`Filed on behalf of: Celgene Corporation
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`Filed: June 28, 2018
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________________
`
`APOTEX INC. AND APOTEX CORP.,
`Petitioners,
`
`v.
`
`CELGENE CORPORATION,
`Patent Owner
`_______________________
`
`Case IPR2018-00685
`U.S. Patent No. 8,741,929
`_______________________
`
`
`PATENT OWNER PRELIMINARY RESPONSE
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`IPR2018-00685
`U.S. Patent 8,741,929
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`TABLE OF CONTENTS
`
`TABLE OF CONTENTS ........................................................................................ i
`
`TABLE OF AUTHORITIES ............................................................................... iii
`
`TABLE OF ABBREVIATIONS ......................................................................... vii
`
`LIST OF EXHIBITS ........................................................................................... viii
`
`I.
`
`II.
`
`INTRODUCTION ........................................................................................ 1
`
`BACKGROUND ........................................................................................... 4
`
`A. MCL Is a Unique and Difficult-to-Treat Cancer.................................. 4
`
`B.
`
`The ’929 Patent .................................................................................... 6
`
`III. SCOPE AND CONTENT OF ALLEGED PRIOR ART .......................... 6
`
`A. Drach .................................................................................................... 6
`
`B.
`
`C.
`
`D.
`
`Zeldis .................................................................................................. 10
`
`Querfeld .............................................................................................. 10
`
`The Press Release ............................................................................... 11
`
`IV. GROUNDS 1 AND 2 SHOULD BE DENIED UNDER 35 U.S.C.
`§ 325(d) BECAUSE THE PTO ALREADY CONSIDERED AND
`REJECTED THE SAME ARGUMENTS ................................................ 11
`
`A. Grounds 1 and 2 Should Be Denied Because the Petitioners’
`Arguments Have Already Been Rejected by the PTO ....................... 12
`
`B.
`
`The Becton Factors Strongly Favor Denying Institution ................... 18
`
`V. GROUNDS 1 AND 2 SHOULD BE DENIED BECAUSE
`PETITIONERS FAIL TO DEMONSTRATE A REASONABLE
`LIKELIHOOD THAT ANY CHALLENGED CLAIMS WOULD
`HAVE BEEN OBVIOUS ........................................................................... 21
`
`A.
`
`B.
`
`Level of Ordinary Skill in the Art and Claim Construction ............... 21
`
`The Challenged Claims Would Not Have Been Obvious Over
`Drach in View of Zeldis (Ground 1) .................................................. 22
`
`1.
`
`A POSA would not have reasonably expected that
`lenalidomide could effectively treat MCL based on what
`was known about thalidomide allegedly treating MCL ........... 23
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`IPR2018-00685
`U.S. Patent 8,741,929
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`2.
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`3.
`
`A POSA would not have reasonably expected that
`lenalidomide could effectively treat relapsed and/or
`refractory MCL based on what was known about
`lenalidomide’s alleged potency in other areas ......................... 31
`
`In the absence of hindsight, a POSA would not have
`arrived at the claimed dosing regimen ..................................... 40
`
`C.
`
`The Challenged Claims Would Not Have Been Obvious Over
`Drach in view of Zeldis and Querfeld (Ground 2) ............................. 41
`
`VI. SECONDARY CONSIDERATIONS SUPPORT THE
`NONOBVIOUSNESS OF THE CHALLENGED CLAIMS .................. 43
`
`A.
`
`B.
`
`C.
`
`Revlimid® Met a Long-Felt and Unmet Need for Treating MCL...... 43
`
`Unexpected Results Further Evidence Nonobviousness .................... 45
`
`Failure of Others to Develop an Improved Treatment for MCL
`Further Evidences Nonobviousness ................................................... 47
`
`VII. GROUND 3 SHOULD BE DENIED BECAUSE PETITIONERS
`FAIL TO DEMONSTRATE A REASONABLE LIKELIHOOD
`THAT ANY CHALLENGED CLAIMS WOULD HAVE BEEN
`ANTICIPATED .......................................................................................... 48
`
`A.
`
`B.
`
`Petitioners Have Failed to Establish that the Press Release Is a
`Printed Publication Under 35 U.S.C. § 311(b)................................... 49
`
`Even if the Press Release Were Prior Art Under § 311(b), It Is
`Not Prior Art Under 35 U.S.C. § 102(a) ............................................ 52
`
`1.
