UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`SANDOZ INC.,
`
`Petitioner
`
`v .
`
`ELI LILLY AND COMPANY,
`
`Patent Owner
`
`
`U.S. Patent 7,772,209
`Issue Date: Aug. 10, 2010
`Title: Antifolate Combination Therapies
`
`
`
`
`
`Inter Partes Review No. 2016-00318
`
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`
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 7,772,209 PURSUANT TO
`35 U.S.C. §§ 311-319 AND 37 C.F.R. § 42
`
`
`
`
`
`
`
`

`

`
`
`TABLE OF CONTENTS
`I. 
`INTRODUCTION ........................................................................................... 1 
`II.  MANDATORY NOTICES UNDER 37 C.F.R. § 42.8(A)(1) ........................ 2 
`A. 
`Real Party-In-Interest ............................................................................ 2 
`B. 
`Related Matters ...................................................................................... 2 
`1. 
`Related Litigations ...................................................................... 2 
`2. 
`Related Proceedings Before the Board ....................................... 4 
`Lead and Back-Up Counsel ................................................................... 5 
`C. 
`Service Information ............................................................................... 6 
`D. 
`III.  GROUNDS FOR STANDING ........................................................................ 6 
`IV. 
`IDENTIFICATION OF CHALLENGE AND STATEMENT OF THE
`PRECISE RELIEF REQUESTED .................................................................. 6 
`THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW ............... 8 
`V. 
`VI.  STATEMENT OF REASONS FOR THE RELIEF REQUESTED ............... 8 
`A. 
`Summary of the Argument .................................................................... 8 
`B. 
`Background of the ’209 Patent ............................................................ 11 
`1. 
`Prior Art Administration of Pemetrexed Resulted in
`Toxicity Caused by Elevated Homocysteine Levels ................ 11 
`It Was Well-Known that Elevated Baseline
`Homocysteine Levels Are Most Effectively Treated by
`Administering Both Folic Acid and Vitamin B12 ..................... 13 
`The ’209 Patent ......................................................................... 15 
`3. 
`The Prosecution of the ’209 Patent ........................................... 15 
`4. 
`Person of Ordinary Skill in the Art ..................................................... 17 
`Claim Construction ............................................................................. 18 
`1. 
`“Patient” .................................................................................... 18 
`2. 
`The “Effective Amount” Limitations ....................................... 21 
`3. 
`“Methylmalonic Acid Lowering Agent” .................................. 22 
`Patents and Printed Publications Relied on in this Petition ................ 23 
`
`C. 
`D. 
`
`2. 
`
`E. 
`
`i
`
`

`

`
`
`F. 
`
`1. 
`
`2. 
`
`4. 
`
`Calvert (Ex. 1007) Teaches that Elevated Baseline
`Homocysteine Levels Associated with Pemetrexed
`Toxicity Are Caused by Either Folic Acid or Vitamin B12
`Deficiencies ............................................................................... 23 
`Niyikiza I (Ex. 1006) Teaches a Strong Correlation
`between Baseline Homocysteine Levels and Pemetrexed
`Toxicity ..................................................................................... 24 
`3.  Worzalla (Ex. 1013) Teaches Pretreating Animal Patients
`with Folic Acid before Pemetrexed Therapy ............................ 25 
`Hammond I (Ex. 1015) Teaches Pretreating Human
`Patients with Folic Acid before Starting Pemetrexed
`Therapy ..................................................................................... 26 
`The Challenged Claims Are Unpatentable as Obvious over the
`Prior Art ............................................................................................... 27 
`1. 
`Calvert and Niyikiza I Would Have Motivated a POSA to
`Add Vitamin B12 to the Folic Acid Pretreatment Regimen
`of Worzalla or Hammond I ....................................................... 27 
`a. 
`A POSA Would Know to Pretreat Patients with
`Vitamin B12 to Reduce High Homocysteine Levels
`Linked to Pemetrexed Toxicity ...................................... 27 
`The Prior Art Taught Combining Antifolates with
`Vitamin B12 and Folic Acid ............................................ 32 
`Claims 1 and 2 Are Obvious Over Calvert and Niyikiza I
`in View of Worzalla or Hammond I, and a POSA’s
`Knowledge of the Relationship between Homocysteine,
`Folic Acid and Vitamin B12 ...................................................... 34 
`a. 
`The POSA Would Have Had a Reasonable
`Expectation of Success ................................................... 39 
`No Secondary Considerations Support Non-
`Obviousness .................................................................... 44 
`The Patent Owner’s “Teaching Away” Arguments
`Lack Merit ...................................................................... 48 
`Claims 3-10, 12, and 14-21 Are Obvious in Further View
`of the Known Dosages and Schedules for Administering
`Folic Acid and Vitamin B12 ..................................................... 51 
`
`b. 
`
`b. 
`
`c. 
`
`2. 
`
`3. 
`
`ii
`
`

