Paper No.___
`Filed: June 30, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________
`
`
`
`WOCKHARDT BIO AG
`
`PETITIONER
`
`V.
`
`ELI LILLY & COMPANY
`
`PATENT OWNER
`
`____________________
`
`CASE NO.: UNASSIGNED
`PATENT NO. 7,772,209
`____________________
`
`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
`
`
`
`
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`

`

`
`
`TABLE OF CONTENTS
`
`Page
`
`C.
`
`INTRODUCTION ........................................................................................... 1
`I.
`II. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a)) ................................. 2
`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
`Claim Construction of Challenged Claims ......................................... 13
`1.
`“Patient” .................................................................................... 14
`2.
`“Methylmalonic acid lowering agent” ...................................... 14
`3.
`“An effective amount of pemetrexed disodium” ...................... 14
`4.
`“An effective amount of folic acid and an effective
`amount of a methylmalonic acid lowering agent” .................... 15
`“Toxicity” .................................................................................. 15
`5.
`6.
`“Antifolate” and “antifolate drug” ............................................ 15
`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 ...................... 21
`
`B.
`
`C.
`
`i
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`
`
`Level of Ordinary Skill in the Art ....................................................... 25
`E.
`VI. DETAILED EXPLANATION OF THE CHALLENGE .............................. 26
`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. ..................................... 26
`Independent Claims 1 and 12 are obvious over
`1.
`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. ............................................................. 26
`Dependent Claims 2–10 and 14–21 are obvious. ..................... 41
`2.
`Dependent Claims 11, 13, and 22 are obvious. ........................ 50
`3.
`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. ................................................................................... 52
`VII. ANY SECONDARY CONSIDERATIONS ARE
`INSUFFICIENT TO OVERCOME THE OBVIOUSNESS OF
`CLAIMS 1–22. .............................................................................................. 56
`VIII. CONCLUSION .............................................................................................. 62
`IX. CERTIFICATE OF COMPLIANCE ............................................................ 63
`
`
`B.
`
`
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`
`ii
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`
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`TABLE OF AUTHORITIES
`
`Cases
`
`Pages
`
`Abbott Labs v. Andrx Pharms., Inc.,
`452 F.3d 1331 (Fed. Cir. 2006) ............................................................................ 51
`
`Bayer Schering Pharma AG v. Barr Labs., Inc.,
`575 F.3d 1341 (Fed. Cir. 2009) ............................................................................ 40
`
`Dow Chem. Co. v. Sumitomo Chem. Co.,
`257 F.3d 1364 (Fed. Cir. 2001) ............................................................................ 32
`
`Dystar Textilfarben GmbH v. C.H. Patrick Co.,
`464 F.3d 1356 (Fed. Cir. 2006) ............................................................................ 51
`
`Ethicon, Inc. v. Quigg,
`849 F.2d 1422 (Fed. Cir. 1988) ............................................................................ 52
`
`Ex parte Gelles,
`22 USPQ2d 1318 (Bd. Pat. App. & Inter. 1992) .................................... 56, 58, 61
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) .............................................................................. 57
`
`Geo M. Martin Co. v. Alliance Mach. Sys. Int’l LLC,
`618 F.3d 1294 (Fed. Cir. 2010) ............................................................................ 61
`
`In re Aller,
`220 F.2d 454 (CCPA 1955) ................................................................................. 35
`
`In re Am. Acad. of Sci. Tech. Ctr.,
`367 F.3d 1359 (Fed. Cir. 2004) ............................................................................ 13
`
`In re Applied Materials, Inc.,
`692 F.3d 1289 (Fed. Cir. 2012) ............................................................... 35, 40, 46
`
`In re Cipro Cases I & II,
`61 Cal. 4th 116 (Cal. 2015) ................................................................................. 52
`
`iii
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`

`
`
`In re Cuozzo Speed Techs., LLC,
`778 F.3d 1271 (Fed. Cir. 2015) ............................................................................ 13
`
`In re Dill,
`604 F.2d 1356 (CCPA 1979) ........................................................................ 59, 61
`
`In re Glatt Air Techniques, Inc.,
`630 F.3d 1026 (Fed. Cir. 2011) ............................................................................ 32
`
`In re Graves,
`69 F.3d 1147 (Fed. Cir. 1995) .............................................................................. 32
`
`In re Icon Health & Fitness, Inc.,
`496 F.3d 1374 (Fed. Cir. 2007) ..................................................................... 26, 33
`
`In re Klosak,
`455 F.2d 1077 (CCPA 1973) ............................................................................... 58
`
`In re Merchant,
`575 F.2d 865 (CCPA 1978) ................................................................................. 58
`
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) ............................................................... 37, 44, 49
`
`In re Preda,
`401 F.2d 825 (CCPA 1968) ................................................................................. 31
`
`In re Swanson,
`540 F.3d 1368 (Fed. Cir. 2008) ............................................................................ 52
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...................................................................................... 40, 52
`
`Leapfrog Enters. Inc. v. Fisher-Price Inc.,
`485 F.3d 1157 (Fed. Cir. 2007) ............................................................................ 56
`
`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) .............................................................................. 56
`
`iv
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`