`
`2.
`
`The Press Release is the inventor’s own work ........................ 52
`
`The claimed invention was conceived before the date on
`the Press Release and then diligently reduced to practice ....... 54
`
`B.
`
`Even if the Press Release Were Prior Art, Petitioners Have
`Failed to Establish that it Anticipates the Challenged Claims ........... 55
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`VIII. CONCLUSION ........................................................................................... 58
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`Cases
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`IPR2018-00685
`U.S. Patent 8,741,929
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`TABLE OF AUTHORITIES
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`Page
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`Abbott Labs. v. Sandoz, Inc.,
`544 F.3d 1341 (Fed. Cir. 2008) .....................................................................33
`
`Apple Inc. v. Cal. Institute of Tech.,
`IPR2017-00702 (P.T.A.B. Sept. 12, 2017)....................................................49
`
`Avanir Pharm. v. Actavis S. Atl.,
`36 F. Supp. 3d 475 (D. Del. 2014),
`aff’d sub nom. Avanir Pharm. v. Par Pharm.,
`612 F. App’x 613 (Fed. Cir. 2015) ................................................................24
`
`Becton, Dickinson and Co. v. B. Braun Melsungen AG,
`No. IPR2017-01586 (P.T.A.B. Dec. 15, 2017) ................................ 18, 19, 20
`
`Boston Sci. v. Johnson & Johnson,
`647 F.3d 1353 (Fed. Cir. 2011) .....................................................................28
`
`Bristol-Myers Squibb v. Teva Pharms. USA,
`752 F.3d 967 (Fed. Cir. 2014) .......................................................................46
`
`Coal. for Affordable Drugs IV v. Pharmacyclics, Inc.,
`IPR2015-01076 (P.T.A.B. Oct. 19. 2015) .............................................. 50, 51
`
`Coal. for Affordable Drugs v. Acorda Therapeutics,
`IPR2015-01850 (P.T.A.B. Mar. 9, 2017) ......................................................53
`
`Coal. for Affordable Drugs VI v. Celgene Corp.,
`No. IPR2015-01169 (P.T.A.B. Nov. 16, 2015) .............................................29
`
`Eli Lilly & Co. v. Teva Pharm. USA,
`657 F. Supp. 2d 967 (S.D. Ind.),
`aff’d, 619 F.3d 1329 (Fed. Cir. 2010) ............................................................53
`
`Ford Motor Co. v. Versata Dev. Grp.,
`IPR2016-01019 (P.T.A.B. Oct. 4, 2016) .......................................................50
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`U.S. Patent 8,741,929
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`
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`Glastetter v. Novartis Pharm.,
`252 F.3d 986 (8th Cir. 2001) .........................................................................28
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`
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`Hengdian Grp. DMEGC Magnetics v. Hitachi Metals, Ltd.,
`IPR2017-01313 (P.T.A.B. Nov. 6, 2017) ......................................................17
`
`In re Cronyn,
`890 F.2d 1158 (Fed. Cir. 1989) .....................................................................49
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) .............................................................. 44, 47
`
`In re Gangadharam,
`889 F.2d 1101 (Fed. Cir. 1989) .....................................................................33
`
`In re Katz,
`687 F.2d 450 (C.C.P.A. 1982) ................................................................ 52, 53
`
`In re Klopfenstein,
`380 F.3d 1345 (Fed. Cir. 2004) .....................................................................49
`
`In re Lister,
`583 F.3d 1307 (Fed. Cir. 2009) .....................................................................50
`
`In re Soni,
`54 F.3d 746 (Fed. Cir. 1995) .........................................................................45
`
`Invitrogen Corp. v. Biocrest, Mfg.,
`424 F.3d 1374 (Fed. Cir. 2005) .....................................................................52
`
`Leo Pharm. v. Rea, 726 F.3d 1346
`(Fed. Cir. 2013) ..............................................................................................45
`
`LG Elecs. v. Advanced Micro Devices,
