`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`___________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________
`
`ALVOGEN PINE BROOK LLC
`
`Petitioner,
`
`v.
`
`CELGENE CORP.
`
`Patent Owner
`___________
`
`Case No. UNASSIGNED
`Patent 7,968,569
`___________
`
`
`PETITION FOR INTER PARTES REVIEW OF CLAIMS 1-15
`OF U.S. PATENT NO. 7,968,569
`
`
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`TABLE OF CONTENTS
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`I. 
`
`Page
`INTRODUCTION ........................................................................................... 1 
`A.  Preliminary Statement ..................................................................................... 1 
`B.  Summary of Unpatentability Grounds ............................................................. 2 
`II.  MANDATORY NOTICES, STANDING, AND FEES .................................. 2 
`A.  Mandatory Notices ........................................................................................... 2 
`B.  Certification of Grounds for Standing ............................................................. 3 
`C.  Fees .................................................................................................................. 4 
`III.  OVERVIEW OF THE ʼ569 PATENT ............................................................ 4 
`A.  The Claims of the ʼ569 Patent ......................................................................... 4 
`B.  The Effective Filing Date of the ’569 Patent Can Be No Earlier than
`November 6, 2002 ........................................................................................... 4 
`IV.  CLAIM CONSTRUCTION ............................................................................ 7 
`V. 
`LEVEL OF ORDINARY SKILL IN THE ART ............................................. 7 
`VI.  SUMMARY OF THE PRIOR ART ................................................................ 8 
`A.  Thalidomide and Thalidomide Analogs (IMiDs) ............................................ 8 
`1.  Muller ........................................................................................................... 8 
`2.  Corral I and II ............................................................................................. 10 
`3.  The ’230 Patent .......................................................................................... 11 
`B.  Multiple Myeloma and Thalidomide ............................................................. 12 
`1.  Palumbo ...................................................................................................... 14 
`C.  Multiple Myeloma and IMiDs ....................................................................... 15 
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`1.  Hideshima ................................................................................................... 16 
`2.  May Press Release ...................................................................................... 18 
`D.  A POSA Would Understand that “Revimid” is Lenalidomide ..................... 20 
`1.  August Press Release ................................................................................. 21 
`2.  Orphan Drug Designation .......................................................................... 23 
`E.  Drug Cycling in Cancer Treatments .............................................................. 25 
`VII.  THERE IS A REASONABLE LIKELIHOOD THAT THE
`CHALLENGED CLAIMS ARE UNPATENTABLE .................................. 29 
`A.  Ground 1: The Combination of Palumbo, the May Press Release, and the
`August Press Release Renders Claims 1-15 Obvious ................................... 29 
`1.  A POSA would have been motivated to combine Palumbo, the May Press
`Release, and the August Press Release ............................................................. 29 
`2.  Claims 1 and 13 .......................................................................................... 30 
`3.  Claims 2 and 4 ............................................................................................ 37 
`4.  Claim 3 ....................................................................................................... 38 
`5.  Claims 5, 6, and 15 ..................................................................................... 38 
`6.  Claims 7–12 ................................................................................................ 39 
`7.  Claim 14 ..................................................................................................... 40 
`B.  Ground 2: Palumbo, Hideshima, and the ʼ230 Patent ................................... 41 
`1.  A POSA would have been motivated to combine Palumbo, Hideshima,
`and the ’230 patent ............................................................................................ 41 
`2.  Claims 1 and 13 .......................................................................................... 43 
`3.  Claims 2 and 4 ............................................................................................ 51 
`4.  Claim 3 ....................................................................................................... 52 
`5.  Claims 5, 6, and 15 ..................................................................................... 53 
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`6.  Claims 7–12 ................................................................................................ 54 
`7.  Claim 14 ..................................................................................................... 55 
`C.  There Are No Secondary Considerations to Overcome Obviousness ........... 56 
`1.  There Are No Unexpected Results ............................................................. 57 
`2.  Revlimid’s Alleged Commercial Success Does Not Support the ’569
`patent ................................................................................................................. 61 
`VIII.  CONCLUSION .............................................................................................. 63 
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`Petition for Inter Partes Review of U.S. Patent No. 7,968,569
`
`LIST OF EXHIBITS
`
`Document
`
`Ex. 1005
`
`Ex. 1006
`
`Exhibit
`No.