`
`
`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) ........................................................................................... 34
`
`Pentec, Inc. v. Graphic Controls Corp.,
`776 F.2d 309 (Fed. Cir. 1985) .............................................................................. 32
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) ............................................................................ 39
`
`Rogers v. Desa Int’l, Inc.,
`198 Fed. Appx. 918 (Fed. Cir. 2006) ................................................................... 34
`
`Sciele Pharma, Inc. v. Lupin Ltd.,
`684 F.3d 1253 (Fed. Cir. 2012) ............................................................................ 45
`
`Trs. of Columbia Univ. v. Illumina, Inc.,
`2015 U.S. App. LEXIS 12343 (Fed. Cir. July 17, 2015) ..................................... 61
`
`Tyco Healthcare Grp. LP v. Ethicon Endo-Surgery, Inc.,
`774 F.3d 968 (Fed. Cir. 2014) ................................................................. 28, 34, 54
`
`
`
`Statutes and Codes
`
`United States Code
`Title 35 Section 102(a) ......................................................................................... 21
`Title 35 Section 102(b) ..................................................................... 16, 21, 23, 24
`Title 35 Section 103 ............................................................................................. 16
`Title 35 Section 103(a) ................................................................................. passim
`Title 35 Section 311 ............................................................................................. 16
`
`
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`v
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`Rules and Regulations
`
`Code of Federal Regualtions
`Title 37 Section 42.10(b) ....................................................................................... 4
`
`Title 37 Section 42.100(b) ................................................................................... 13
`Title 37 Section 42.103 .......................................................................................... 4
`Title 37 Section 42.103(a) ...................................................................................... 4
`Title 37 Section 42.104(a) ...................................................................................... 2
`Title 37 Section 42.15(a) ....................................................................................... 4
`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
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`vi
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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
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`
`
`Exhibit 1018
`
`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”)
`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
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`

`
`
`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 Amended 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
`Statewide Illinois Library Catalog record for Annals of Oncology
`Exhibit 1033
`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
`Statewide Illinois Library Catalog record for Haematologica
`Exhibit 1037
`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
`On June 3, 2016, the Board instituted Inter Partes Review (“IPR”) of claims
`
`1-22 of U.S. Patent No. 7,772,209 (“the ’209 Patent”) (Ex. 1001) in IPR2016-
`
`00237. In its decision of institution, the Board determined that it is reasonably
`
`likely that claims 1-22 would have been obvious in view of the following
`
`references: (1) 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”)
`
`(Ex. 1008); (2) U.S. Patent No. 5,217,974 (“the ‘974 Patent”) (Ex. 1009); and (3)
`
`European Patent Application No. 0,595,005 AI (“EP 005”) (Ex. 1010). Neptune
`
`Generics, LLC v. Eli Lilly & Company, Paper 13 at 18-19 (PTAB June 3, 2016).
`
` Wockhardt Bio AG (“Wockhardt”) submits this Petition for IPR
`
`(“Petition”) also seeking cancellation of claims 1-22 of the ‘209 Patent as
`
`unpatentable under 35 U.S.C. section 103(a) over Niyikiza in view of the ‘974
`
`Patent, and further in view of EP 005. This petition presents the same arguments,
`
`based on the same prior art presented in the IPR2016-00237 Petition (IPR2016-
`
`00237, Paper 1), and on which the Board instituted IPR in IPR2016-00237, along
`
`with a Motion for Joinder to join this Petition with the IPR2016-00237
`
`1
`
`

