`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`————————————————
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`————————————————
`
`DR. REDDY’S LABORATORIES, INC.
`Petitioner,
`v.
`CELGENE CORP.
`Patent Owner.
`————————————————
`IPR2018-01504
`
`Patent No. 9,056,120
`————————————————
`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 9,056,120
`
`
`
`
`
`
`
`

`

`TABLE OF CONTENTS
`INTRODUCTION .......................................................................................... 1
`I.
`II. GROUNDS FOR STANDING ....................................................................... 1
`III.
`IDENTIFICATION OF CHALLENGE AND STATEMENT OF THE
`PRECISE RELIEF REQUESTED ................................................................. 2
`IV. THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW ............ 2
`V.
`STATEMENT OF REASONS FOR THE RELIEF REQUESTED .............. 3
`A.
`Summary of the Argument ................................................................... 3
`B.
`The ’120 Patent and Its Prosecution ..................................................... 6
`1.
`The ’120 Patent .......................................................................... 6
`2.
`The Prosecution of the ’120 Patent ............................................ 2
`The Person of Ordinary Skill in the Art ............................................... 3
`Claim Construction .............................................................................. 4
`Scope and Content of the Prior Art ...................................................... 4
`1.
`Background on MDS ................................................................. 5
`2.
`TNFα Was a Known Target for MDS. ...................................... 7
`a.
`Shetty 1996 ...................................................................... 7
`Thalidomide Clinical Trials Showed Promise, Including
`in Inhibiting TNFα. .................................................................... 8
`a.
`Raza 2000b ...................................................................... 8
`b.
`Raza 2000d ...................................................................... 9
`c.
`Raza 2001 ...................................................................... 10
`Revimid (Lenalidomide) Was a Known Compound with
`Increased Potency over Thalidomide. ...................................... 12
`a.
`Thomas 2000a (continued) ............................................ 13
`b.
`Corral 1999b .................................................................. 13
`Clinical Trials of Revimid ....................................................... 18
`5.
`The Law of Obviousness .................................................................... 22
`
`C.
`D.
`E.
`
`F.
`
`3.
`
`4.
`
`i
`
`
`
`

`

`G. Ground 1: Claims 1–8, 12–34, and 38–53 Were Unpatentable
`As Obvious over List 2001 in View of the ’230 Patent and
`Celgene Press Releases 5/8/2001 and 8/28/2001. .............................. 23
`1.
`Independent Claims 1 and 28 Were Obvious. ......................... 24
`2.
`Dependent Claim 2 Was Obvious. ........................................... 27
`3.
`Dependent Claims 3–6 and 29–32 Were Obvious. .................. 28
`4.
`Dependent Claims 24–27 and 50–53 Were Obvious. .............. 29
`5.
`Dependent Claims 16–21 and 42–47 Were Obvious. .............. 30
`6.
`Dependent Claims 7–8, and 33–34 Were Obvious. ................. 31
`7.
`Dependent Claims 12 and 38 Were Obvious. .......................... 32
`8.
`Dependent Claims 13–15, 22–23, 39–41 and 48–49 Were
`Obvious. ................................................................................... 33
`H. Ground 2: Claims 1–8, 12–34, and 38–53 Were Unpatentable
`As Obvious Over Thomas 2000a in View of the ’230 Patent and
`the Celgene Press Releases 5/8/2001 and 8/28/2001. ........................ 37
`1.
`Independent Claims 1 and 28 Were Obvious. ......................... 37
`2.
`Dependent Claim 2 Was Obvious. ........................................... 40
`3.
`Dependent Claims 3–6 and 29–32 Were Obvious. .................. 41
`4.
`Dependent Claims 24–27 and 50–53 Were Obvious. .............. 41
`5.
`Dependent Claims 16–21 and 42–47 Were Obvious. .............. 42
`6.
`Dependent Claims 7–8, and 33–34 Were Obvious. ................. 43
`7.
`Dependent Claims 12 and 38 Were Obvious. .......................... 44
`8.
`Dependent Claims 13–15, 22–23, 39–41, and 48–49
`Were Obvious. ......................................................................... 45
`The POSA was Motivated to Combine the Prior Art Teachings. ...... 46
`Any Secondary Considerations Fail to Overcome the Showing
`of Obviousness. .................................................................................. 50
`1.
`Revlimid Sales Do Not Save the ’120 Patent. ......................... 51
`a.
`There Is No Nexus Between the Claims and
`Secondary Considerations of Nonobviousness. ............ 51
`
`I.
`J.
`
`ii
`
`
`
`