`IPR2015-00329 (P.T.A.B. July 10, 2015) .....................................................50
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`Microsoft Corp. v. Corel Software,
`IPR2016-01300 (P.T.A.B. Jan. 4, 2017) .......................................................51
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`Neil Ziegman, N.P.Z. v. Stephens,
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`U.S. Patent 8,741,929
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`IPR2015-01860 (P.T.A.B. Sept. 6, 2017) ......................................................12
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`Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co.,
`851 F.3d 1270 (Fed. Cir. 2017) .....................................................................58
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`Novartis Pharm. v. West-Ward Pharm.,
`287 F. Supp. 3d 505 (D. Del. 2017) ..............................................................23
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`Par Pharm. v. Novartis AG,
`No. IPR2016-00084 (P.T.A.B. Jan. 11, 2018) ..............................................29
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`Pfizer Inc. v. Teva Pharm. U.S.A.,
`882 F. Supp. 2d 643 (D. Del. 2012) ..............................................................28
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`Pfizer Inc. v. Watson Pharm., Inc.,
`920 F. Supp. 2d 552 (D. Del. 2013) ..............................................................28
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`Pictometry Int’l Corp. v. Geospan Corp.,
`No. 2011-010700, 2011 WL 4857918 (B.P.A.I. Oct. 7, 2011) .....................52
`
`Proctor & Gamble Co. v. Teva Pharm. USA,
`566 F.3d 989 (Fed. Cir. 2009) .......................................................................21
`
`R.J. Reynolds Vapor Co. v. Fontem Holdings 1 B.V.,
`IPR2017-01642 (P.T.A.B. Jan. 16, 2018) .....................................................17
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`Sanofi v. Watson Labs,
`875 F.3d 636 (Fed. Cir. 2017) ................................................................ 23, 25
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`Siemens Healthcare Diagnostics Inc. v. Radiometer Medical ApS,
`IPR2018-00311 (P.T.A.B. June 25, 2018) ....................................................17
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`Supernus Pharm. v. Actavis Inc.,
`2016 WL 5278387 (D.N.J. Feb. 5, 2016),
`aff’d, 665 F. App’x 901 (Fed. Cir. 2016) ......................................................45
`
`TRW Automotive US LLC v. Magna Elecs.,
`IPR2014-00258 (P.T.A.B. Aug. 27, 2014) ............................................. 16, 32
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`Unified Patents Inc. v. John L. Berman,
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`IPR2018-00685
`U.S. Patent 8,741,929
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`IPR2016–01571 (P.T.A.B. Dec. 14, 2016) ............................................. 12, 15
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`Varian Med. Sys. v. William Beaumont Hosp.,
`IPR2016-00170 (P.T.A.B. May 4, 2017) ......................................................45
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`Statutes
`
`35 U.S.C. § 102(a) ........................................................................................... passim
`
`35 U.S.C. § 311(b) ...................................................................................... 49, 51, 52
`
`35 U.S.C. § 325(d) ........................................................................................... passim
`
`Regulations
`
`37 C.F.R. § 42.107(a) ................................................................................................. 1
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`37 C.F.R. § 42.65(a) .......................................................................................... 16, 32
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`U.S. Patent 8,741,929
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`TABLE OF ABBREVIATIONS
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`POSA
`
`person of ordinary skill in the art
`
`PTO
`
`NHL
`
`MCL
`
`MM
`
`United States Patent and Trademark Office