`

`
`
`4. 
`
`5. 
`
`Claim 11 Is Obvious in Further View of the POSA’s
`Knowledge of the Benefit of Combining Cisplatin with
`Pemetrexed ................................................................................ 57 
`Claims 13 and 22 Are Obvious over Worzalla or
`Hammond I in View of Niyikiza I, Calvert in Further
`View of the POSA’s Knowledge of the Claimed
`Dosages, Schedules and Combination with Cisplatin .............. 59 
`VII.  CONCLUSION .............................................................................................. 59 
`
`
`iii
`
`

`

`
`
`CASES 
`
`TABLE OF AUTHORITIES
`
`
`
`Aventis Pharma Deutschland GmbH v. Lupin, Ltd.,
`499 F.3d 1293 (Fed. Cir. 2007) ............................................................................ 32
`Bayer Healthcare Pharm., Inc. v. Watson Pharm. Inc.,
`713 F.3d 1369 (Fed. Cir. 2013) ............................................................................ 46
`Bell Commc’ns Research, Inc. v. Vitalink Commc’ns Corp., 55 F.3d
`615, 623 (Fed. Cir. 1995) ..................................................................................... 32
`Bristol-Myers Squibb Co. v. Teva Pharm. USA, Inc.,
`923 F. Supp. 2d 602 (D. Del. 2013) ..................................................................... 47
`Dow Jones & Co., Inc. v. Ablaise Ltd.,
`606 F.3d 1338 (Fed. Cir. 2010) ............................................................................ 46
`In re Am. Acad. of Sci. Tech. Ctr.,
`367 F.3d 1359 (Fed. Cir. 2004) ............................................................................ 21
`In re Cuozzo Speed Techs., LLC,
`793 F.3d 1268 (Fed. Cir. 2015) ............................................................................ 18
`In re Droge,
`695 F.3d 1334 (Fed. Cir. 2012) ............................................................................ 39
`In re Fulton,
`391 F.3d 1195 (Fed. Cir. 2004) ............................................................................ 48
`In re Trans Texas Holdings Corp.,
`498 F.3d 1290 (Fed. Cir. 2007) .............................................................................. 4
`In re Young,
`927 F.2d 588 (Fed. Cir. 1991) .............................................................................. 51
`Key Pharm. Inc. v. Hercon Labs. Corp.,
`161 F.3d 709 (Fed. Cir. 1998) ....................................................................... 21, 23
`Medichem S.A. v. Rolabo S.L.,
`437 F.3d 1157 (Fed. Cir. 2006) ............................................................................ 44
`Merck & Co. v. Teva Pharm. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005) ............................................................................ 48
`
`iv
`
`

`

`
`
`Noven Pharm., Inc. v. Novartis AG,
`No. IPR2014-549, 2015 WL 5782080 (PTAB Sept. 28, 2015) ............................. 4
`Novo Nordisk A/S v. Eli Lilly & Co.,
`No. 98-643 WL 1094213 (D. Del. Nov. 18, 1999) ....................................... 20, 21
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) ............................................................................ 45
`Santarus, Inc. v. Par Pharm., Inc.,
`720 F. Supp. 2d 427 (D. Del. 2010) ..................................................................... 47
`Syntex (U.S.A.) LLC v. Apotex, Inc.,
`407 F.3d 1371 (Fed. Cir. 2005) ..................................................................... 49, 50
`Tyco Healthcare Grp. LP v. Mut. Pharm. Co. Inc.,
`642 F.3d 1370 (Fed. Cir. 2011) ............................................................................ 46
`STATUTES 
`
`35 U.S.C. § 102 ........................................................................................... 14, 26, 58
`35 U.S.C. § 103 ......................................................................................................4, 6
`35 U.S.C. § 314(a) ..................................................................................................... 8
`35 U.S.C. § 315 ......................................................................................................2, 5
`OTHER AUTHORITIES 
`
`21 C.F.R. § 312.30 ................................................................................................... 47
`37 C.F.R. § 42 ................................................................................................. 1, 7, 18
`37 C.F.R. § 42.104 ...................................................................................................... 6
`No table of authorities entries found.
`
`
`
`v
`
`