`

`b.
`
`Any Commercial Success of Revlimid Is
`Attributable to Celgene’s Extensive Marketing
`Efforts and REMS Program. .......................................... 53
`The Claimed Methods Produced No Unexpected Results. ...... 54
`2.
`The ’120 Patent Satisfied No Long-Felt But Unmet Need. ..... 54
`3.
`Copying Is Irrelevant. .............................................................. 55
`4.
`VI. MANDATORY NOTICES .......................................................................... 55
`A.
`Real Parties-In-Interest (37 C.F.R. § 42.8(b)(1)) ............................... 55
`B.
`Related Matters (37 C.F.R. § 42.8(b)(2)) ........................................... 55
`C.
`Identification of Counsel (37 C.F.R. § 42.8(b)(3)) and Service
`Information (37 C.F.R. § 42.8(b)(4)) ................................................. 56
`Service Information (37 C.F.R. § 42.8(b)(4)) .................................... 57
`
`D.
`
`
`
`
`
`
`iii
`
`
`
`

`

`Exhibit
`1001
`
`1002
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`LIST OF EXHIBITS
`
`Description
`U.S. Patent No. 9,056,120, titled Methods of Treating
`Myelodysplastic Syndromes with a Combination Therapy
`Using Lenalidomide and Azacitidine
`File History for U.S. Patent No. 9,056,120
`in Support of
`Declaration of Mark Levin, M.D.,
`Petition for Inter Partes Review of U.S. Patent No. 9,056,120
`Alan F. List et al., Rational Approaches to Design of
`Therapeutics Targeting Molecular Markers: Targeting
`Angiogenesis in Hematologic Malignancies, HEMATOLOGY,
`2001 AM. SOC. HEMATOLOGY (ASH) EDUC. PROGRAM BOOK
`443 (2001)
`Deborah A. Thomas, M.D. & Hagop M. Kantarjian, M.D.,
`Current Role of Thalidomide in Cancer Treatment, 12
`CURRENT OPINION IN ONCOLOGY 564 (2000)
`U.S. Patent No. 6,281,230, titled Isoindolines, Method of Use,
`and Pharmaceutical Compositions
`Press Release, Celgene Corp., Celgene Advances
`Immunomodulatory Drug (IMiD™) Clinical Program (Feb.
`29, 2000)
`Press Release, Celgene Corp., PR Newswire, Positive Interim
`Results Presented at the VIIIth International Myeloma
`Workshop on Celgene Corporation’s Lead
`IMiD(™)
`(REVIMID(™)) (May 8, 2001)
`Press Release, Celgene Corp., PR Newswire, Initial Phase I
`Solid Tumor Data on Celgene’s Lead Imid™, Revimid™
`(June 7, 2001)
`Press Release, Celgene Corp., PR Newswire, Celgene
`Corporation Awarded Additional Patent Protection for Lead
`IMiD(™), REVIMID(™); Comprehensive Patent Protection
`for REVIMID Includes Coverage of the Active Ingredient,
`Pharmaceutical Compositions, and Therapeutic Uses (Aug.
`28, 2001)
`
`iv
`
`
`
`

`

`Exhibit
`1011
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`in Solid Tumors,
`
`Description
`Press Release, Celgene Corp., PR Newswire, Imids(™)
`Activity Against Multiple Myeloma Cells Presented at the
`American Society of Hematology Meeting (Dec. 5, 2000)
`Press Release, Celgene Corp., PR Newswire, Investigators
`Report Revimid(™) demonstrates Anti-Tumor Activity in
`Phase I/II Clinical Trials in Multiple Myeloma; Celgene
`Corporation Will Significantly Expand Clinical Development
`of REVIMID, (Dec. 11, 2001)
`Celgene Drug Promises Activity
`thepharmaletter, Aug. 6, 2001
`Jim Ritter, Thalidomide Substitute Could be Disease Fighter,
`CHICAGO SUN TIMES, Aug. 14, 2001
`Vilasini Shetty et al., Measurement of Apoptosis,
`Proliferation and Three Cytokines in 46 Patients with
`Myelodysplastic Syndromes, 20(11/12) LEUKEMIA RES. 891
`(1996)
`Laura G. Corral & Gilla Kaplan, Immunomodulation by
`Thalidomide and Thalidomide Analogues, 58 ANNALS OF
`RHEUMATIC DISEASES I107 (1999)
`J. Blake Marriott et al., Immunotherapeutic and Antitumour
`Potential of Thalidomide Analogues, 1(4) EXPERT OPIN. BIOL.
`THER. 675 (2001)
`A. Raza et al., Apoptosis in Bone Marrow Biopsy Samples
`Involving Stromal and Hematopoietic Cells in 50 Patients
`with Myelodysplastic Syndromes, 86(1) BLOOD 268 (1995)
`A. Raza et al., A Paradigm Shift in Myelodysplastic
`Syndromes, 10 LEUKEMIA 1648 (1996)
`Azra Raza et al., Patients with Myelodysplastic Syndromes
`Benefit
`from Palliative Therapy with Amifostine,
`Pentoxifylline, and Ciprofloxacin with or Without
`Dexamethasone, 95(5) BLOOD 1580 (2000)
`
`v
`
`
`
`