`Ex. 1001 U.S. Patent No. 7,968,569 (“the ’569 patent”)
`Ex. 1002
`Prosecution History excerpts for U.S. Patent No. 7,968,569
`Ex. 1003
`Expert Declaration of Dr. Guido Tricot
`Ex. 1004
`Sampaio et al., “Thalidomide selectively inhibits tumor necrosis
`factor alpha production by stimulated human monocytes,” J. Exp.
`Med., 173(3): 699-703 (1991). (“Sampaio”)
`Tramontana et al., “Thalidomide Treatment Reduces Tumor Necrosis
`Factor α Production and Enhances Weight Gain in Patients with
`Pulmonary Tuberculosis,” Molecular Medicine, 1:384-397 (1995).
`(“Tramontana”)
`Singhal et al., “Antitumor Activity of Thalidomide in Refractory
`Multiple Myeloma,” N. Engl. J. Med., 341:1565-1571 (1999)
`(“Singhal”)
`Ex. 1007 Durie & Stepan, “Efficacy of Low Dose Thalidomide in Multiple
`Myeloma,” Electronic Journal of Oncology, 1:1-8 (2000). (“Durie”)
`Ex. 1008 Muller et al., “Amino-substituted Thalidomide Analogues: Potent
`Inhibitors of TNF-α Productions,” Bioorganic & Medicinal
`Chemistry Letters, 9:1625-1630 (1999). (“Muller”)
`Ex. 1009 Corral et al., “Differential Cytokine Modulation and T Cell
`Activation by Two Distinct Classes of Thalidomide Analogues That
`are Potent Inhibitors of TNF-α,” J. Immunol., 163: 380-386 (1999).
`(“Corral I”)
`Ex. 1010 Corral & Kaplan, “Immunomodulation by thalidomide and
`thalidomide analogues,” Ann. Rheum. Dis., 58: I107-I113 (1999).
`(“Corral II”)
`Ex. 1011 Rajkumar & Kyle, “Thalidomide in the Treatment of Plasma Cell
`Malignancies,” J. of Clinical Oncology, 19(16):3593-3595 (Aug.
`2001). (“Rajkumar 2001”)
`Ex. 1012 Celgene Corp., “Positive Interim Results Presented at the VIIIth
`International Myeloma Workshop on Celgene Corporation's Lead
`IMiD(TM) (REVIMID(TM)); Lead Investigators from Dana-Farber
`Cancer Institute and the Arkansas Cancer Research Center Reported
`on REVIMID's Activity and Safety Profile,” May 8, 2001. (“May
`Press Release”)
`Ex. 1013 Celgene Corp., “Celgene Corporation Awarded Additional Patent
`
`
`
`iv
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`Petition for Inter Partes Review of U.S. Patent No. 7,968,569
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`Document
`
`Exhibit
`No.
`
`Ex. 1015
`
`Protection For Lead IMiD(TM), REVIMID(TM); Comprehensive
`Patent Protection for REVIMID Includes Coverage of the Active
`Ingredient, Pharmaceutical Compositions, and Therapeutic Uses,”
`August 28, 2001. (“August Press Release”)
`Ex. 1014 Celgene Corp., “Celgene Corporation Receives Orphan Drug
`Designation for Revimid(TM) For Multiple Myeloma,” October 8,
`2001. (“October Press Release”)
`Palumbo, et al, “Low-dose thalidomide plus dexamethasone is an
`effective salvage therapy for advanced myeloma,” Hematologica,
`86(4):399-403 (April 2001). (“Palumbo”)
`Ex. 1016 Hideshima, et al., “Thalidomide and its analogs overcome drug
`resistance of human multiple myeloma cells to conventional
`therapy,” Blood, 96:2943-2950 (2000). (“Hideshima”)
`Ex. 1017 V. T. DeVita, Jr., “Chapter 16: Principles of Chemotherapy,”
`Cancer: Principles and Practice of Oncology, Fourth Edition (1993)
`(“Principles of Chemotherapy”)
`Enzinger et al., “Phase II clinical trial of 13-cis-retinoic acid and
`interferon-α-2a in patients with advanced esophageal carcinoma,”
`Cancer, 85:1213–1217 (1999). (“Enzinger”)
`Jacobs et al., “Prednisone in MOPP chemotherapy for Hodgkin's
`disease,” Br. Med. J., 2:1469-1471 (1976). (“Jacobs”)
`Ex. 1020 Gebbia et al., “Single agent 2',2'-difluorodeoxycytidine in the
`treatment of metastatic urothelial carcinoma: a phase II study,” La
`Clinica Terapeutica, 150(1):11-15 (1999). (“Gebbia”)
`Ex. 1021 Gordon et al., “A Phase I Trial of Recombinant Human Interleukin-
`11 (Neumega rhIL-11 Growth Factor) in Women With Breast Cancer
`Receiving Chemotherapy,” Blood J., 87: 3615-3624 (1996).
