Paper No. ____
`Filed: June 30, 2016
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`WOCKHARDT BIO AG
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`PETITIONER
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`V.
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`ELI LILLY & COMPANY
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`PATENT OWNER
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`CASE NO.: UNASSIGNED
`PATENT NO. 7,772,209
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`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 7,772,209
`UNDER 35 U.S.C. §§ 311-319 and 37 C.F.R. §§ 42.1-.80, 42.100-.123
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`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`TABLE OF CONTENTS
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`Page
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`INTRODUCTION ........................................................................................... 1
`I.
`GROUNDS FOR STANDING (37 C.F.R. § 42.104(a))................................. 2
`II.
`III. MANDATORY NOTICES (37 C.F.R. § 42.8) ............................................... 2
`A.
`Real Parties-in-Interest (37 C.F.R. § 42.8(b)(1)) .................................. 2
`B.
`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
`IV. PAYMENT OF FEES (37 C.F.R. § 42.15(a) and § 42.103) ........................... 4
`V.
`IDENTIFICATION OF CHALLENGE .......................................................... 5
`A. Overview of U.S. Patent No. 7,772,209 ................................................ 5
`1.
`The ’209 Patent Specification ..................................................... 5
`2.
`The ’209 Patent Claims ............................................................... 7
`3.
`The ’209 Prosecution History ..................................................... 8
`
`C.
`
`B.
`
`C.
`
`Claim Construction of Challenged Claims ......................................... 13
`1.
`“Patient” .................................................................................... 14
`2.
`“Methylmalonic acid lowering agent” ...................................... 14
`3.
`“An effective amount of pemetrexed disodium” ...................... 15
`4.
`“An effective amount of folic acid and an effective
`amount of a methylmalonic acid lowering agent” .................... 15
`“Toxicity” .................................................................................. 15
`“Antifolate” and “antifolate drug” ............................................ 16
`
`5.
`6.
`
`Statement of Precise Relief Requested for
`Each Claim Challenged ....................................................................... 16
`1.
`Claims for Which Review is Requested ................................... 16
`2.
`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
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`i
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`Level of Ordinary Skill in the Art ....................................................... 24
`E.
`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 Rusthoven
`in view of EP 005 and the knowledge of one of ordinary
`skill in the art. ...................................................................................... 25
`Claims 1 and 12 are obvious over Rusthoven
`1.
`in 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. ..................... 38
`Dependent Claims 11, 13, and 22 are obvious. ........................ 46
`
`2.
`3.
`
`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. ...................................... 49
`VII. ANY SECONDARY CONSIDERATIONS ARE INSUFFICIENT TO
`OVERCOME THE OBVIOUSNESS OF CLAIMS 1–22. ........................... 50
`VIII. CONCLUSION .............................................................................................. 56
`IX. CERTIFICATE OF COMPLIANCE ............................................................ 57
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`TABLE OF AUTHORITIES
`
`Cases
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` Pages
`
`Abbott Labs v. Andrx Pharms., Inc.,
`452 F.3d 1331 (Fed. Cir. 2006) .......................................................................... 48
`
`In re Am. Acad. of Sci. Tech. Ctr.,
`367 F.3d 1359 (Fed. Cir. 2004) .......................................................................... 13
`
`In re Applied Materials, Inc.,
`692 F.3d 1285 (Fed. Cir. 2012) .......................................................................... 38
`
`Bayer Schering Pharma AG v. Barr Labs., Inc.,
`575 F.3d 1341 (Fed. Cir. 2009) .......................................................................... 38
`
`In re Cipro Cases I & II,
`61 Cal. 4th 116 (Cal. 2015)................................................................................. 49
`
`In re Cuozzo Speed Techs., LLC,
`778 F.3d 1271 (Fed. Cir. 2015) .......................................................................... 13
`
`Concrete Appliances Co. v. Gomery,
`269 U.S. 177 (1925) ............................................................................................ 56
`
`In re Dill,
`604 F.2d 1356 (CCPA 1979) ........................................................................ 53, 54
`
`Dow Chem. Co. v. Sumitomo Chem. Co.,
`257 F.3d 1364 (Fed. Cir. 2001) .......................................................................... 30
`
`Dystar Textilfarben GmbH v. C.H. Patrick Co.,
`464 F.3d 1356 (Fed. Cir. 2006) .......................................................................... 48
`
`Ecolochem, Inc. v. S. Cal. Edison Co.,
`227 F.3d 1361 (Fed. Cir. 2000) .......................................................................... 56
`
`Ethicon, Inc. v. Quigg,
`849 F.2d 1422 (Fed. Cir. 1988) .......................................................................... 49