`

`Exhibit
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
`Description
`A. Raza et al., Improvement in Cytopenias of Patients with
`Myelodysplastic Syndromes
`(MDS)
`in Response
`to
`28(7)
`ABSTRACTS/EXPERIMENTAL
`Thalidomide,
`HEMATOLOGY 103 (2000)
`A. Raza et al., Encouraging Improvement in Cytopenias of
`Patients with Myelodysplastic Syndromes with Thalidomide,
`19
`AM.
`SOC.
`CLINICAL
`ONCOLOGY
`OF
`PROGRAM/PROCEEDINGS 30a (2000)
`Azra Raza et al., Thalidomide Produces Transfusion
`Independence in Long-Standing Refractory Anemias of
`Patients with Myelodysplastic Syndromes, 98(4) BLOOD 958
`(2001)
`U.S. Patent No. 5,635,517 titled Method of Reducing TNFα
`Levels With Amino Substituted 2-(2,6-Dioxopiperidin-3-yl)-
`1-Oxo-and 1,3-Dioxoisonindolines
`George W. Muller et al., Amino-Substituted Thalidomide
`Inhibitors of TNF-α Production, 9
`Analogs: Potent
`BIOORGANIC & MED. CHEM. LETTERS 1625 (1999)
`Agostino Cortelezzi et al., Efficacy of N-Acetylcysteine and
`All-Trans Retinoic Acid in Restoring in vitro Effective
`Hemopoiesis in Myelodysplastic Syndromes, 24 LEUKEMIA
`RES. 129 (1999)
`Suneel D. Mundle et al., Evidence for Involvement of Tumor
`Necrosis Factor-α in Apoptotic Death of Bone Marrow Cells
`in Myelodysplastic Syndromes, 60 AM. J. HEMATOLOGY 36
`(1999)
`Rajat Goyal et al., Biologic Characteristics of Patients with
`Hypocellular Myelodysplastic Syndromes, 23 LEUKEMIA RES.
`357 (1999)
`Bruce D. Cheson et al., Novel Therapeutic Agents for the
`Treatment of Myelodysplastic Syndromes, 27(5) SEMINARS IN
`ONCOLOGY 560 (2000)
`Robert J. D’Amato et al., Thalidomide is an Inhibitor of
`Angiogenesis, 91 PROC. NAT’L ACAD. SCI. USA 4082 (1994)
`
`vi
`
`
`
`

