
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) .......................................................................48
`
`Geo M. Martin Co. v. Alliance Mach. Sys. Int’l LLC,
`618 F.3d 1294 (Fed. Cir. 2010) .....................................................................20
`
`In re Am. Acad. of Sci. Tech. Ctr.,
`367 F.3d 1359 (Fed. Cir. 2004) .....................................................................12
`
`In re Applied Materials, Inc.,
`692 F.3d 1285 (Fed. Cir. 2012) .....................................................................37
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`Patent No. 7,772,209
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`In re Cipro Cases I & II,
`61 Cal. 4th 116 (Cal. 2015) ...........................................................................48
`
`In re Cuozzo Speed Techs., LLC,
`778 F.3d 1271 (Fed. Cir. 2015) .....................................................................12
`
`In re Dill,
`604 F.2d 1356 (CCPA 1979) .........................................................................51
`
`In re Glatt Air Techniques, Inc.,
`630 F.3d 1026 (Fed. Cir. 2011) .....................................................................29
`
`In re Graves,
`69 F.3d 1147 (Fed. Cir. 1995) .......................................................................29
`
`In re Icon Health & Fitness, Inc.,
`496 F.3d 1374 (Fed. Cir. 2007) .............................................................. 25, 30
`
`In re Klosak,
`455 F.2d 1077 (CCPA 1973) .........................................................................51
`
`In re Merchant,
`575 F.2d 865 (CCPA 1978) ...........................................................................51
`
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) ........................................................ 33, 40, 45
`
`In re Preda,
`401 F.2d 825 (CCPA 1968) ...........................................................................28
`
`In re Swanson,
`540 F.3d 1368 (Fed. Cir. 2008) .....................................................................47
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007)................................................................................ 37, 47
`
`Leapfrog Enterprises Inc. v. Fisher-Price Inc.,
`485 F.3d 1157 (Fed. Cir. 2007) .....................................................................49
`
`Nat'l Steel Car, Ltd. v. Canadian Pac. Ry., Ltd.,
`
`357 F.3d 1319, 1337-1338 (Fed. Cir. 2004)…. .............................................20
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`Patent No. 7,772,209
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`Newell Cos., Inc. v. Kenney, Mfg. Co.,
`864 F.2d 757 (Fed. Cir. 1988) .......................................................................49
`
`NPF Ltd. v. Smart Parts, Inc.,
`187 Fed. Appx. 973 (Fed. Cir. 2006)………………………… ........... ……20
`
`
`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) ....................................................................................31
`
`Pentec, Inc. v. Graphic Controls Corp.,
`776 F.2d 309 (Fed. Cir. 1985) .......................................................................29
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .............................................................. 34, 36
`
`Rogers v. Desa Int’l, Inc.,
`198 Fed. Appx. 918 (Fed. Cir. 2006) ............................................................31
`
`See Sciele Pharma, Inc. v. Lupin Ltd.,
`684 F.3d 1253 (Fed. Cir. 2012) .....................................................................41
`
`Trs. of Columbia Univ. v. Illumina, Inc.,
`2015 U.S. App. LEXIS 12343 (Fed. Cir. July 17, 2015) ..............................20
`
`Tyco Healthcare Grp. LP v. Ethicon Endo-Surgery, Inc.,
`774 F.3d 968 (Fed. Cir. 2014) ................................................................ 26, 31
`
`Statutes
`
`35 U.S.C. § 102(b) ...................................................................................................15
`
`35 U.S.C. § 103 ........................................................................................................15
`
`35 U.S.C. § 103(a) .................................................................................. 7, 15, 24, 48
`
`35 U.S.C. § 311 ........................................................................................................15
`
`Regulations
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`Patent No. 7,772,209
`Patent No. 7,772,209
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`37 C.F.R. § 42.100(b) ..............................................................................................12
`37 CPR. § 42.100(b) .............................................................................................. 12
`
`37 C.F.R. § 42.103 ..................................................................................................... 3
`37 CPR. § 42.103 ..................................................................................................... 3
`
`37 C.F.R. § 42.103(a) ................................................................................................. 3
`37 C.F.R. § 42.103(a) ................................................................................................. 3
`
`37 C.F.R. § 42.104(a) ................................................................................................. 1
`37 CPR. § 42.104(a) ................................................................................................. 1
`
`37 C.F.R. § 42.15(a) ................................................................................................... 3
`37 CPR. § 42.15(a) ................................................................................................... 3
`
`37 C.F.R. § 42.8(b)(1) ................................................................................................ 1
`37 CPR. § 42.8(b)(1) ................................................................................................ 1
`
`37 C.F.R. § 42.8(b)(2) ................................................................................................ 2
`37 CPR. § 42.8(b)(2) ................................................................................................2
`
`37 C.F.R. § 42.8(b)(3) ................................................................................................ 3
`37 CPR. § 42.8(b)(3) ................................................................................................ 3
`
`37 C.F.R. § 42.8(b)(4) ................................................................................................ 3
`37 CPR. § 42.8(b)(4) ................................................................................................ 3
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`Patent No. 7,772,209
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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 Rusthoven ’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 Curriculum Vitae of W. Archie Bleyer, M.D., FRCP[Glasg]
`(Attachment 1 to Bleyer Declaration)
`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”)
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`Patent No. 7,772,209
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`Description
`Exhibit No.