`
`non-Hodgkin’s lymphoma
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`mantle cell lymphoma
`
`multiple myeloma
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`CTCL
`
`cutaneous T-cell lymphoma
`
`TNF-α
`
`tumor necrosis factor alpha
`
`CLL
`
`chronic lymphocytic leukemia
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`IPR2018-00685
`U.S. Patent 8,741,929
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`LIST OF EXHIBITS
`
`2004
`
`Description
`EX
`2001 The Merck Manual (17th ed. 1999)
`2002 The Non-Hodgkin’s Lymphoma Classification Project, “A Clinical
`Evaluation of the International Lymphoma Study Group Classification of
`Non-Hodgkin’s Lymphoma,” Blood, 89(11):3909–3918 (1997)
`2003 G. Lenz et al., “Mantle cell lymphoma: established therapeutic options and
`future directions,” Ann. Hematol., 83:71–77 (2004)
`J.M. Foran et al., “Treatment of mantle-cell lymphoma with Rituximab,”
`Annals Oncol., 11(Suppl. 1):S117–121 (2000)
`2005 R.I. Fisher et al., “Mantle Cell Lymphoma: At Last, Some Hope for
`Successful Innovative Treatment Strategies,” J. Clin. Oncol., 23(4): 657–
`58 (2005)
`2006 A. Goy et al., “Single-Agent Lenalidomide in Patients with Mantle-Cell
`Lymphoma Who Relapsed or Progressed After or Were Refractory to
`Bortezomib: Phase II MCL-001 (EMERGE) Study,” J. Clin. Oncol.,
`31(29):3688–95 (2013)
`2007 Excerpts from 929 Patent File History
`2008 E.A. Wilson et al., “Response to thalidomide in chemotherapy-resistant
`mantle cell lymphoma: a case report,” Br. J. Haematol., 119:128–30
`(2002)
`2009 G. Damaj et al., “Thalidomide therapy induces response in relapsed mantle
`cell lymphoma,” Leukemia, 17:1914–15 (2003)
`2010 H. Kaufmann et al., “Antitumor activity of rituximab plus thalidomide in
`patients with relapsed / refractory mantle cell lymphoma,” Blood,
`104:2269–71 (2004)
`2011 H.S. Zackheim, “Prognosis in cutaneous T-cell lymphoma by skin stage:
`Long-term survival in 489 patients,” J. Am. Acad. Dermat., 40(3):418–25
`(1999)
`2012 B. Pro et al., “Thalidomide for Patients with Recurrent Lymphoma,”
`Cancer, 100(6):1186–89 (2004)
`Intentionally Left Blank
`Intentionally Left Blank
`
`2013
`2014
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`U.S. Patent 8,741,929
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`2015 L.A. Nguyen et al., “Chiral Drugs: An Overview,” Int’l. J. Biomed. Sci.,
`2(2):85–100 (2006)
`2016 D.C. Manning et al., “Lenalidomide for Complex Regional Pain Syndrome
`Type 1: Lack of Efficacy in a Phase II Randomized Study,” J. Pain,
`15(12):1366–76 (2014)
`2017 S.P. Treon et al., “Lenalidomide and Rituximab in Waldenstrom’s
`Macroglobulinemia,” Clin. Cancer Res., 15(1):355–360 (2009)
`2018 S.B. Desai & D.E. Furst, “Problems encountered during anti-tumour
`necrosis factor therapy,” Best Practice & Res. Clin. Rheumat., 20(4):757–
`90 (2006)
`2019 S.L Brown et al., “Tumor necrosis factor antagonist therapy and
`lymphoma development: twenty-six cases reported to the Food and Drug
`Administration,” Arthritis Rheum., (46):3151–58 (2002)
`2020 N. Scheinfeld, “A comprehensive review and evaluation of the side effects
`of the tumor necrosis factor alpha blockers etanercept, infliximab and
`adalimumab,” Journal of Dermatological Treatment, 15(5):280–294
`(2004)
`2021 P.D. Ziakas et al., “Lymphoma development in a patient receiving anti-
`TNF therapy,” Haematologica, 88(7):108–109 (2003)
`2022 M. Schuler et al., “Cytokines in the pathophysiology and treatment of
`chronic B-cell malignancies,” Ann. Hematol., 71:57–63 (1995)
`J.M. Jacobson et al., “Thalidomide for the Treatment of Oral Aphthous
`Ulcers,” New England J. Med., 336(21):1487–93 (1997)
`2024 P. Wolkenstein et al., “Randomised comparison of thalidomide versus
`placebo in toxic epidermal necrolysis,” Lancet, 352:1–4 (1998)
`2025 A. Tsimeridou, “Pilot study of recombinant human soluble tumor necrosis
`factor (TNF) receptor (p75) fusion protein (TNFR:Fc; Enbrel) in patients
`with refractory multiple myeloma: increase in plasma TNFα levels during
`treatment,” Leukemia Res., 27:375–80 (2003)
`2026 R. Kuppers, “Mechanisms of B-cell Lymphoma Pathogenesis,” Nat. Rev.
`Cancer., 5:251–262 (2005)
`2027 K. Miller et al., “Clinical Characteristics and Management Strategy of
`Revlimid Induced Tumor Flare Reaction in Patients with CLL,” Oncol.