`

`Exhibit
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`1038
`
`1039
`
`1040
`
`1041
`
`Description
`Seema Singhal, M.D. et al., Antitumor Activity of Thalidomide
`in Refractory Multiple Myeloma, 341(21) NEW ENG. J. MED.
`1565 (1999)
`Seema Singhal, M.D. & Jayesh Mehta, Thalidomide in
`Cancer, 15(3) BIODRUGS 163 (2001)
`Eva Hellström-Lindberg et al., Treatment of Anemia in
`Myelodysplastic Syndromes with Granulocyte Colony-
`Stimulating Factor Plus Erythropoietin: Results From a
`Randomized Phase II Study and Long-Term Follow-up of 71
`Patients, 92(1) BLOOD 68 (1998)
`al., Achievements
`Eva Hellström-Lindberg
`et
`in
`Understanding and Treatment of Myelodysplastic Syndromes,
`HEMATOLOGY, 2000 AM. SOC. HEMATOLOGY (ASH) EDUC.
`PROGRAM BOOK (2000)
`Peter Greenberg et al., International Scoring System for
`Evaluating Prognosis in Myelodysplastic Syndromes, 89(6)
`BLOOD 2079 (1997)
`Peter Greenberg et al., Myelodysplastic Syndromes,
`HEMATOLOGY, 2002 AM. SOC. HEMATOLOGY (ASH) EDUC.
`PROGRAM BOOK 136 (2002)
`Mitchell S. Cairo, M.D., Does Reductions and Delays:
`Limitations of Myelosuppressive Chemotherapy, 14(8)
`ONCOLOGY 21 (2000)
`M.C. Montero et al., Economic Study of Neutropenia Induced
`by Myelotoxic Chemotherapy, 16(4) PHARM. WORLD SCI. 187
`(1994)
`CANCER PRINCIPLES & PRACTICE OF ONCOLOGY (Vincent T.
`DeVita, Jr. et al. eds., 5th ed. 1997)
`U.S. Patent No. 6,140,346 titled Treatment of Cancer with
`Thalidomide Alone or in Combination with Other Anti-
`Cancer Agents
`M.K. Oehler & R. Bicknell, The Promise of Anti-Angiogenic
`Cancer Therapy, 82(4) BRIT. J. CANCER 749 (2000)
`
`vii
`
`
`
`

`

`Exhibit
`1042
`
`1043
`
`1044
`
`1045
`
`1046
`
`1047
`
`1048
`
`1049
`
`1050
`
`1051
`
`Description
`P.G. Richardson et al., A Phase 1 Study of Oral CC5013 on
`Immunomodulatory Thalidomide
`(Thal) Derivative,
`in
`Patients with Relapsed and Refractory Multiple Myeloma
`(MM), 98(11) BLOOD 775a, Abstract# 3225 (2001)
`Paul G. Richardson et al., Thalidomide: Emerging Rose in
`Cancer Medicine, 53 ANN. REV. MED. 629 (2002)
`Paul G. Richardson et al., Immunomodulatory Drug CC-5013
`Overcomes Drug Resistance and is Well Tolerated in Patients
`with Relapsed Multiple Myeloma, 100(9) BLOOD 3063 (2002)
`Deborah A. Thomas, Pilot Studies of Thalidomide in Acute
`Myelogenous Leukemia, Myelodysplastic Syndromes, and
`37(1)
`SEMINARS
`Myeloproliferative Disorders,
`IN
`HEMATOLOGY 26 (2000)
`F. Bertolini et al., Thalidomide in Multiple Myeloma,
`Myelodysplastic Syndromes and Histiocytosis. Analysis of
`Clinical Results and of Surrogate Angiogenesis Markers, 12
`ANNALS OF ONCOLOGY 987 (2001)
`S.V. Rajkumar et al., Thalidomide Plus Dexamethasone
`(Thal/Dex) and Thalidomide Alone (Thal) as First Line
`Therapy for Newly Diagnosed Myeloma (MM), 96(11) BLOOD
`168a, Abstract# 722 (2000)
`S. Vincent Rajkumar, MD, et al., Thalidomide in the
`Treatment of Relapsed Multiple Myeloma, 75 MAYO CLINIC
`PROC. 897 (2000)
`S. Vincent Rajkumar & Robert A. Kyle, Thalidomide in the
`Treatment of Plasma Cell Malignancies, 19(16) J. CLINICAL
`ONCOLOGY 3593 (2001)
`S. Vincent Rajkumar et al., Combination Therapy with
`Thalidomide Plus Dexamethasone for Newly Diagnosed
`Myeloma, 20(21) J. CLINICAL ONCOLOGY 4319 (2002)
`Bart Barlogie et al., Thalidomide in the Management of
`Multiple Myeloma, 38(3) SEMIN. HEMATOL. 250 (2001)
`
`viii
`
`
`
`