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ............................................................................ 50
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`iii
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`Ex parte Gelles,
`22 USPQ2d 1318 (Bd. Pat. App. & Inter. 1992) .................................... 50, 52, 55
`
`Geo M. Martin Co. v. Alliance Mach. Sys. Int’l LLC,
`618 F.3d 1294 (Fed. Cir. 2010) .......................................................................... 55
`
`In re Glatt Air Techniques, Inc.,
`630 F.3d 1026 (Fed. Cir. 2011) .......................................................................... 30
`
`In re Graves,
`69 F.3d 1147 (Fed. Cir. 1995) ............................................................................ 30
`
`In re Icon Health & Fitness, Inc.,
`496 F.3d 1374 (Fed. Cir. 2007) .................................................................... 26, 31
`
`In re Klosak,
`455 F.2d 1077 (CCPA 1973) .............................................................................. 52
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...................................................................................... 38, 49
`
`Leapfrog Enters. Inc. v. Fisher-Price Inc.,
`485 F.3d 1157 (Fed. Cir. 2007) .......................................................................... 51
`
`In re Merchant,
`575 F.2d 865 (CCPA 1978) ................................................................................ 52
`
`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) ............................................................................ 50
`
`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 (2014) .......................................................................................... 32
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`iv
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`Pentec, Inc. v. Graphic Controls Corp.,
`776 F.2d 309 (Fed. Cir. 1985) ............................................................................ 30
`
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) .............................................................. 34, 41, 46
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .................................................................... 35, 37
`
`In re Preda,
`401 F.2d 825 (CCPA 1968) ................................................................................ 29
`
`Rogers v. Desa Int’l, Inc.,
`198 Fed. Appx. 918 (Fed. Cir. 2006) .................................................................. 32
`
`Sciele Pharma, Inc. v. Lupin Ltd.,
`684 F.3d 1253 (Fed. Cir. 2012) .......................................................................... 42
`
`In re Swanson,
`540 F.3d 1368 (Fed. Cir. 2008) .......................................................................... 49
`
`Trs. of Columbia Univ. v. Illumina, Inc.,
`2015 U.S. App. LEXIS 12343 (Fed. Cir. July 17, 2015) ................................... 55
`
`Tyco Healthcare Grp. LP v. Ethicon Endo-Surgery, Inc.,
`774 F.3d 968 (Fed. Cir. 2014) ...................................................................... 27, 32
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`Statutes and Codes
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`United States Code
`Title 35 Section 102(b) ........................................................................... 16, 22, 23
` Title 35 Section 103 ............................................................................................ 16
` Title 35 Section 103(a) ................................................................................passim
` Title 35 Section 311 ............................................................................................ 16
`Rules and Regulations
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`Code of Federal Regulations
`Title 37 Section 42.8 ............................................................................................. 2
` Title 37 Section 42.8(b)(1)) .................................................................................. 2
` Title 37 Section 42.8(b)(2)) .................................................................................. 3
` Title 37 Section 42.8(b)(3)) .................................................................................. 4
` Title 37 Section 42.8(b)(4)) .................................................................................. 4
`Title 37 Section 42.10 ........................................................................................... 4
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` Title 37 Section 42.15(a) ...................................................................................... 4
`Title 37 Section 42.l5(a) .................................................................................... ..4
` Title 37 Section 42.100(b) .................................................................................. 13
`Title 37 Section 42.l00(b) ................................................................................ ..l3
` Title 37 Section 42.103 ......................................................................................... 4
`Title 37 Section 42.103 ....................................................................................... ..4
`Title 37 Section 42.103 ......................................................................................... 4
` Title 37 Section 42.104(a)) ................................................................................... 2
`Title 37 Section 42.l04(a)) ................................................................................. ..2
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`Title 37 Section 42.103 ....................................................................................... ..4
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`Exhibit No.