`

`
`
`
`
`Exhibit
`No.
`
`Exhibit
`1001:
`
`Exhibit
`1002:
`
`Exhibit
`1003:
`
`Exhibit
`1004:
`
`Exhibit
`1005:
`
`Exhibit
`1006:
`
`EXHIBIT LIST
`
`Description
`
`U.S. Patent No. 7,772,209
`
`File History of U.S. Patent Application
`No. 11/776,329, which issued as U.S. Patent
`No. 7,772,209 on August 10, 2010
`
`Findings Of Fact And Conclusions Of Law
`Following Bench Trial August 19, 2013, in
`Eli Lilly & Co. v. Teva Parenteral
`Medicines, Inc., Case No. 1:10-cv-1376,
`Dkt. 336 (S.D. Ind. March 31, 2014)
`
`Referred To In
`The Petition As
`
`“’209 patent”
`
`“’209 file history”
`
`“Teva Decision”
`
`Declaration of Ron D. Schiff, M.D., Ph.D.
`
`“Schiff Decl.”
`
`U.S. Patent No. 5,217,974
`
`C. Niyikiza, et al., MTA (LY231514):
`Relationship of vitamin metabolite profile,
`drug exposure, and other patient
`characteristics to toxicity, Annals Oncology 9
`(Suppl. 4): 125-140, Abstract 609P, (1998)
`
`“’974 patent”
`
`“Niyikiza I”
`
`Exhibit
`1007:
`
`Hilary Calvert, An Overview of Folate
`Metabolism: Features Relevant to the Action
`and Toxicities of Antifolate Anticancer
`Agents, Seminars Oncology, 26: 3-10 (1999)
`
`“Calvert”
`
`Exhibit
`1008:
`
`Textbook of Small Animal Medicine (John K.
`Dunn ed. 1999)
`
`“Animal Medicine”
`
`Exhibit
`1009:
`
`Sidney Farber, et al., Temporary Remissions in
`acute leukemia in children produced by folic
`vi
`
`“Farber”
`
`

`

`
`
`
`
`Exhibit
`No.
`
`Description
`
`Referred To In
`The Petition As
`
`Exhibit
`1010:
`
`Exhibit
`1011:
`
`Exhibit
`1012:
`
`Exhibit
`1013
`
`Exhibit
`1014
`
`Exhibit
`1015
`
`acid antagonist, 4-aminopteroylglutamic acid
`(aminopterin), New Eng. J. Med., 238(23):
`787-793
`
`Sarah L. Morgan, et al., Supplementation with
`Folic Acid during Methotrexate Therapy for
`Rheumatoid Arthritis, Annals Internal Med.,
`121: 833-841 (1994)
`
`G.B. Grindey, et al., Reversal of the toxicity but
`not the antitumor activity of Lometrexol by folic
`acid, Am. Ass’n Cancer Res., 32: 324, Abstract
`1921 (1991)
`
`Laurane G. Mendelsohn, et al., Preclinical and
`Clinical Evaluation of the Glycinamide
`Ribonucleotide Formyltransferase Inhibitors
`Lometrexol and LY309887, in Anticancer Drug
`Dev. Guide: Antifolate Drugs Cancer Therapy,
`(Ann L. Jackman, ed.) Ch. 12: 261-80 (1999)
`
`John F. Worzalla, et al., Role of Folic Acid in
`Modulating the Toxicity and Efficacy of the
`Multitargeted Antifolate, LY231514, Anticancer
`Res., 18: 3235-3240 (1998)
`
`L. Hammond, et al., A Phase I and
`Pharmacokinetic (PK) Study of the
`Multitargeted Antifol (MTA) LY231514 with
`Folic Acid, Proc. Am. Soc’y Clinical
`Oncology, 17: Abstract 866 (1998)
`
`L. Hammond, et al., A phase I and
`pharmacokinetic (PK) study of the multitargeted
`antifolate (MTA, LY231514) with folic acid
`(FA), Annals Oncology, 9: 129, Abstract 620P
`(1998)
`
`“Morgan”
`
`“Grindey”
`
`“Mendelsohn”
`
`“Worzalla”
`
`“Hammond II”
`
`“Hammond I”
`
`vii
`
`

`

`
`
`
`
`Exhibit
`No.
`
`Exhibit
`1016
`
`Exhibit
`1017
`
`Exhibit
`1018
`
`Exhibit
`1019
`
`Exhibit
`1020
`
`Exhibit
`1021
`
`Exhibit
`1022
`
`Description
`
`C. Niyikiza, et al., LY231514 (MTA):
`Relationship of vitamin metabolite profile to
`toxicity, Proc. Am. Ass’n Cancer Res., 17: 558a,
`Abstract 2139 (1998)
`
`R. Thödtmann, et al., Preliminary Results of a
`Phase I Study with MTA (LY231415) in
`Combination with Cisplatin in Patients with
`Solid Tumors, Seminars Oncology, 26 (2, Suppl.
`6): 89-93 (1999)
`
`Referred To In
`The Petition As
`
`“Niyikiza II”
`
`“Thödtmann I”
`
`U.S. Patent No. 5,563,126
`
`“’126 patent”
`
`Ernest Beutler & James K. Weick, Blood and
`Neoplastic Disorders, in Current Clinical
`Practice (Messerli, ed., 1987), Ch. 1: 291-302
`
`“Beutler”
`
`“Brattström”
`
`“Shih”
`
`“Westerhof”
`
`Lars Brattström, Vitamins as Homocysteine-
`Lowering Agents, J. Nutrition, 126: 1276S-
`1280S (1996)
`
`Chuan Shih, et al., LY231514, a Pyrrolo[2,3-
`d]pyrimidine-based Antifolate That Inhibits
`Multiple Folate-requiring Enzymes, Cancer
`Res., 57, 1116- 1123 (1997)
`
`G. Robbin Westerhof, et al., Carrier- and
`Receptor-Mediated Transport of Folate
`Antagonists Targeting Folate-Dependent
`Enzymes: Correlates of Molecular-Structure
`and Biological Activity, Am. Soc’y
`Pharmacology Experimental Therapeutics, 48:
`459-471 (1995)
`
`Exhibit
`1023
`
`F. G. Arsenyan, et al., Influence of
`Methylcobalamin on the Antineoplastic Activity
`of Methotrexate, Pharmaceutical Chemistry J.,
`
`“Arsenyan”
`
`viii
`
`