`

`Exhibit
`1052
`
`1053
`
`1054
`
`1055
`
`1056
`
`1057
`
`1058
`
`1059
`
`1060
`
`1061
`
`1062
`
`Description
`Interview with Bart Barlogie, M.D., Arkansas Cancer Res.
`Ctr., in Banff, Alberta, Canada, Highlights from the VIIIth
`Inter’l Myeloma Workshop (May 4–8, 2001)
`Antonio Palumbo et al., Low-Dose Thalidomide Plus
`Dexamethasone is an Effective Salvage Therapy for Advanced
`Myeloma, 86(4) HAEMATOLOGICA 399 (2001)
`M.A. Dimopoulos et al., Thalidomide and Dexamethasone
`Combination
`for Multiple Myeloma Refractory
`to
`Dexamethasone-Based Regimens, 96(11) Blood 286b,
`Abstract#4978 (2000)
`A. Glasmacher et al., Oral Idarubicin, Dexamethasone and
`Vincristine (VID) in the Treatment of Multiple Myeloma, 11
`LEUKEMIA S22 (1997)
`M.A. Dimopoulos et al., Thalidomide and Dexamethasone
`Combination for Refractory Multiple Myeloma, 12 ANNALS
`ONCOLOGY 991 (2001)
`Robert H. Carlson, Thalidomide-Combo Trials Vary Widely,
`23(4) ONCOLOGY TIMES 26 (2001)
`Teru Hideshima et al., Thalidomide (Thal) and its Analogs
`Overcome Drug Resistance of Human Multiple Myeloma
`(MM) Cells to Conventional Therapy, 96(11) BLOOD 304a,
`Abstract# 1313 (2000)
`Teru Hideshima et al., Thalidomide and its Analogs
`Overcome Drug Resistance of Human Multiple Myeloma
`Cells to Conventional Therapy, 96(9) BLOOD 2943 (2000)
`Gunnar Juliusson et al., Frequent Good Partial Remissions
`from Thalidomide Including Best Response Ever in Patients
`with Advanced Refractory and Relapsed Myeloma, 109 BRIT.
`J. HAEMATOLOGY 89 (2000)
`Everardus J. Ariëns, Stereochemistry: A Source of Problems
`in Medicinal Chemistry, 6(4) MED. RES. REVS. 451 (1986)
`Wilson H. DeCamp, The FDA Perspective on
`the
`Development of Stereoisomers, 1 CHIRALITY 2 (1989)
`
`ix
`
`
`
`

`

`Exhibit
`1063
`
`1064
`
`1065
`
`1066
`
`1067
`
`1068
`
`1069
`
`1070
`
`1071
`
`1072
`1073
`1074
`1075
`
`
`
`TO
`
`Description
`Jean Jacques et al., ENANTIOMERS, RACEMATES, AND
`RESOLUTIONS (1981)
`INTRODUCTION
`Ph.D.,
`Howard
`C. Ansel,
`PHARMACEUTICAL DOSAGE FORMS (3d ed. 1981)
`Robert Thornton Morrison, Robert Neilson Boyd, ORGANIC
`CHEMISTRY (4th ed. 1982)
`Roger Crossley, CHIRALITY AND THE BIOLOGICAL ACTIVITY
`OF DRUGS (1995)
`B. Yu. Shekunov, P. York, Crystallization Processes in
`Pharmaceutical Technology and Drug Delivery Design, 211
`J. CRYSTAL GROWTH 122 (2000)
`Tommy Eriksson et al., Clinical Pharmacology of
`Thalidomide, 57 EUR. J. CLINICAL PHARM. 365 (2001)
`Interview of Kenneth Anderson, M.D., Dana-Farber Cancer
`Inst., Banff, Alberta, Canada, Highlights from the VIIIth
`Inter’l Myeloma Workshop (May 4–8, 2001)
`RevlimidREMS®, Welcome to the REVLIMID REMS®
`program.pdf, http://www.revlimidrems.com
`Statement from FDA Commissioner Scott Gottlieb, M.D., on
`new policies to reduce the ability of brand drug makers to use
`REMS programs as a way to block timely generic drug entry,
`helping promote competition and access, FDA.GOV (May 31,
`2018)
`U.S. Patent Pub. No. 2003/0235898
`U.S. Patent App. Pub. No. 2004/0067953
`U.S. Patent App. Pub. No. 002/0035090
`Maurizio Zangari et al., Results of Phase I Study of CC-5013
`for the Treatment of Multiple Myeloma (MM) Patients Who
`Relapse after High Dose Chemotherapy (HDCT), 98(11)
`BLOOD 775a, Abstract# 3226 (2001)
`
`
`x
`
`
`
`