`Exhibit 1001
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`Exhibit 1002
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`Exhibit 1003
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`Exhibit 1004
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`Exhibit 1005
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`Exhibit 1006
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`Exhibit 1007
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`Exhibit 1008
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`Exhibit 1009
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`Exhibit 1010
`Exhibit 1011
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`Exhibit 1012
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`Exhibit 1013
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`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 Rusthoven ’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”)
`Curriculum Vitae of W. Archie Bleyer, M.D., FRCP[Glasg]
`(Attachment 1 to Bleyer Declaration)
`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”)
`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 (“Clavert
`
`vii
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`
`
`Exhibit No.
`
`Exhibit 1014
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`Exhibit 1015
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`Exhibit 1016
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`Exhibit 1017
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`Exhibit 1018
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`Exhibit 1019
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`Exhibit 1020
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`Exhibit 1021
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`Exhibit 1022
`
`Description
`
`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: 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”)
`
`viii
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`Exhibit No.
`Exhibit 1023
`
`Exhibit 1024
`Exhibit 1025
`
`Exhibit 1026
`
`Exhibit 1027
`
`Exhibit 1028
`Exhibit 1029
`Exhibit 1030
`
`Exhibit 1031
`
`Exhibit 1032
`
`Exhibit 1033
`
`Exhibit 1034
`Exhibit 1035
`Exhibit 1036
`
`Exhibit 1037
`Exhibit 1038
`
`Exhibit 1039
`
`Description
`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)
`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.
`Online copy of Rusthoven from the Web site of the Journal of
`Clinical Oncology
`University of Illinois at Urbana-Champaign Library directory
`entry for the Journal of Clinical Oncology
`Statewide Illinois Library Catalog record for the Journal of
`Clinical Oncology
`Copy of Rusthoven from the University of Illinois at Chicago
`Library
`Web of Science entry for Rusthoven
`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
`
`ix
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`
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`I.
`
`INTRODUCTION
`On June 3, 2016, the Board instituted Inter Partes Review (“IPR”) of claims
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`1-22 of U.S. Patent No. 7,772,209 (“the ’209 Patent”) (Ex. 1001) in IPR2016-
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`00240. In its decision of institution, the Board determined that it is reasonably
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`likely that claims 1-22 of the ‘209 patent would have been obvious in view of the
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`following references: (1) Rusthoven et al., Multitargeted Antifolate LY231514 as
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`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”) (Ex. 1011); and (2) European Patent
`
`Application No. 0,595,005 AI (“EP 005”) (Ex. 1010). Neptune Generics, LLC v.
`
`Eli Lilly & Co., IPR 2016-00240, Paper 14 at 18-19 (PTAB June 3, 2016).
`
` Wockhardt Bio AG (“Wockhardt”) submits this Petition for IPR
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`(“Petition”) also seeking cancellation of claims 1-22 of the ‘209 Patent as
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`unpatentable under 35 U.S.C. section 103(a) over Rusthoven in view of EP
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`005. This petition presents the same arguments, based on the same prior art
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`presented in the IPR2016-00240 Petition (IPR2016-00240, Paper 1), and on which
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`the Board instituted IPR in IPR2016-00240, along with a Motion for Joinder to
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`1
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`

`

`
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`join this Petition with the IPR2016-00240 proceedings. Indeed, this petition is an
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`almost verbatim copy of the petition in IPR2016-002401.
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`For the reasons explained below, and for the reasons the Board instituted
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`IPR in IPR2016-00240, Wockhardt is reasonably likely to prevail on Ground 1
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`with respect to the challenged claims. Wockhardt requests that this Board institute
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`IPR and cancel each of claims 1-22 of the ’209 Patent.
`
`II. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a))
`Pursuant to 37 C.F.R. § 42.104(a), Wockhardt certifies that the ’209 Patent
`
`is available for IPR and that Wockhardt is not barred or estopped from requesting
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`IPR challenging the claims of the ’209 Patent on the grounds identified in this
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`Petition.
`
`III. MANDATORY NOTICES (37 C.F.R. § 42.8)
`A. Real Parties-in-Interest (37 C.F.R. § 42.8(b)(1))
`In accordance with 37 C.F.R. § 42.8(b)(1), Petitioner identifies the real
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`party-in-interest as Wockhardt Bio AG, Wockhardt Limited, Wockhardt USA
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`LLC, and Morton Grove Pharmaceuticals, Inc. (collectively “Wockhardt”).