`

`
`
`
`
`Exhibit
`No.
`
`Description
`
`12(10): 1299-1303 (1978)
`
`Referred To In
`The Petition As
`
`Exhibit
`1024
`
`File History of U.S. Patent Application
`No. 11/288,807, Abandoned
`
`“’807 File History”
`
`Exhibit
`1025
`
`Exhibit
`1026
`
`Exhibit
`1027
`
`Exhibit
`1028
`
`Exhibit
`1029
`
`Exhibit
`1030
`
`Exhibit
`1031
`
`U.S. Food & Drug Administration, Approved
`Drug Products with Therapeutic Equivalents
`Evaluations (30th ed. 2010)
`
`“Orange Book
`Listing for
`Alimta®”
`
`Z.P. Sofyina, et al., Possibility to Increase the
`Antitumor Effect of Folic Acid Antagonist with
`the Help of Methylcobalamine Analogs, Sci.
`Center Oncology 1:72-78 (1979)
`
`Victor Herbert, The Role of Vitamin B12 and
`Folate in Carcinogenesis, Advances
`Experimental Med. Biology, 206: 293-311
`(1986)
`
`“Sofyina”
`
`“Herbert”
`
`Glenn Tisman, et al., Overcoming Colon Cancer
`Resistance to Hepatic Artery Infusional 5FUdR
`Chemotherapy with Folinic Acid, Clinical Res.,
`33(2): 459A (1985)
`
`“Tisman”
`
`J.D. Kinloch, Maintenance Treatment of
`Pernicious Anaemia by Massive Parenteral
`Doses of Vitamin B12 at Intervals of Twelve
`Weeks, Brit. Med. J., 1:99-100 (1960)
`
`“Kinloch”
`
`D. Wray, et al., Recurrent Aphthae: Treatment
`with Vitamin B12, Folic Acid, and Iron, Brit.
`Med. J., 2:490-93 (1975)
`
`“Wray”
`
`J. Tamura, et al., Immunomodulation by Vitamin
`B12: Augmentation of CD8+ T Lymphocytes and
`Natural Killer (NK) Cell Activity in Vitamin
`B12-Deficient Patients by Methyl-B12
`Treatment, Clin. Experimental Immunology,
`
`“Tamura”
`
`ix
`
`

`

`
`
`
`
`Exhibit
`No.
`
`Exhibit
`1032
`
`Exhibit
`1033
`
`Exhibit
`1034
`
`Exhibit
`1035
`
`Exhibit
`1036
`
`Exhibit
`1037
`
`Exhibit
`1038
`
`Exhibit
`1039
`
`Description
`
`Referred To In
`The Petition As
`
`116:28-32 (1999)
`
`Carrasco et al., Acute Megaloblastic Anemia:
`Homocysteine Levels Are Useful for Diagnosis
`and Follow-Up, Haematologica, 84: 767- 768
`(1999)
`
`“Carrasco”
`
`European Patent Application No. 0 595 005
`
`“EP005”
`
`U.S. Patent No. 5,344,932
`
`Amended Joint Claim Construction Statement
`in Eli Lilly & Co. v. Teva Parenteral
`Medicines, Inc. et al., No. 1:10-cv-1376 (S.D.
`Ind.), filed April 19, 2012 (Dkt. 110)
`
`Excerpts from transcript of the trial on
`invalidity held between August 19 and August
`29, 2013 in Eli Lilly & Co. v. Teva Parenteral
`Medicines, Inc., Case No. 1:10-cv-1376 (S.D.
`Ind.)
`
`E. Bajetta et al., Phase II study of pemetrexed
`disodium (Alimta®) administered with oral
`folic acid in patients with advanced gastric
`cancer, Annals of Oncology 14:1543-48
`(2003).
`
`“’932 patent”
`
`“Joint Claim
`Construction
`Statement”
`
`“Teva Litigation
`Trial Tr.”
`
`“Bajetta”
`
`Letter dated February 4, 2004 from Robert
`Temple to John Worzalla concerning NDA 21-
`462
`
`“Alimta®
`Approval Letter”
`
`Johan B. Ubbink et al., Vitamin Requirements
`for the Treatment of Hyperhomocysteinemia in
`Humans, J. Nutrition 124:1927-1933 (1994)
`
`“Ubbink I”
`
`Exhibit Anja Brönstrup et al., Effects of folic acid and
`
`“Brönstrup”
`
`x
`
`