`

`TABLE OF AUTHORITIES
`
`CASES
`Bayer Healthcare Pharms., Inc. v. Watson Pharms., Inc.,
`713 F.3d 1369 (Fed. Cir. 2013) .......................................................................... 54
`Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc.,
`752 F.3d 967 (Fed. Cir. 2014) ............................................................................ 22
`
`Celgene Corp. v. Dr. Reddy’s Laboratories, Ltd. and Dr. Reddy’s
`Laboratories, Inc.,
`Case No. 2:17-cv-05314-SDW-LDW (D.N.J.) .................................................. 54
`
`Celgene Corp. v. Lotus Pharm. Co., Ltd. and Alvogen Pine Brook,
`LLC,
`Case No. 2:17-cv-06842-SDW-LDW (D.N.J.) .................................................. 54
`
`Celgene Corp. v. Natco Pharma Ltd., Arrow Int’l Ltd., and Watson
`Labs., Inc.,
`Case No. 2:10-cv-05197-SDW-LDW (D.N.J.) .................................................. 55
`Cuozzo Speed Techs., LLC v. Lee,
`136 S. Ct. 2131 (2016) .......................................................................................... 3
`Ex parte Standish,
`No. 870178, 1988 WL 252397 (B.P.A.I. July 26, 1988) .................................... 50
`Galderma Labs. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ............................................................................ 53
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) ................................................................................................ 21
`In re Huai-Hung Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .......................................................................... 50
`J.T. Eaton & Co. v. Atl. Paste & Glue Co.,
`106 F.3d 1563 (Fed. Cir. 1997) .......................................................................... 52
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...................................................................................... 21, 22
`
`xi
`
`
`
`

`

`McNeil-PPC, Inc. v. L. Perrigo Co., S.A.,
`337 F.3d 1362 (Fed. Cir. 2003) .......................................................................... 52
`Merck & Co. v. Teva Pharms. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005) .......................................................................... 51
`Pentec, Inc. v. Graphic Controls Corp.,
`776 F.2d 309 (Fed. Cir. 1985) ............................................................................ 52
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) ...................................................................passim
`Stratoflex, Inc. v. Aeroquip Corp.,
`713 F.2d 1530 (Fed. Cir. 1983) .......................................................................... 50
`Therasense, Inc. v. Becton, Dickinson & Co.,
`593 F.3d 1289 (Fed. Cir. 2010) .................................................................... 51, 52
`STATUTES
`35 U.S.C. § 103(a) (2006) ........................................................................................ 21
`35 U.S.C. §§ 311–319 ................................................................................................ 1
`35 U.S.C. § 314(a) ..................................................................................................... 2
`REGULATIONS
`37 C.F.R. § 42 ............................................................................................................ 1
`37 C.F.R. § 42.6(c) ..................................................................................................... 2
`37 C.F.R. § 42.6(e) ..................................................................................................... 1
`37 C.F.R. § 42.8 ............................................................................................. 54, 55, 1
`37 C.F.R. § 42.10(b) .................................................................................................. 1
`37 C.F.R. § 42.15(a) ................................................................................................... 1
`37 C.F.R. § 42.24(a)(1) .............................................................................................. 1
`37 C.F.R. § 42.63(e) ................................................................................................... 1
`37 C.F.R. § 42.100(b) ................................................................................................ 3
`
`
`xii
`
`

`

`37 C.F.R. § 42.103 ..................................................................................................... 1
`37 C.F.R. § 42.104(a) ................................................................................................. 1
`37 C.F.R. § 42.105 ..................................................................................................... 1
`37 C.F.R. § 42.106(a) ................................................................................................. 1
`OTHER AUTHORITIES
`MPEP § 716 ............................................................................................................. 50
`MPEP § 716.03(b) .................................................................................................... 50
`
`
`
`
`
`
`
`
`xiii
`
`
`
`