`Nursing Forum, 33(2):394–491 (Abstract 46) (2006)
`
`2023
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`U.S. Patent 8,741,929
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`2028 R. Van Horssen et al., “TNF-α in cancer treatment: molecular insights,
`antitumor effects, and clinical utility,” The Oncologist, 11(4):397–408
`(2006)
`2029 G.M. Anderson et al., “Tumor necrosis factor-α in the pathogenesis and
`treatment of cancer,” Current opinion in pharmacology, 4(4):314–320
`(2004)
`2030 A.M. Eggermont et al., “Current uses of isolated limb perfusion in the
`clinic and a model system for new strategies,” Lancet Oncol., 4:429–437
`(2003)
`2031 V. Ruggiero et al., “Cytostatic and cytotoxic activity of tumor necrosis
`factor on human cancer cells,” J Immunol., 138:2711–2717 (1987)
`2032 N. Watanabe et al., “Toxic effect of tumor necrosis factor on tumor
`vasculature in mice,” Cancer Res., 48:2179–2183 (1998)
`2033 Revlimid® Label
`2034 P.L. Bergsagel, et al., “Molecular Pathogenesis and a Consequent
`Classification of Multiple Myeloma,” J. of Clinical Oncology,
`23(26):6333-38 (2005)
`2035 A.L. Schaffer et al., “Lymphoid Malignancies: The Dark Side of B-Cell
`Differentiation,” Nature Reviews, 2:1-13 (2002)
`2036 R. Bataille, “Biologic Effects of Anti-Interleukin-6 Murine Monoclonal
`Antibody in Advanced Multiple Myeloma,” Blood, 86(2):685–91 (1995)
`2037 H.C.T. Van Zaanen, “Chimaeric anti-interleukin 6 monoclonal antibodies
`in the treatment of advanced multiple myeloma: a phase I dose-escalating
`study,” Brit. J. Haemat., 102:783–90 (1998)
`2038 O.A. O’Connor et al., “Phase II Clinical Experience With the Novel
`Proteasome Inhibitor Bortezomib in Patients With Indolent Non-
`Hodgkin’s Lymphoma and Mantle Cell Lymphoma,” J. Clin. Oncol.,
`23(4):676–684 (2005)
`2039 B. Maes et al., “Among diffuse large B-cell lymphomas, T-cell-rich /
`histiocyte-rich BCL and CD30+ anaplastic B-cell subtypes exhibit distinct
`clinical features,” Ann. Oncol., 12:853–58 (2001)
`2040 EP 1682131 B1 (“CCI-779 For Treating Mantle Cell Lymphoma”)
`2041 M. Ghielmini et al., “The effect of Rituximab on patients with follicular
`and mantle-cell lymphoma,” Ann. Oncol., 11(Suppl. 1):S123–126 (2000)
`
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`2046
`
`2042 G. Lenz et al., “The Role of Fludarabine in the Treatment of Follicular and
`Mantle Cell Lymphoma,” Cancer, 101(5):883–893 (2004)
`2043 W. Hiddeman & M. Dreyling, “Mantle Cell Lymphoma: Therapeutic
`Strategies Are Different from CLL,” Curr. Treat. Opt. Oncol., 4:219–26
`(2003)
`2044 R.I. Fisher et al., “A Clinical Analysis of Two Indolent Lymphoma
`Entities,” Blood, 85(4):1075–1082 (1995)
`2045 Bertoni, F. et al., “Mantle Cell Lymphoma,” Current Opinion in
`Hematology, 11:411–418 (2004)
`J. Brody et al, “Treatment of mantle cell lymphoma: Current approach and
`future directions,” Crit. Rev. in Oncol. / Hemat., 58:258–65 (2006)
`2047 T. Witzig et al., “Phase II Trial of Single-Agent Temsirolimus (CCI-779)
`for Relapsed Mantle Cell Lymphoma,” J. Clin. Oncol., 23(23): 5347–56
`(2005)
`2048 N. Ketterer et al., “Intensive therapy with peripheral stem cell
`transplantation in 16 patients with mantle cell lymphoma,” Annals of
`Oncol., 8:701–04 (1997)
`2049 R. Oinonen et al., “Mantle cell lymphoma: clinical features, treatment and
`prognosis of 94 patients,” Eur. J. Cancer, 34(3): 329–336 (1998)
`2050 P. Richardson et al., “Thalidomide: Emerging Role in Cancer Medicine,”
`Ann. Rev. Med., 53:629-57 (2002)
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`I.