`(“Gordon”)
`Ex. 1022 Celesti et al., “The association of cyclophosphamide and
`dexamethasone in advanced refractory multiple myeloma patients,”
`Haematologica, 82(3):351-353 (1997). (“Celesti”)
`Ex. 1023 Koo et al., “Vancomycin-induced neutropenia,” Drug Intell. Clin.
`Pharm., 20(10):780-782 (1986). (“Koo”)
` Cytovene®-IV, Physicians’ Desk Reference 2623-2629 (54th ed.
`2000) (“Cytovene Label”)
`
`Ex. 1018
`
`Ex. 1019
`
`Ex. 1024
`
`Ex. 1025
`
`Imashuku et al., “Management of severe neutropenia with
`cyclosporin during initial treatment of Epstein-Barr virus-related
`
`
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`

`Petition for Inter Partes Review of U.S. Patent No. 7,968,569
`
`Exhibit
`No.
`
`Document
`
`hemophagocytic lymphohistiocytosis,” Leuk. Lymphoma, 36(3-
`4):339-346 (2000). (“Imashuku”)
`Ex. 1026 Revlimid Label
`Ex. 1027
`Pomalyst Label
`Ex. 1028 U.S. Patent No. 6,281,230 (“the ʼ230 Patent”)
`Ex. 1029
`Parameswaran et al., “CCNU (lomustine), idarubicin and
`dexamethasone (CIDEX): an effective oral regimen for the treatment
`of refractory or relapsed myeloma,” Br. J. Haematol., 109(3):571-
`575 (2000). (“Parameswaran”)
`Ex. 1030 Bilgrami et al., “Dexamethasone, paclitaxel, etoposide,
`cyclophosphamide (d-TEC) and G-CSF for stem cell mobilisation in
`multiple myeloma,” Bone Marrow Transplantation, 28:137–143
`(July 2001). (“Bilgrami”)
`Ex. 1031 Moreira et al., “Thalidomide exerts its inhibitory action on tumor
`necrosis factor alpha by enhancing mRNA degradation,” J Exp Med.,
`177:1675-1680 (1993)
`Ex. 1032 Barlogie et al., “Effective treatment of advanced multiple myeloma
`refractory to alkylating agents,” N Engl J Med., 310(21):1353-1356
`(1984). (“Barlogie”)
`Ex. 1033 Marisavljevic et al., “Results of treatment of patients with advanced
`multiple myeloma with the vincristine-adriamycin-dexamethasone
`protocol,” Srp Arh Celok Lek, 124(11-12):292-296 (1996).
`(“Marisavljevic”)
`Ex. 1034 Browman et al., “Modified adriamycin-vincristine-dexamethasone
`(m-VAD) in primary refractory and relapsed plasma cell myeloma:
`an NCI (Canada) pilot study,” Br. J. Haematol., 82(3):555-559
`(1992). (“Browman”)
`J. Bladé and J. Esteve, “Treatment Approaches for Relapsing and
`Refractory Multiple Myeloma,” Acta Oncologica, 39(7):843-847
`(2000). (“Blade”)
`Ex. 1036 Rajkumar, S.V., et al., “Combination therapy with lenalidomide plus
`dexamethasone (Rev/Dex) for newly diagnosed myeloma,” Blood,
`106:4050-4053 (2005) (“Rajkumar 2005”)
`Ex. 1037 Dimopoulos, M., et al., “Lenalidomide plus dexamethasone for
`relapsed or refractory multiple myeloma,” N. Engl. J. Med.
`357(21):2123-2132 (2007) (“Dimopoulos 2007”)
`Lacy, M.Q., et al., “Long-term Results of Response to Therapy,
`
`Ex. 1038
`
`Ex. 1035
`
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`Exhibit
`No.
`
`Document
`
`Ex. 1043
`
`Time to Progression, and Survival With Lenalidomide Plus
`Dexamethasone in Newly Diagnosed Myeloma,” Mayo Clin. Proc.