`

`TABLE OF ABBREVIATIONS
`
`3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione .......................... lenalidomide
`
`immunomodulatory (or immunomodulatory imide) drug .................................. IMiD
`
`multiple myeloma ................................................................................................. MM
`
`myelodysplastic syndrome(s) .............................................................................. MDS
`
`refractory anemia ................................................................................................... RA
`
`refractory anemia with ringed sideroblasts ....................................................... RARS
`
`refractory anemia with excess blasts ................................................................. RAEB
`
`refractory anemia with excess blasts in transformation ................................. RAEB-t
`
`chromic myelomonocytic leukemia ................................................................ CMML
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`red blood cells .................................................................................................... RBCs
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`selective cytokine inhibitory drugs ................................................................ SelCiDs
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`transfusion dependent anemia ............................................................................. TDA
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`tumor necrosis factor alpha ............................................................. TNFα (or TNF-α)
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`U.S. Food and Drug Administration .................................................................... FDA
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`U.S. Patent No. 6,238,230 .................................................................... the ’230 patent
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`U.S. Patent No. 7,189,740 ................................................................... the ’740 patent
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`U.S. Patent No. 8,404,717 ................................................................... the ’717 patent
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`U.S. Patent No. 9,056,120 ................................................................... the ’120 patent
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`xiv
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`I.
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`INTRODUCTION
`Pursuant to 35 U.S.C. §§ 311–319 and 37 C.F.R. § 42, Dr. Reddy’s
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`Laboratories, Inc. (“Petitioner”) petitions for Inter Partes Review (“IPR”) of claims
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`1–8, 12–34, and 38–53 of U.S. Patent No. 9,056,120 (“the ’120 patent”) (Ex. 1001),
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`currently assigned to Celgene Corporation (“Patent Owner”), and seeks a
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`determination that these claims of the ’120 patent be cancelled as unpatentable.
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`This Petition is filed in accordance with 37 C.F.R. § 42.106(a). Concurrently
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`filed herewith is a Power of Attorney and exhibit list pursuant to 37 C.F.R. § 42.10(b)
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`and §42.63(e). Pursuant to 37 C.F.R. § 42.103, the fee set forth in § 42.15(a)
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`accompanies this Petition.
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`This Petition demonstrates that a preponderance of the evidence shows a
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`reasonable likelihood that claims 1–8, 12–34, and 38–53 of the ’120 patent are
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`unpatentable over the prior art. Specifically, the ’120 patent claims the use of about
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`1–25 mg/day of lenalidomide to treat myelodysplastic syndromes (MDS) and
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`transfusion dependent anemia due to low to intermediate-1-risk myelodysplastic
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`syndrome.
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`II. GROUNDS FOR STANDING
`As required by 37 C.F.R. § 42.104(a), Petitioner certifies that the ’120 patent
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`is available for inter partes review and that the Petitioner is not barred or estopped
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`from requesting inter partes review on the grounds identified herein.
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`1
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`III.
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`IDENTIFICATION OF CHALLENGE AND STATEMENT OF THE
`PRECISE RELIEF REQUESTED
`Petitioner requests inter partes review and cancellation of claims 1–8, 12–34,
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`38–53 of the ’120 patent on the grounds set forth below.
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`
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`Petitioner challenges 1–8, 12–34, and 38–53 of the ’120 patent as
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`unpatentable on the following grounds:
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`Ground 1: Claims 1–8, 12–34, and 38–53 were unpatentable as obvious over
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`List 2001 in view of the ’230 patent and Celgene Press Releases 5/8/2001 and
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`8/28/2001.
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`Ground 2: Claims 1–8, 12–34, and 38–53 were obvious over Thomas 2000a
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`in view of the ’230 patent and Celgene Press Releases 5/8/2001 and 8/28/2001.
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`The ’120 patent is to be reviewed under pre-AIA § 103. Petitioner’s detailed
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`statement of the reasons for the relief requested is set forth below. In support of
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`these grounds of unpatentability, Petitioner submits the expert declaration of Dr.
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`Levin (Ex. 1003) and also relies on Exhibits set forth in the concurrently filed Listing
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`of Exhibits, filed in accordance with 37 C.F.R. § 42.6(c).
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`IV. THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW
`A petition for inter partes review must demonstrate “a reasonable likelihood
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`that the petitioner would prevail with respect to at least 1 of the claims challenged
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`in the petition.” 35 U.S.C. § 314(a). This Petition meets this threshold.
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`2
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`V.
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`STATEMENT OF REASONS FOR THE RELIEF REQUESTED
`A.
`Summary of the Argument
`Prior to the priority date, a skilled artisan was aware of at least the following:
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`lenalidomide and its position as the “next generation,” more potent analog of
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`thalidomide; lenalidomide’s and thalidomide’s successful clinical administrations in
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`myelodysplastic syndromes (MDS), including MDS with resulting transfusion-
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`dependent anemia (TDA), as well as success in other cancerous conditions such as
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`multiple myeloma (MM) and solid tumors; and lenalidomide’s repeated, successful
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`clinical administrations at 5–50 and “up to 25” mg/day. Lenalidomide was known