`

`
`
`proceedings. Indeed, this petition is an almost verbatim copy of the petition in
`
`IPR2016-002371.
`
`For the reasons explained below, and for the reasons the Board instituted
`
`IPR in IPR2016-00237, Wockhardt is reasonably likely to prevail on Ground 1
`
`with respect to the challenged claims. Wockhardt requests that this Board institute
`
`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
`
`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))
`In accordance with 37 C.F.R. § 42.8(b)(1), Petitioner identifies the real
`
`party-in-interest as Wockhardt Bio AG, Wockhardt Limited, Wockhardt USA
`
`LLC, and Morton Grove Pharmaceuticals, Inc. (collectively “Wockhardt”).
`
`
`1 Wockhardt’s intention is to copy the relevant portions of IPR2016-00237
`
`verbatim. To the extent discrepancies exist between the respective petitions, those
`
`differences are due to solely to transcription errors.
`
`2
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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
`
`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);
`
`Eli Lilly and Company et al. v. Nang Kuang Pharm. Co., Ltd. et al., INSD-1:14-cv-
`
`01647 (filed Oct. 8, 2014); Eli Lilly and Company v. Glenmark Pharm. Ltd. et al.,
`
`INSD-1:14-cv-00104 (filed Jan. 23, 2014); Eli Lilly and Company v. Sun Pharm.
`
`Global FZE et al., INSD-1:13-cv-01469 (filed Sept. 13, 2013); Petition for Inter
`
`Partes Review by Accord Healthcare, Inc., PTAB-IPR2013-00356 (filed June 14,
`
`2013); Eli Lilly and Company v. Accord Healthcare, Inc., USA, INSD-1:13-cv-
`
`00335 (filed Feb. 28, 2013); Eli Lilly and Company v. Apotex, Inc. et al., INSD-
`
`1:12-cv-00499 (filed Apr. 17, 2012); Eli Lilly and Company v. Accord Healthcare,
`
`Inc., USA, INSD-1:12-cv-00086 (filed Jan. 20, 2012); Eli Lilly and Company v.
`
`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.
`
`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.
`
`Doody as lead counsel and Bryan P. Collins as back-up counsel. Concurrently
`
`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. §§
`
`42.103(a) and 42.15(a). If any additional fees are due during this proceeding, the
`
`4
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`

`
`
`Office is authorized to charge such fees to Deposit Account No. 033975. Any
`
`overpayment or refund of fees may also be deposited in this Deposit Account.
`
`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
`
`5
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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
`
`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
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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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`that “we have discovered that the combination of a methylmalonic acid lowering
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`agent and folic acid synergistically reduces the toxic events associated with the
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`administration of antifolate drugs.” (Id. at 2:47–50.)
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`The ’209 Patent’s invention can be summarized as: (1) administration of
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`pemetrexed disodium to a patient in combination with an effective amount of folic
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`acid and an effective amount of MMA lowering agent, such as vitamin B12; (2)
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`pretreatment with folic acid prior to pemetrexed disodium treatment; (3)
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`pretreatment with folic acid and vitamin B12 prior to pemetrexed disodium
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`treatment; (4) repetition of vitamin B12 administration; and (5) administering
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`cisplatin with pemetrexed disodium to the patient. (Id. at 10:56–12:29.)
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`The patent also states that a physician determines the amount of MMA
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`lowering agent to be administered based on “the relevant circumstances, including
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`the condition to be treated, the chosen route of administration, the actual agent
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`administered, the age, weight, and response of the individual patient, and the
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`severity of the patient’s symptoms….” (Id. at 5:37–50; 6:41–52.)
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`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.
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`(Id. at 10:56–65.)
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`Claim 12 provides:
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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.
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`(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 310.) At the time of this rejection, Claims 40–52 were pending. (Id. At
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`307.) Claim 40, the only independent claim, recited “[a] method for administering
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`pemetrexed disodium to a patient in need thereof comprising administering an
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`effective amount of pemetrexed disodium in combination with a methylmalonic
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`acid lowering agent….” (Id. at 345.)
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`The Examiner rejected Claims 40–52, stating that Taylor taught “N-
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`(pyrrolo(2,3-D)pyrimidin-3-ylacyl)-glutamic acid derivatives,” including
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`pemetrexed (LY 231514) and pemetrexed disodium, as effective antineoplastic
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`agents for inhibition of tumor growth, where other antineoplastic agents could be
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`combined with pemetrexed, while Poydock taught “a methylmalonic acid lowering
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`agent such as hydroxocobalamin” for inhibition of tumors implanted in mice. (Id.
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`at 310–11.) The Examiner further stated that Worzalla taught “the supplementation
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`of folic acid with LY 231514 to enhance LY 231514 antitumor activity,” while
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`Cleare taught “malonato platinum anti-tumor compounds such as cisplatin to treat
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`malignant tumors.” (Id. at 311.) The Examiner concluded that “one skilled in the
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`art would have assumed the combination of three antineoplastic agents into a
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`single composition would give an additive effect in the absence of evidence to the
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`contrary.” (Id.) The Examiner further stated that although the cited references do
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`not teach the dosage range for the MMA lowering agent, “those skilled in the art
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`would have [] readily optimized effective dosages and concurrent administration
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`dosage forms as determined by good medical practice and the clinical condition of
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`the individual patient.” (Id. at 311.)
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`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 MMA lowering agent did not possess antitumor activity. (Id. at 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 Tsao teaches “a methylmalonic acid lowering agent such as
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`cobalamin (vitamin B12) is effective as having antitumor activity,” and maintained
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`rejections with respect to Taylor, Worzalla, and Cleare. (Id. at 108–09.)
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`Applicant then canceled Claims 45–46, added new Claims 53–63, and
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`amended Claim 40 by adding, among other limitations, “administering an effective
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`amount of folic acid and an effective amount of a methylmalonic acid lowering
`
`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
`
`and animal studies with conflicting results on the effectiveness of vitamin B12
`
`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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`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
`
`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
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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 c