`

`Exhibit
`No.
`1040
`
`Exhibit
`1041
`
`Exhibit
`1042
`
`Exhibit
`1043
`
`Exhibit
`1044
`
`Exhibit
`1045
`
`Exhibit
`1046
`
`Exhibit
`1047
`
`Exhibit
`1048
`
`
`
`
`
`Description
`
`Referred To In
`The Petition As
`
`combinations of folic acid on plasma
`homocysteine concentrations in healthy, young
`women, Am. J. Clin. Nutr. 1998:68:1104-10
`(1998)
`
`J. B. Ubbink, The role of vitamins in the
`pathogenesis and treatment of
`hyperhomocyst(e)inaemia, J. Inherited
`Metabolic Disease, 20:316-25 (1997)
`
`S. Sörenson et al., A systematic overview of
`chemotherapy effects in non-small cell lung
`cancer, Acta Oncologica 40(2-3):327-29 (2001)
`
`R. Thödtmann et al., Phase I study of different
`sequences of MTA (LY231514) in combinaition
`with cisplatin in patients with solid tumours,
`Annals Oncology, 9: 129, 618P (Abstract)
`(1998)
`
`“Ubbink II”
`
`“Sörenson”
`
`“Thödtmann II”
`
`Complaint filed in Eli Lilly & Co. v. Teva
`Parenteral Medicines, Inc., No. 1:08-cv-335 (D.
`Del.) on June 5, 2008
`
`“Delaware Teva
`Litigation
`Complaint”
`
`Calvert, MTA: Summary and Conclusions,
`Seminars in Oncology, 26 (2, Suppl. 6): 105-08
`(1999)
`
`“MTA: Summary
`& Conclusions”
`
`Center for Drug Evaluation and Research,
`Product Development under the Animal Rule:
`Guidance for the Industry (October 2015)
`
`“FDA Animal
`Rule Guidance”
`
`A.H. Calvert & J.M. Walling, Clinical Studies
`with MTA, British J. Cancer (1998) 78 (Suppl.
`3): 35-40
`
`“Calvert &
`Walling”
`
`Center for Drug Evaluation and Research,
`Guidance for Industry: Single Dose Acute
`Toxicity Testing for Pharmaceuticals (August
`xi
`
`“FDA Single Dose
`Guidance”
`
`

`

`Exhibit
`No.
`
`Exhibit
`1049
`
`Exhibit
`1050
`
`Description
`
`Referred To In
`The Petition As
`
`1996)
`
`Center for Drug Evaluation and Research, E6
`Good Clinical Practice: Consolidated Guidance
`(April 1996)
`
`“FDA E6
`Guidance”
`
`Robert H. Allen et al., Diagnosis of Cobalamin
`Deficiency I: Usefulness of Serum
`Methylmalonic Acid and Total Homocysteine
`Concentrations, Am. J. Hematology 34:90-98
`(1990)
`
`Allen
`
`Exhibit
`1051
`
`Eli Lilly & Company, Alimta® Labeling
`(Revised Sept. 2013)
`
`Rusthoven et al., Multitargeted Antifolate
`LY231514 as First-Line Chemotherapy for
`Patients with Advanced Non-Small-Cell Lung
`Cancer: A Phase II Study, J. Clin. Oncology, 17
`(4) 1194-99 (April 1999)
`
`“Alimta Labeling”
`
`“Rusthoven”
`
`
`
`
`
`
`
`Exhibit
`1052
`
`Exhibit
`1053
`
`Exhibit
`1054
`
`Return of Service, Eli Lilly & Co. v. Sandoz
`Inc., Case No. 1:14-cv-2008 (S.D. Ind. Dec. 29,
`2014)
`
`“Return of
`Service”
`
`FDA, Electronic Orange Book: Approved Drug
`Products and Therapeutic Equivalence
`Evaluations Entry for Alimta®, available at
`http://www.accessdata.fda.gov/scripts/cder/ob/d
`ocs/patexclnew.cfm?Appl_No=021462&Produc
`t_No=001&table1=OB_Rx (last accessed Dec.
`14, 2015)
`
`“2015 Alimta®
`Orange Book
`Listing”
`
`xii
`
`