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`INTRODUCTION
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`IPR2018-00685
`U.S. Patent 8,741,929
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`Pursuant to 35 U.S.C. § 313 and 37 C.F.R. § 42.107(a), Patent Owner Celgene
`
`Corporation (“Celgene”) submits this Preliminary Response to Petitioners Apotex
`
`Inc.’s and Apotex Corp.’s (collectively, “Petitioners”) Petition seeking inter partes
`
`review of claims 1–4, 8–9, 15, and 20 of Celgene’s U.S. Patent No. 8,741,929
`
`(“the ’929 patent”). The Petition should be denied.
`
`Petitioners’ invalidity assertions are rooted in two fundamentally mistaken
`
`principles: That all blood cancers (including all non-Hodgkin’s lymphomas
`
`(“NHL”)) are the same, and that thalidomide and lenalidomide are interchangeable
`
`compounds because they are “structurally similar.” Each of the challenged claims
`
`requires using specific doses and cycling regimens of the novel immunomodulatory
`
`agent lenalidomide to treat resistant (refractory) or recurring (relapsed) mantle cell
`
`lymphoma (“MCL”), a rare and notoriously difficult-to-treat sub-type of NHL that
`
`has long had one of the worst prognoses of all cancers. The prior art taught only the
`
`use of lenalidomide to treat other disease states (not MCL), and for MCL reported
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`only preliminary studies using thalidomide (not lenalidomide). Nothing in the prior
`
`art teaches, discloses, or even suggests using lenalidomide to treat relapsed and/or
`
`refractory MCL, let alone using the claimed dosages or cycling regimens.
`
`Confronted with gaping holes in the prior art, Petitioners attempt to mix-and-
`
`match disease states and treatments using the benefit of hindsight, when the matter
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`was not so simple at the time without the ’929 patent’s guidance. Indeed, at the time
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`
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`of invention, skilled artisans understood that MCL was much different and more
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`difficult to treat than other types of NHL, and that using thalidomide or lenalidomide
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`to treat any given disease state was unpredictable. Petitioners’ oversimplification
`
`does not withstand scrutiny, and institution should be denied for multiple reasons.
`
`First, the Board should exercise its discretion and deny institution under 35
`
`U.S.C. § 325(d) because Petitioners’ primary grounds—Grounds 1 and 2—do not
`
`raise anything new. Petitioners merely rehash the same arguments and the same
`
`combinations of prior art that were fully evaluated and overcome during prosecution,
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`and without even acknowledging that history. Indeed, the art and arguments upon
`
`which Petitioners rely was expressly rejected by the Examiner even after having
`
`maintained an obviousness rejection based on those arguments in three separate
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`Office Actions. Petitioners never even mention that the Examiner thoroughly
`
`considered and evaluated these references, and each of the non-exclusive factors
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`articulated in the Board’s informative Becton decision weighs strongly in favor of
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`discretionary denial under § 325(d).
`
`Second, institution should be denied because Grounds 1 and 2 fail to raise a
`
`reasonable likelihood that any of the challenged claims is unpatentable. The
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`Examiner reached the correct conclusion during prosecution—the claims are
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`patentable over a reference that discloses the use of lenalidomide for the treatment
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`IPR2018-00685
`U.S. Patent 8,741,929
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`of various disease states (but not MCL) in combination with a reference that
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`discusses a small number of MCL patients using thalidomide (but not lenalidomide).
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`The prior art does not disclose or suggest the treatment of MCL patients with
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`lenalidomide, let alone in the recited cycling regimen and dosages. Faced with this,
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`Petitioners: (1) overstate what the references actually disclose; (2) rely on a
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`conclusory and unsupported “expert” declaration; and (3) allege motivation to
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`combine without evidentiary support. Also, beyond Petitioners’ failure to set forth
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`a prima facie case of obviousness, the claimed invention met a long felt and
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`unresolved need, yielded unexpected results, and successfully improved MCL
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`treatment options where others had failed—further demonstrating that Grounds 1
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`and 2 lack merit.