`82(10):1179-1184 (2007) (“Lacy 2007”)
`Ex. 1039 Gay, F., et al., “Lenalidomide plus dexamethasone versus
`thalidomide plus dexamethasone in newly diagnosed multiple
`myeloma: a comparative analysis of 411 patients,” Blood, 115:1343-
`1350 (2010) (“Gay 2010”)
`Ex. 1040 Weber, D., et al., “Lenalidomide plus dexamethasone for relapsed
`multiple myeloma in North America,” N. Engl. J. Med.
`357(21):2133-2142 (2007) (“Weber 2007”)
`Ex. 1041 Armoiry, X., et al., “Lenalidomide in the treatment of multiple
`myeloma: a review,” J. Clin. Pharm. Ther. 33:219-226 (2008)
`(“Armoiry 2008”)
`Ex. 1042 Morgan J. et al., “Overall survival with dexamethasone in phase III
`multiple myeloma trials after adjustment for cross-over to
`lenalidomide,” Haematologica 93(s1), Abstract 0441 (2008)
`(“Morgan 2008”)
`Palumbo, A., et al., “Lenalidomide: A new therapy for multiple
`myeloma,” Cancer Treatment Reviews 34:283–291 (2008)
`(“Palumbo 2008”)
`Ex. 1044 Dimopoulos, M.A., et al., “Long-term follow-up on overall survival
`from the MM-009 and MM-010 phase III trials of lenalidomide plus
`dexamethasone in patients with relapsed or refractory multiple
`myeloma,” Leukemia 23:2147–2152 (2009) (“Dimopoulos 2009”)
`Ex. 1045 Gandhi, A.K., “Dexamethasone Synergizes with Lenalidomide to
`Inhibit Multiple Myeloma Tumor Growth, But Reduces
`Lenalidomide-Induced Immunomodulation of T and NK Cell
`Function,” Curr. Cancer Drug Targets, 10:155-167 (2010) (“Gandhi
`2010”)
`Ex. 1046 Malpas, “Management of Multiple Myeloma,” Br Med J., 2:163-165
`(1969) (“Malpas”)
`Palmer et al., “Dose Intensity Analysis of Melphalan and Prednisone
`in Multiple Myeloma” J Natl Cancer Inst, 80:414-418 (1988)
`(“Palmer”)
`Ex. 1048 Oken et al., “Contribution of Prednisone to the Effectiveness of
`Hexamethylmelamine in Multiple Myeloma,” Cancer Treatment
`Reports, 71:807-811 (1987) (“Oken”)
`
`Ex. 1047
`
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`Document
`
`Exhibit
`No.
`Ex. 1049 Bell et al., “Chapter 5. The Hematopoietic System and Development
`of Blood Cells,” The Johns Hopkins Atlas of Human Functional
`Anatomy, 4th ed. 1997 (“Bell”)
`Ex. 1050 Gennaro, A., Remington: The Science and Practice of Pharmacy,
`20th Edition (2000) (“Remington”)
`Ex. 1051 U.S. Food and Drug Administration, “List of Orphan Designations
`and Approvals,” available at
`https://www.accessdata.fda.gov/scripts/opdlisting/oopd/ (published
`online and in print October 2001) (“Orphan Drug Designation”)
`Ex. 1052 U.S. Provisional Application No. 60/380,842 (“the ’842
`provisional”)
`Ex. 1053 Barlogie et al., “Extended survival in advanced and refractory
`multiple myeloma after single-agent thalidomide: identification of
`prognostic factors in a phase 2 study of 169 patients,” Blood
`98(2):492-494 (July 2001) (“Barlogie 2001”)
`Ex. 1054 Affidavit of Christopher Butler, Internet Archive
`Ex. 1055 Declaration of James L. Mullins, Ph.D.
`Ex. 1056
`21 C.F.R. 300-499 (as of April 1, 2001)
`Ex. 1057
`Lotus Pharmaceutical Co., Ltd. and Alvogen Pine Brook LLC’s First
`Set of Requests for Admission (Nos. 1-3)
`Lotus Pharmaceutical Co., Ltd. and Alvogen Pine Brook LLC’s First
`Set of Interrogatories (Nos. 1-31)
`Ex. 1059 Malpas and Rohatiner, “Principles of Cancer Chemotherapy,”
`Advances in Oncology 1:317-350 (1996) (“Malpas 1996”)
`Ex. 1060 Orange Book: Approved Drug Products with Therapeutic
`Equivalence Evaluations, Patent and Exclusivity for: N021880
`
`Ex. 1058
`
`
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`
`
`I.