`

`
`
`I.
`
`INTRODUCTION
`
`Pursuant to 35 U.S.C. §§ 311-319 and 37 C.F.R. § 42, Sandoz Inc.
`
`(“Sandoz” or “Petitioner”) respectfully requests Inter Partes Review (“IPR”) of all
`
`claims (i.e., claims 1-22) of U.S. Patent No. 7,772,209 to Niyikiza, titled
`
`“Antifolate Combination Therapies” (“’209 patent,” Ex. 1001), which is currently
`
`assigned to Eli Lilly and Company (“Lilly” or “Patent Owner”). The Petitioner
`
`authorizes the Patent and Trademark Office to charge Deposit Account No. 23-
`
`1925 for the fees set in 37 C.F.R. § 42.15(a) for this Petition for IPR, and further
`
`authorizes payment of any additional fees to be charged to this Deposit Account.
`
`This Petition demonstrates a reasonable likelihood that claims 1-22 of the
`
`’209 patent are unpatentable. The claims of the ’209 patent are generally directed
`
`to a method of pretreating a patient with folic acid and a methylmalonic acid
`
`(“MMA”) lowering agent (e.g., vitamin B12) prior to administering pemetrexed.
`
`But this pretreatment regimen was obvious more than a year before the earliest
`
`claimed priority date for the ’209 patent (June 2000).
`
`The case for obviousness is straightforward. Prior to June 1999, the patentee
`
`(Niyikiza) published studies linking pemetrexed toxicity with elevated baseline
`
`homocysteine levels. Ex. 1006, Niyikiza I; see also Ex. 1016, Niyikiza II. Calvert
`
`pointed to this known link and further explained that the elevated homocysteine
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`levels associated with pemetrexed toxicity are caused by a folic acid and/or
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`1
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`

`

`
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`vitamin B12 deficiency. Ex. 1007, Calvert. Thus, based on Calvert and Niyikiza I,
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`it was known that sufficient amounts of both folic acid and vitamin B12 are
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`necessary to lower homocysteine levels. In view of the teachings of Calvert and
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`Niyikiza I, it would have been obvious to add vitamin B12 to the folic acid
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`pretreatment regimens for pemetrexed of Worzalla or Hammond I, which had
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`previously been published by the Patent Owner. See Ex. 1013, Worzalla;
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`Ex. 1015, Hammond I. The reasonably expected result: the lowering of baseline
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`homocysteine levels with a corresponding reduction in the prevalence and/or
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`severity of pemetrexed toxicity.
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`II. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8(a)(1)
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`A. Real Party-In-Interest
`Sandoz Inc. is the real party-in-interest for the instant petition.
`
`B. Related Matters
`
`Related Litigations
`
`1.
`Petitioner is not aware of any reexamination certificates or pending
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`prosecution concerning the ’209 patent. Petitioner is a defendant in the following
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`litigation involving the ’209 patent: Eli Lilly & Co. v. Sandoz Inc., No. 1:14-cv-
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`2008 (S.D. Ind., filed December 5, 2014) (“Sandoz Litigation”). Sandoz has
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`timely filed this petition pursuant to 35 U.S.C. § 315(b) within one year of the date
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`2
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`

`
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`“on which the petitioner . . . [was] served with [the] complaint alleging
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`infringement of the patent” – December 15, 2014. Ex. 1053, Return of Service.
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`The Patent Owner has also asserted the ’209 patent in the following
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`additional litigations in which Petitioner was not and is not a party: Eli Lilly & Co.
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`v. Teva Parenteral Medicines, Inc., No. 1:10-cv-1376 (S.D. Ind., filed October 29,
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`2010) (“Teva Litigation”); Eli Lilly & Co. v. APP Pharmaceuticals, LLC, No.
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`1:11-cv-942 (S.D. Ind., filed July 15, 2011); Eli Lilly & Co. v. Accord Healthcare,
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`Inc., USA, No. 1:12-cv-86 (S.D. Ind., filed January 20, 2012); Eli Lilly & Co. v.
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`Apotex Inc., No. 1:12-cv-499 (S.D. Ind., filed April 17, 2012); Eli Lilly & Co. v.
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`Accord Healthcare Inc., USA, No. 1:13-cv-335 (S.D. Ind., filed February 28,
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`2013); Eli Lilly & Co. v. Sun Pharmaceutical Industries Ltd., No. 1:13-cv-1469
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`(S.D. Ind., filed September 13, 2013); Eli Lilly & Co. v. Glenmark Generics Inc.,
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`USA, No. 1:14-cv-104 (S.D. Ind., filed January 23, 2014); Eli Lilly & Co. v. Nang
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`Kuang Pharmaceutical Co., Ltd., No. 1:14-cv-1647 (S.D. Ind., filed October 8,
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`2014); Eli Lilly & Co. v. Fresenius Kabi USA, LLC, No. 1:15-cv-96 (S.D. Ind.,
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`filed January 23, 2015); Eli Lilly & Co. v. Mylan Laboratories Ltd., No. 1:15-cv-
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`1083 (S.D. Ind., filed July 10, 2015); and Eli Lilly & Co. v. Emcure
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`Pharmaceuticals Ltd., No. 1:15-cv-1244 (S.D. Ind., filed August 7, 2015).
`
`On March 31, 2014, the U.S. District Court for the Southern District of
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`Indiana ruled in the Teva Litigation that Teva failed to establish by clear and
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`3
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`