`Exhibit 1013 Calvert AH & Walling JM, “Clinical studies with MTA.” British
`Journal of Cancer (1998) 78 (Suppl. 3), 35-40 (“Clavert 1998”)
`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”)
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`Patent No. 7,772,209
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`Description
`Exhibit No.
`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”)
`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 Declaration of W. Archie Bleyer, M.D., FRCP[Glasg]
`Exhibit 1025 Eli Lilly and Company v. Teva Parental Medicines, Inc., et al.,
`INSD-1:10-cv-01376 Markman Order (June 20, 2012) (“Teva”)
`Exhibit 1026 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 1027 Eli Lilly and Company v. Teva Parental Medicines, Inc., et al.,
`INSD-1:10-cv-01376 Decision (March 31, 2014) (“Teva
`Decision”)
`Exhibit 1028 Curriculum Vitae of Scott Bennett, Ph.D.
`Exhibit 1029 Declaration of Scott Bennett, Ph.D.
`Exhibit 1030 Online copy of Rusthoven from the Web site of the Journal of
`Clinical Oncology
`Exhibit 1031 University of Illinois at Urbana-Champaign Library directory entry
`for the Journal of Clinical Oncology
`Exhibit 1032 Statewide Illinois Library Catalog record for the Journal of
`Clinical Oncology
`Exhibit 1033 Copy of Rusthoven from the University of Illinois at Chicago
`Library
`Exhibit 1034 Web of Science entry for Rusthoven
`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
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`Patent No. 7,772,209
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`Description
`Exhibit No.
`Exhibit 1038 Copy of Carrasco from the University of Michigan Taubman
`Medical Library
`Exhibit 1039 Web of Science entry for Carrasco
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`I.
`
`INTRODUCTION
`
`
`
`Patent No. 7,772,209
`
`Neptune Generics, LLC (“Neptune”), requests 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. 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.
`
`III. MANDATORY NOTICES (37 C.F.R. § 42.8)
`A. Real Parties-in-Interest (37 C.F.R. § 42.8(b)(1))
`Pursuant to 37 C.F.R. § 42.8(b)(1), Petitioner certifies that the following
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`information: Neptune Generics, LLC, Niagara FundingCo, LLC, GKC Partners II,
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`LP, GKC General Partner II, LLC and Gerchen Keller Capital, LLC are the real
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`parties in interest (collectively, “RPI”). Neptune Generics, LLC, a New York
`
`limited liability company, is 100% owned by Niagara FundingCo, LLC, a New
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`York limited liability company, which itself is 100% owned by GKC Partners II,
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`LP, a Delaware limited partnership. GKC General Partner II, LLC, a Delaware
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`limited liability company, is the general partner of, and Gerchen Keller Capital,
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`LLC, a Delaware limited liability company, is the investment manager to, GKC
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`Partners II, LP. No other person (including any investor, limited partner, or
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`Patent No. 7,772,209
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`member or any other person in any of Neptune Generics, LLC, Niagara
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`FundingCo, LLC, GKC Partners II, LP, GKC General Partner II, LLC, or Gerchen
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`Keller Capital, LLC) has authority to direct or control (i) the timing of, filing of,
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`content of, or any decisions or other activities relating to this Petition or (ii) any
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`timing, future filings, content of, or any decisions or other activities relating to the
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`future proceedings related to this Petition. All of the costs associated with this
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`Petition are expected to be borne by Neptune Generics, LLC, Niagara FundingCo,
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`LLC, GKC Partners II, LP, GKC General Partner II, LLC, and Gerchen Keller
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`Capital, 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
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`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
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`al. v. Nang Kuang Pharm. Co., Ltd. et al., INSD-1:14-cv-01647 (filed Oct. 8,
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`2014); Eli Lilly and Company v. Glenmark Pharm. Ltd. et al., INSD-1:14-cv-
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`00104 (filed Jan. 23, 2014); Eli Lilly and Company v. Sun Pharm. Global FZE et
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`al., INSD-1:13-cv-01469 (filed Sept. 13, 2013); Petition for Inter Partes Review by
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`Accord Healthcare, Inc., PTAB-IPR2013-00356 (filed June 14, 2013); Eli Lilly
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`and Company v. Accord Healthcare, Inc., USA, INSD-1:13-cv-00335 (filed
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`Feb. 28, 2013); Eli Lilly and Company v. Apotex, Inc. et al., INSD-1:12-cv-00499
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`(filed Apr. 17, 2012); Eli Lilly and Company v. Accord Healthcare, Inc., USA,
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`INSD-1:12-cv-00086 (filed Jan. 20, 2012); Eli Lilly and Company v. App Pharm.,
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`LLC, INSD-1:11-cv-00942 (filed Jul. 15, 2011); and Eli Lilly and Company v.