`
`INTRODUCTION
`Alvogen Pine Brook LLC (“Alvogen” or “Petitioner”) requests inter partes
`
`review (“IPR”) under 35 U.S.C. §§ 311-319 and 37 C.F.R. § 42.100 et seq. of
`
`claims 1–15 of U.S. Patent No. 7,968,569 (“the ’569 patent”).
`
`Petitioner asserts that there is a reasonable likelihood that the challenged
`
`claims are unpatentable and requests review of, and cancellation of, the challenged
`
`claims under 35 U.S.C. § 103.
`
`A.
`Preliminary Statement
`The ’569 patent is directed to methods of treating multiple myeloma
`
`(“MM”) by administering lenalidomide on a 28-day cycle that includes a 7-day rest
`
`period, in combination with 40 mg of dexamethasone. It is listed in the Orange
`
`Book as covering the use of Celgene’s Revlimid® drug product (Ex. 1060) and
`
`asserted in multiple cases to prevent potential competitors from marketing generic
`
`versions of the product. Numerous publications, which are prior art under § 102(b)
`
`to the ʼ569 patent, publicly disclosed that lenalidomide is effective to treat MM in
`
`clinical trials, as well as against human MM cells in vitro, and exhibits enhanced
`
`anti-tumor activity when coupled with dexamethasone. It was standard practice to
`
`administer cancer drug therapies in cycles and incorporate rest periods to combat
`
`toxicity. Therefore, the method claims of the ʼ569 patent comprise nothing more
`
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`Petition for Inter Partes Review of U.S. Patent No. 7,968,569
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`than the routine combination of two known, anti-MM drugs, administered
`
`according to standard practices, as taught by the prior art.
`
`B.
`Summary of Unpatentability Grounds
`Petitioner requests the cancellation of claims 1–15 as obvious under
`
`35 U.S.C. § 103(a) on the following grounds:
`
`Ground
`1
`
`2
`
`Summary
`Claims 1-15 are obvious in view of Palumbo, the May Press
`Release, and the August Press Release
`Claims 1-15 are obvious in view of Palumbo, Hideshima, and
`the ’230 patent
`
`
`
`II. MANDATORY NOTICES, STANDING, AND FEES
`A. Mandatory Notices
`Real Parties-in-Interest: The real parties-in-interest are Alvogen Pine Brook
`
`LLC and Lotus Pharmaceutical Co., Ltd.
`
`Related Matters: The ’569 patent is the subject of the following currently
`
`pending patent infringement lawsuits brought by Celgene:
`
` Celgene Corporation v. Sun Pharma Global FZE et al., No. 2-18-cv-
`
`11630-SDW-LDW (D.N.J.);
`
` Celgene Corporation v. Lotus Pharmaceutical Co., Ltd. et al., No. 17-
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`cv-06842-SDW-LDW (D.N.J.);
`
` Celgene Corporation v. Cipla Ltd., No. 17-cv-06163-SDW-LDW
`
`
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`Petition for Inter Partes Review of U.S. Patent No. 7,968,569
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`(D.N.J.);
`
` Celgene Corporation v. Zydus Pharmaceuticals (USA) Inc. et al., No.
`
`17-cv-02528 (D.N.J.); and
`
` Celgene Corporation v. Dr. Reddy’s Laboratories, Inc., No. 2016-cv-
`
`07704-SDW-LDW (D.N.J.).
`
`The ’569 patent was also the subject of the litigation captioned Celgene
`
`Corporation v. Natco Pharma Limited et al., No. 12-cv-04571-SDW-MCA, which
`
`was dismissed on January 4, 2016.
`
`Lead Counsel: Lead Counsel is Stephen M. Hash (Reg. No. 45,490) and
`
`Back-up Counsel are Margaret J. Sampson (Reg. No. 47,052) and Jeffrey S.
`
`Gritton (Reg. No. 65,314), each of Baker Botts L.L.P.
`
`Service Information: Baker Botts L.L.P., 98 San Jacinto Boulevard, Suite
`
`1500, Austin, Texas 78701-4078; Tel. (512) 322-2500; Fax (512) 322-2501.
`
`Petitioner consents to service by electronic mail at:
`
`BBAlvogen-Celgene@BakerBotts.com. Powers of Attorney are filed concurrently
`
`herewith under 37 C.F.R. § 42.10(b).
`
`B. Certification of Grounds for Standing
`Petitioner certifies that the ’569 patent is available for inter partes review
`
`and that Petitioner is not barred or estopped from requesting this inter partes
`
`review on the grounds identified herein.