`
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`convincing evidence that claims 9, 10, 12, 14, 15, 18, 19, and 21 of the ’209 patent
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`are invalid as obvious under 35 U.S.C. § 103. Ex. 1003, Teva Decision at 9-27.
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`An appeal of the Teva Decision is currently pending in the Federal Circuit. Eli
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`Lilly & Co. v. Teva Parenteral Meds., No. 1:10-cv-1376, 2015 U.S. Dist. LEXIS
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`112221 (S.D. Ind. Aug. 25, 2015), appeal docketed, No. 15-2067 (Fed. Cir. Sept.
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`25, 2015).
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`The Teva Decision is not binding in this proceeding. See Noven Pharm.,
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`Inc. v. Novartis AG, No. IPR2014-549, 2015 WL 5782080, at *2 (PTAB Sept. 28,
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`2015) (“[W]hile we have considered the Federal Circuit’s decision, we have
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`independently analyzed patentability of the challenged claims based on the
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`evidence and standards that are applicable to this proceeding.”); In re Trans Texas
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`Holdings Corp., 498 F.3d 1290, 1297 (Fed. Cir. 2007) (finding the PTO, in a
`
`reexamination procedure, was not bound by prior district court litigation to which
`
`it was not a party). Moreover, the district court made erroneous factual and legal
`
`findings that if corrected would likely have led to a different outcome under the
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`standards applicable in that proceeding.
`
`Related Proceedings Before the Board
`
`2.
`The ’209 patent has also been challenged before the Board in the following
`
`proceedings in which Petitioner was not and is not a party: Accord Healthcare,
`
`Inc., USA v. Eli Lilly & Co., IPR2013-356 (PTAB, filed June 14, 2013); Neptune
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`4
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`

`
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`Generics, LLC v. Eli Lilly & Co., IPR2016-237 (PTAB, filed November 24, 2015);
`
`and Neptune Generics, LLC v. Eli Lilly & Co., IPR2016-240 (PTAB, filed
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`November 24, 2015). On October 1, 2013, the Board denied institution of Accord
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`Healthcare Inc.’s petition in IPR2013-356 because the petition was not filed within
`
`the time limit imposed by 35 U.S.C. § 315(b). Neptune Generics, LLC’s
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`(“Neptune”) two petitions are pending before the Board.
`
`The grounds raised in Neptune’s petitions rely primarily on a combination of
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`European Patent Application No. 0595005 with one or more of the following:
`
`Nikiyiza I; U.S. Patent No. 5,217,974; and/or Rusthoven (Ex. 1052). IPR2016-
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`240, Paper No. 1, Petition at 16; IPR2016-237, Paper No. 1, Petition at 15. By
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`contrast, Sandoz’s petition relies on Calvert and Niyikiza I combined with the
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`teachings of either Hammond I or Worzalla that folic acid pretreatment reduces
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`pemetrexed toxicity without compromising efficacy. Neptune cites Hammond I
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`and Worzalla, but does not rely on either to support its grounds. Accordingly, this
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`petition is not redundant with Neptune’s petitions.
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`C. Lead and Back-Up Counsel
`Lead Counsel
`Back-Up Counsel
`Laura Lydigsen
`Ralph J. Gabric (Reg. No. 34,167)
`(pro hac vice motion to be filed)
`rgabric@brinksgilson.com
`llydigsen@brinksgilson.com
`Brinks Gilson & Lione
`Brinks Gilson & Lione
`Suite 3600 NBC Tower
`Suite 3600 NBC Tower
`455 Cityfront Plaza Drive
`455 Cityfront Plaza Drive
`Chicago IL 60611-5599
`Chicago IL 60611-5599
`T: 312-321-4200, F: 312-321-4299
`
`5
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`