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`Teva Parental Medicines, Inc., et al., INSD-1:10-cv-01376 (filed Oct. 29, 2010).
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`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 Sarah E. Spires, Reg. No. 61,501,
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`sarah.spires@skiermontpuckett.com. Back-up counsel are Dr. Parvathi Kota, Reg.
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`No. 65,122, parvathi.kota@skiermontpuckett.com; and Paul J. Skiermont (pro hac
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`vice requested), paul.skiermont@skiermontpuckett.com—all of Skiermont Puckett
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`LLP, 2200 Ross Ave., Ste. 4800W, Dallas, Texas 75201, P: 214-978-6600/F: 214-
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`978-6601. Petitioner consents to electronic service.
`
`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). If any additional fees are due during this proceeding, the
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`Office is authorized to charge such fees to Deposit Account No. 506293. Any
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`overpayment or refund of fees may also be deposited in this Deposit Account.
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`V.
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`Patent No. 7,772,209
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`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
`
`binding agent.” (Id. at 3:1–5.) “A preferred FBP binding agent is folic acid,” and a
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`preferred methylmalonic acid lowering agent is vitamin B12. (Id. at 3:5–6, 4:47–
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`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.
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`Patent No. 7,772,209
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`(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 2:14–17.) 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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`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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`“We have discovered that the combination of a methylmalonic acid lowering agent
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`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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`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 methylmalonic acid lowering agent, such as
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`vitamin B12; (2) pretreatment with folic acid prior to pemetrexed disodium
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`treatment; (3) pretreatment with folic acid and vitamin B12 prior to pemetrexed
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`Patent No. 7,772,209
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`disodium treatment; (4) repetition of vitamin B12 administration; and (5)
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`administration of cisplatin in combination with pemetrexed disodium to the patient.
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`(Id. at 10:56–12:29.)
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`The patent also states that a physician determines the amount of
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`methylmalonic acid lowering agent to be administered based on “the relevant
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`circumstances, including the condition to be treated, the chosen route of
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`administration, the actual agent administered, the age, weight, and response of the
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`individual patient, and the severity of the patient’s symptoms….” (Id. at 5:37–50;
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`6:41–52.)
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`The ’209 Patent Claims
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`2.
`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-
`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:
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`Patent No. 7,772,209
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`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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`The ’209 Prosecution History
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`3.
`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 3101.) 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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`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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`1 All references to Ex. 1002 pin-cites are to the Bates-labeled page number.
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`Patent No. 7,772,209
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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 methylmalonic acid lowering agent, “those
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`skilled in the art would have [] readily optimized effective dosages and concurrent
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`administration dosage forms as determined by good medical practice and the
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`clinical condition of the individual patient….” (Id. at 311–12.)
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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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`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 methylmalonic acid lowering agent did not possess antitumor activity. (Id. at
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`188–89.)
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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 that Tsao teaches that “a methylmalonic acid lowering agent
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`such as cobalamin (vitamin B12) is effective as having antitumor activity,” and
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`maintained rejections with respect to Taylor, Worzalla, and Cleare. (Id. at 108–
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`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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`Patent No. 7,772,209
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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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`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 (DHFR), thymidine synthase (TS), and GAR formyltransferase
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`(GARFT)”—competes with folate at each of the enzymes’ folate binding sites. (Id.
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`at 88.) Applicant additionally argued that “[i]f there is an excess of the natural
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`ligand (the natural folate source) for the three enzymes then the effectiveness of
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`pemetrexed disodium is reduced.” (Id.)
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`Applicant also argued that “[a]t the time of the invention, the skilled artisan
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`would have been aware it was standard of care to avoid vitamins in patients
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`undergoing chemotherapy, because the usage of vitamins could decrease the
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`effectiveness of the chemotherapy.” (Id.) Applicant then stated that AstraZeneca’s
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`compound Tomudex® (TS inhibitor), if administered wi