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`in the prior art, as was its clinical use. Both lenalidomide and its structural analog
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`and precursor, thalidomide, acted on similar therapeutic targets (most notably, a cell
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`signaling protein called tumor necrosis factor alpha, or TNFα), targets that are shared
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`among multiple cancerous conditions (including MDS and multiple myeloma
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`(MM)). However, lenalidomide’s anti-TNFα potency over thalidomide—indeed, its
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`position to be the “next generation” for thalidomide—was well-established in the
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`art. A skilled artisan was aware that lenalidomide’s successes had motivated
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`searches for additional therapeutic applications, and would have been motivated to
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`administer lenalidomide for MDS/TDA.
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`Similarly, it would have been obvious to “upgrade” to lenalidomide for
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`conditions in which thalidomide had already shown promise, such as MDS/TDA,
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`3
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`MM, and solid tumors. Thalidomide suffered from recognized drawbacks, including
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`its toxicity profile and known teratogenicity. Lenalidomide, with increased potency,
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`decreased toxicity/side effects, and action on the same therapeutic target, helped
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`remedy thalidomide’s known drawbacks.
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`Clinical trials of lenalidomide in MM showed that doses of 5–50 and “up to
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`25” mg/day were safe, well-tolerated, and showed efficacy (including by reduction
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`in a validated clinical marker). A study of lenalidomide in solid tumors likewise
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`showed the safety and toleration of 5–50 mg/day, and sufficient promise for a
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`clinical trial to be expanded. And additional clinical trials for MM—and for MDS—
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`were underway.
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`Whether a skilled artisan was searching for new anti-TNFα applications of the
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`promising drug lenalidomide, or was searching for improved treatments over
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`thalidomide and the other limited therapies known for MDS/TDA patients,
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`lenalidomide was an obvious choice for administering to a patient in need of
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`treatment for MDS/TDA.
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`By 2001, the skilled artisan would have understood lenalidomide to be the
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`improved, “next generation” of thalidomide, that first thalidomide and then
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`lenalidomide had already been used to clinically treat MDS/TDA, and that about 5–
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`50 mg/day of lenalidomide was a repeatedly recognized safe, well-tolerated, and
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`even efficacious dosage to use as a starting point for treating other cancerous
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`4
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`conditions. The skilled artisan would apply this rationale to treat MDS patients,
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`including patients with TDA due to low to intermediate-1-risk MDS, using
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`lenalidomide as recited in the claims of the ’120 patent, and with routine adjustment
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`to determine the proper patient-specific dosing, would have had a reasonable
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`expectation that doses of about 1–25 mg/day would be efficacious. Simply put, there
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`were no scientific hurdles to clear.
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`The dependent claims are likewise obvious. Lenalidomide could have been
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`formulated in various forms, including a salt, solvate, stereoisomer, or “other” form
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`such as amorphous or free base, and all these were within the knowledge and
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`expectation of a POSA. A POSA would have expected success in treating
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`MDS/TDA patients of all five MDS classifications, as well as success in treating
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`both untreated and previously treated MDS patients. Given the therapies then-
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`available, a POSA would also have also administered lenalidomide to patients at
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`some point before or after certain blood or stem cell transplantations. And a POSA,
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`aware of cycled cancer therapies generally and, more specifically, known MDS and
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`thalidomide cycled therapies, would have administered lenalidomide in a similarly
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`cycled therapy of, for example, 28 days, and from there would have further
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`optimized the dosing intervals and amount to suit the patient’s needs.
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`Given this knowledge, and as further explained below, claims 1–8, 12–34, and
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`38–53 of the ’120 patent were obvious.
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`5
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`B.
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`The ’120 Patent and Its Prosecution
`1.
`The ’120 Patent
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`The ’120 patent was filed on March 13, 2013, and claimed priority to
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`provisional application No. 60/418,468 filed October 15, 2002. The § 102(b) date
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`for the ’120 patent, therefore, is October 15, 2001. The ’120 patent names Jerome
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`B. Zeldis as inventor and Celgene Corporation as assignee.
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`The ’120 patent issued with 53 claims on June 16, 2012. Claims 1 and 28, the
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`independent claims, relate to methods of treating MDS (claim 1) and transfusion-
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`dependent anemia due to low to intermediate-1-risk MDS (claim 28) by
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`administering about 1 to 25 mg per day of lenalidomide (3-(4-amino-l-oxo-1,3-
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`dihydro-isoindol-2-yl)-piperidine-2,6-dione) or
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`) or a
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`“pharmaceutically acceptable salt, solvate or stereoisomer thereof.”
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`The dependent claims are largely analogous, and summarized below:
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`6
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`Limitation
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`to treat specific MDS
`subtypes
`not a