`

`
`
`
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`T: 312-321-4200, F: 312-321-4299
`
`Bryan T. Richardson, Ph.D. (Reg. No.
`70,572)
`brichardson@brinksgilson.com
`Brinks Gilson & Lione
`4721 Emperor Boulevard
`Suite 220
`Durham, NC 27703-8580
`T: 919-998-5700, F: 919-998-5701
`
`
`Service Information
`
`D.
`Please address all correspondence to the lead and backup counsel at the
`
`contact information above. Petitioner also consents to service by email at
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`rgabric@brinksgilson.com and llydigsen@brinksgilson.com.
`
`III. GROUNDS FOR STANDING
`As required by 37 C.F.R. § 42.104(a), Petitioner certifies that the ’209 patent
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`is available for IPR and that Petitioner is not barred or estopped from requesting
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`IPR on the grounds identified herein.
`
`IV.
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`IDENTIFICATION OF CHALLENGE AND STATEMENT OF THE
`PRECISE RELIEF REQUESTED
`Petitioner requests inter partes review and cancellation of claims 1-22 of the
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`’209 patent on one or more of grounds pursuant to 35 U.S.C. § 103 as set forth
`
`herein. The ’209 patent is to be reviewed under pre-AIA § 103. Petitioner’s
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`detailed statement of the reasons for the relief requested is set forth below in the
`
`section titled “Statement of Reasons for the Relief Requested.” In accordance with
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`6
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`
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`37 C.F.R. § 42.6(c), copies of the exhibits are filed herewith. In addition, the
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`Petition is accompanied by the declaration of Dr. Ron D. Schiff. Ex. 1004.
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`Claims 1-22 of the ’209 patent are unpatentable based upon the following
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`grounds:
`
`Ground 1: Claims 1-22 are obvious over Calvert in view of Niyikiza I,
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`Worzalla, and the knowledge of a person of ordinary skill.
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`Ground 2: Claims 1-22 are obvious over Calvert in view of Niyikiza I,
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`Hammond I, and the knowledge of a person of ordinary skill.
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`The addition of limitations directed to specific dosages, dosing schedules,
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`and the combination of the known chemotherapy drug cisplatin add nothing
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`patentable to independent claims 1 and 12 because these parameters were well
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`known to the person of ordinary skill in the art (“POSA”).
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`There is no redundancy in Grounds 1 and 2. Ground 1 (which is directed to
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`claims 1-22) relies on Calvert, Niyikiza I, and Worzalla as primary references.
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`Worzalla expressly discloses folic acid pretreatment in mice. Ground 2 (which is
`
`also directed to claims 1-22) differs because it relies on Hammond I as the third
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`primary reference. Hammond I expressly discloses folic acid pretreatment in
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`humans.
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`7
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`

`
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`V. THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW
`This petition meets the threshold requirement for inter partes review
`
`because it establishes “a reasonable likelihood that the petitioner would prevail
`
`with respect to at least 1 of the claims challenged in the petition.” 35 U.S.C.
`
`§ 314(a). As explained below, for each of the grounds of unpatentability proposed
`
`below, there is a reasonable likelihood that Petitioner will prevail with respect to at
`
`least one of the challenged claims.
`
`VI. STATEMENT OF REASONS FOR THE RELIEF REQUESTED
`
`Summary of the Argument
`
`A.
`Pemetrexed is the active pharmaceutical ingredient in Lilly’s Alimta®
`
`chemotherapy product, which was approved by the U.S. Food & Drug
`
`Administration (“FDA”) in February 2004. Ex. 1038, Alimta® Approval Letter.
`
`In the early 1990s, Lilly obtained patent coverage for pemetrexed with the issuance
`
`of U.S. Patent Nos. 5,217,974 (“’974 patent”) and 5,344,932 (“’932 patent”). The
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`’974 patent expired in 2012 and patent exclusivity for the ’932 patent will expire in
`
`2017. Ex. 1025, Orange Book Listing for Alimta® at 1025-0003; Ex. 1054, 2015
`
`Alimta® Orange Book Listing. The ’209 patent, which expires in 2022, is Lilly’s
`
`effort to extend its patent monopoly for pemetrexed for an additional 5 years
`
`beyond the 2017-expiration date of Lilly’s ’932 patent. But the claims of the ’209
`
`patent are directed to an obvious method for administering the known drug
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`8
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`

`
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`pemetrexed disodium. As such, the claims of the ’209 patent should be canceled,
`
`and Lilly’s patent monopoly over pemetrexed should end with the expiration of the
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`’932 patent in 2017, which will clear the way for Petitioner’s lower-priced generic
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`product.
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`In the late 1990s, pemetrexed was one of several known antifolates, which
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`are a class of antitumor drugs. Antifolates interfere with the growth and
`
`proliferation of cancer cells by disrupting DNA synthesis. Ex. 1004, Schiff Decl.
`
`¶ 28. Antifolates disrupt DNA synthesis by competing with folic acid (actually the
`
`metabolic derivatives of folic acid) for binding sites on certain enzymes. Id. ¶ 30.
`
`Unfortunately, antifolates also interfere with the growth and proliferation of
`
`healthy cells, which leads to “toxicity.” Id. ¶ 29. In order to maintain sufficient
`
`folate pools to support DNA synthesis in healthy cells (but not faster reproducing
`
`cancer cells), it was known to pretreat patients with appropriate amounts of folic
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`acid prior to starting therapy with antifolates such as pemetrexed. Id. ¶ 39; Ex.
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`1005, ’974 patent, 2:1-24, 6:22-47; Ex. 1015, Hammond I; Ex. 1014, Hammond II;
`
`Ex. 1012, Mendelsohn at 270.
`
`Lilly’s ’209 patent is generally directed to adding vitamin B12 to this known
`
`folic acid pretreatment regimen. Ho