`
`
`1 Wockhardt’s intention is to copy the relevant portions of IPR2016-00240
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`verbatim. To the extent discrepancies exist between the respective petitions,
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`those differences are due to solely to transcription errors.
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`2
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`

`
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`B. Related Judicial and Administrative Matters (37 C.F.R. §
`42.8(b)(2))
`
`Pursuant to 37 C.F.R. § 42.8(b)(2), Wockhardt states that the ’209 Patent has
`
`been the subject of the following lawsuits: Eli Lilly and Company v. Biocon
`
`Limited, INSD-1:16-cv-00469 (filed Feb 26, 2016); Eli Lilly and Company v. Dr.
`
`Reddy's Laboratories, Ltd. et al., INSD-1:16-cv-00308 (filed Feb. 5, 2016);
`
`Petition for Inter Partes Review by Sandoz Inc., PTAB-IPR2016-00318 (filed Dec.
`
`14, 2015); Petition for Inter Partes Review by Neptune Generics, LLC, PTAB-
`
`IPR2016-00237 (filed Nov. 24, 2015); Petition for Inter Partes Review by Neptune
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`Generics, LLC, PTAB-IPR2016-00240 (filed Nov. 24, 2015); 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);
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`Eli Lilly and Company et al. v. Nang Kuang Pharm. Co., Ltd. et al., INSD-1:14-cv-
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`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.
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`Global FZE et al., INSD-1:13-cv-01469 (filed Sept. 13, 2013); Petition for Inter
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`Partes Review by Accord Healthcare, Inc., PTAB-IPR2013-00356 (filed June 14,
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`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.
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`3
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`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.
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`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))
`
`In accordance with 37 C.F.R. § 42.8(b)(3), Petitioner identifies Patrick A.
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`Doody as lead counsel and Bryan P. Collins as back-up counsel. Concurrently
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`filed is a Power of Attorney pursuant to 37 C.F.R. § 42.10(b).
`
`In accordance with 37 C.F.R. § 42.8(b)(4), Petitioner identifies the following
`
`service information:
`
`Back-up Counsel
`Lead Counsel
`Bryan P. Collins, Reg. No. 43,560
`Patrick A. Doody, Reg. No. 35,022
`Pillsbury Winthrop Shaw Pittman LLP Pillsbury Winthrop Shaw Pittman LLP
`1650 Tysons Boulevard
`1650 Tysons Boulevard
`McLean, VA 22102
`McLean, VA 22102
`Direct Line: (703) – 770-7755
`Direct Line: (703) – 770-7538
`Fax: (703) – 770-7901
`Fax: (703) – 770-7901
`email:
`email:
`patrick.doody@pillsburylaw.com
`bryan.collins@pillsburylaw.com
`
`
`Wockhardt 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. §
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`42.103(a) and 42.15(a). If any additional fees are due during this proceeding, the
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`4
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`Office is authorized to charge such fees to Deposit Account No. 033975. Any
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`overpayment or refund of fees may also be deposited in this Deposit Account.
`
`V.
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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
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`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
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`mammal in need thereof, comprising administering an effective amount of said
`
`antifolate in combination with a methylmalonic acid lowering agent and a FBP
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`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
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`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
`
`remains a major limitation to the optimal administration of antifolates,” while
`
`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.)
`
`The ’209 Patent’s purported invention was designed “to lower cytotoxic
`
`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
`
`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 methylmalonic acid lowering agent, such as
`
`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
`
`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.
`
`(Id. at 10:56–12:29.)
`
`The patent also states that a physician determines the amount of
`
`methylmalonic acid 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 twenty
`
`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.)
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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.)
`
`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 3102.) 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
`
`2 All references to Ex. 1002 pin-cites are to the Bates-labeled page number.
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`pemetrexed (LY 231514) and pemetrexed disodium, as effective antineoplastic
`
`agents for inhibition of tumor growth, where other antineoplastic agents could be
`
`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 methylmalonic acid 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 311–12.)
`
`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
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`that methylmalonic acid lowering agent did not possess antitumor activity. (Id. at
`
`188–89.)
`
`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 that Tsao teaches that “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
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`Applicant’s invention in view of the scientific uncertainty concerning vitamin B12
`
`and its use as an antitumor agent.” (Id. at 87.)
`
`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 formyltrans