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`Third, Petitioners’ final argument (anticipation asserted in Ground 3) does not
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`save the Petition, as this argument fails on a threshold issue: Petitioners have failed
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`to even allege, let alone establish, that the allegedly anticipating reference—a
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`purported Celgene press release (the “Press Release”)—qualifies as a prior-art
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`printed publication. Specifically, Petitioners provide no evidence of when the
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`document was allegedly made public, from where it was allegedly accessible, or how
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`it was allegedly accessed by a person of ordinary skill in the art (“POSA”)—let alone
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`why a POSA would have looked to a press release in the first place. Moreover, even
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`assuming the Press Release was publicly available, it still cannot constitute prior art
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`because it merely describes the work of the inventor, not work “by another.” Indeed,
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`the record demonstrates that the claimed inventions were conceived prior to the
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`purported date of the Press Release and diligently reduced to practice. Furthermore,
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`even if the Press Release could be used as prior art, it does not disclose all elements
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`of the challenged claims.
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`For these reasons, Petitioners cannot demonstrate a reasonable likelihood that
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`any of the challenged claims is unpatentable, and the Board should deny institution.
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`II. BACKGROUND
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`A. MCL Is a Unique and Difficult-to-Treat Cancer
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`“Cancer” is a generic name for a collection of diseases wherein some of the
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`body’s cells divide abnormally and spread into surrounding tissues. Normally, cells
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`grow and divide to form new cells as needed. When normal cells are old or damaged,
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`they die and are replaced by new cells. Cancer disrupts this orderly process, causing
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`old or damaged cells to survive when they should die, and new cells to form when
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`they are not needed. These extra cells can divide without stopping and may form
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`growths called tumors. Malignant tumors can spread into and invade nearby tissues.
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`Through a process called metastasis, tumors can travel through the blood or lymph
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`system to form new tumors throughout the body.
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`The medical literature describes an enormous variety of cancers. Lymphoma
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`is one type of cancer that arises in the reticuloendothelial and lymphatic systems.
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`(See Ex. 2001 at 2.) 1 NHL is a subtype of lymphoma, referring to malignant
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`monoclonal proliferation of lymphoid cells in the immune system. (See id. at 5.)
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`There are a wide variety of NHLs, including at least twenty distinct subtypes as of
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`the priority date in 2006. (See Ex. 2002 at 3.)
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`MCL is a distinct entity among the NHLs, accounting for only approximately
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`6% of all cases of NHL. (See Ex. 1003 at 6.) “[I]n contrast to other lymphoma
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`subtypes, the etiology and molecular pathogenesis of [MCL] remains unknown.”
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`(Ex. 2003 at 1.) At the time of invention, MCL was “considered incurable with
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`present therapy.” (Ex. 2004 at 1.) Indeed, a POSA would have been well aware that
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`“patients with MCL could be viewed as having the worst prognosis of all forms of
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`lymphoma.” (Ex. 2005 at 1; see also Ex. 1003 at 11.)
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`MCL patients may be relapsed and/or refractory to chemotherapy. Relapsed
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`MCL patients are those who, after achieving remission, experience a return of
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`lymphoid cells in the immune systems. (Ex. 1001 at 12:11-13.) Refractory MCL
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`patients are those who, even after intensive treatment, have residual lymphoid cells
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`in the immune systems. (Id. at 12:13-15.) MCL patients who are relapsed or
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`refractory to chemotherapy are even more difficult to treat than those who are
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`1 All citations are to the page numbers stamped on each exhibit.
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`chemotherapy naïve. (See Ex. 2006 at 1) (noting that the treatment of “MCL remains
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`challenging, especially in the relapsed/refractory setting.”). The claims of the 929
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`patent are directed to the treatment of this rare and often incurable condition.
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`B.
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`The ’929 Patent
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`The ’929 patent issued on June 3, 2014. The patent is directed to a novel
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`method of treatment of relapsed, refractory, or relapsed and refractory MCL with
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`specific dosages of lenalidomide in a repeating 28-day cycle. The ’929 patent and
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`its patent family were the first to disclose cyclically treating MCL using
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`lenalidomide. The patent covers an FDA-approved use of Celgene’s Revlimid® drug
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`product.
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`The ’929 patent claims priority to a provisional application filed on August 3,
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`2006. Petitioners concede that the challenged claims are entitled to a priority date
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`of no later than August 3, 2006. (Pet. 13.)
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`III. SCOPE AND CONTENT OF ALLEGED PRIOR ART
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`A. Drach
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`Drach is a review article from 2005 that surveys then-current treatment
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`options for MCL. As an initial matter, Petitioners’ assertion that Drach “was not
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`considered by the examiner during prosecution of the ’929 patent” (Pet. 15) is
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`incorrect. Drach was, in fact, considered by the Examiner (Ex. 2007 at 28), and is
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`also explicitly referenced in the background section of the ’929 patent’s specification
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`(Ex. 1001 at 2:4–40).
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`Drach describes a number of potential MCL treatments. Lenalidomide is
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`notably absent from the list. Drach does not provide any new or suggested treatment
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`regimens for MCL—rather, it provides a summary of studies reported elsewhere.
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`Drach is also silent as to the cycling regimen and dosages claimed in the ’929 patent.
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`Drach explains that MCL “is a distinct entity among the [NHLs] characterized
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`by a specific chromosomal translocation,” that it “remains difficult to treat and
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`belongs to the lymphomas with the poorest long-term outcome,” and that it “has
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`remained a challenge for clinical oncologists.” (Ex. 1003 at Abstract & 11.) Drach
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`recognized that treatments that had been successful in other types of aggressive
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`NHLs—such as high dose chemotherapy supported by autologous stem cell
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`transplantation—“have yielded discouraging results” in MCL. (Id. at 7.) Thus,
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`Drach teaches that MCL is a unique and distinct form of NHL that does not
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`necessarily respond to treatments successful in other types of NHL.
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`Drach includes five paragraphs under the heading “thalidomide” in which it
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`summarizes three papers that the Patent Office considered during prosecution of
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`the ’929 patent. (Id. at 10.) Drach first references “two case reports”—presented in
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`Wilson (Ex. 2008) and Damaj (Ex. 2009), respectively—in which thalidomide was
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`administered as a single agent at a daily dose of between 100 and 800 mg to a total
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`of three patients. (Id.) Drach then references a study conducted by the “authors”—
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`and presented in Kaufmann (Ex. 2010)—of fewer than 20 patients treated with
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`thalidomide in combination with rituximab, in which thalidomide was administered
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`at a daily dose of 200 mg for two weeks and then 400 mg thereafter. (Id.) Drach
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`does not suggest, let alone teach, cycling therapy using thalidomide for 21 days,
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`followed by 7 days of rest in a 28-day repeating cycle, at low doses (i.e., between 5
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`and 25 mg/day), which is the cyclic dosing regimen claimed for lenalidomide in the
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`challenged claims. And as discussed in detail below, these three references (Wilson,
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`Damaj, and Kaufmann) were thoroughly analyzed by the Examiner during
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`prosecution and combined with Zeldis for an obviousness rejection in the same way
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`that Petitioners are now attempting to combine Drach and Zeldis.
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`Petitioners contend—using bolded italics—that “Drach explicitly taught that
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`lenalidomide was an important agent for the new treatment paradigm of MCL at the
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`time.” (Pet. 18 (quoting Ex. 1003 at 10); see also id. at 16.) This is false. The only
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`“new treatment paradigm” discussed by Drach refers to a different cancer, multiple
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`myeloma (“MM”). (See Ex. 1003 at 9-10.) Recognizing this, Petitioners add “for
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`MCL” to a disclosure where it does not appear and does not belong. Specifically,
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`Petitioners refer to Drach as disclosing that “‘[t]halidomide and its analogues (e.g.,
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`lenalidomide) are therefore important agents for the new treatment paradigm’ for
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`MCL.” (Id. at 18-19.) Petitioners’ inclusion of “for MCL” does not accurately
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`reflect the disclosure of Drach. Instead, Drach actually states—in a paragraph
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`discussing only MM, not MCL—that “[t]halidomide and its analogues (e.g.,
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`lenalidomide) are therefore important agents for the new treatment paradigm of
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`targeting both the tumor cell and its microenvironment.” (Ex. 1003 at 10
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`(emphasis added); see also id. at 9 (referring to “multiple myeloma (MM), where
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`targeting the tumor cell and its microenvironment represents a new treatment
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`paradigm”).) Contrary to