`
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`Petition for Inter Partes Review of U.S. Patent No. 7,968,569
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`C.
`Fees
`The Office is authorized to charge any fees that become due in connection
`
`with this Petition to Deposit Account No. 02-0384, Ref. No. 084280.0118, as well
`
`as any additional fees that might be due in connection with this Petition.
`
`III. OVERVIEW OF THE ʼ569 PATENT
`A. The Claims of the ʼ569 Patent
`The ’569 patent includes 15 claims. Claims 1 and 13 are independent and are
`
`directed generally to methods of treating multiple myeloma (“MM”) by
`
`administering lenalidomide on a 28-day cycle that includes a 7-day rest period, in
`
`combination with 40 mg of dexamethasone.
`
`Dependent claims 2-12 and 14-15 depend from claim 1 and include
`
`additional limitations regarding dosage form, strength, route of administration, or
`
`the form of MM being treated.
`
`B.
`
`The Effective Filing Date of the ’569 Patent Can Be No Earlier
`than November 6, 2002
`The ’569 patent issued on June 28, 2011, from Application Serial No.
`
`10/438,213 (“the ’213 application”), which was filed on May 15, 2003. Ex. 1001 at
`
`1. The ’213 application claims priority to two provisional applications: Provisional
`
`Application No. 60/380,842 (Ex. 1052, “the ’842 provisional”), filed on May 17,
`
`2002, and Provisional Application No. 60/424,600 (“the ’600 provisional”), filed
`
`on November 6, 2002. Id. Claims 1-15 of the ’569 patent, however, are not entitled
`
`
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`Petition for Inter Partes Review of U.S. Patent No. 7,968,569
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`to claim priority to at least the ’842 provisional, because the ’842 provisional does
`
`not provide adequate support under 35 U.S.C. § 112, first paragraph, for the claims
`
`of the ʼ569 patent. See Ex. 1003 at ¶¶ 31-37. Accordingly, the effective filing date
`
`of the ʼ569 patent can be no earlier than November 6, 2002, the filing date of the
`
`’600 provisional.1 See New Railhead Mfg., L.L.C. v. Vermeer Mfg. Co., 298 F.3d
`
`1290, 1294 (Fed. Cir. 2002).
`
`The ’569 patent cannot claim priority to the ’842 provisional because its
`
`claims are not adequately supported by the specification of the ’842 provisional
`
`under 35 U.S.C. § 112 for two reasons. First, the ’842 provisional does not
`
`describe the 28-day treatment cycle required by the claims of the ’569 patent,
`
`wherein lenalidomide is administered for 21 consecutive days followed by seven
`
`consecutive days of rest. Id. Ex. 1003 at ¶ 32. The ’842 Provisional has no
`
`description of a 28-day drug administration cycle. Indeed, the use of cycling is not
`
`mentioned anywhere in the ’842 Provisional. Id.
`
`Second, the ’842 provisional does not disclose the combination of
`
`
`1 Because the prior art references cited herein were all published more than a year
`
`before November 6, 2002, it is unnecessary for Petitioner to address in this Petition
`
`which, if any, of the claims of the ʼ569 patent are actually entitled to claim priority
`
`to the ’600 provisional.
`
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`Petition for Inter Partes Review of U.S. Patent No. 7,968,569
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`lenalidomide and dexamethasone to treat MM, or any cancer as required by the
`
`claims of the ’569 patent. Id. at ¶ 33.
`
`The ʼ842 provisional is directed to “methods of treating and/or managing
`
`cancer using the combined administration of a small molecule-based active agent,
`
`such as a derivative or analogue of thalidomide, . . . and a large molecule-based
`
`active agent.” Id. at ¶ 34 [citing Ex. 1052 at 1:6–9]. The ʼ842 provisional defines
`
`large molecules as “preferably biological molecules, such as naturally occurring or
`
`artificially made proteins” (Ex. 1052 at 24:8-10), and further describes them as
`
`“e.g., a protein such as a growth-factor or cytokine” (Id. at 10:17-18). The ʼ842
`
`provisional does not state or suggest that dexamethasone is a “large molecule.” Ex.
`
`1003 at ¶ 35. Instead, dexamethasone is a small molecule and is mentioned only
`
`once in the context of the invention, when it is listed among hundreds of other
`
`compounds as an optional “additional active agent.” Id. [citing Ex. 1052 at 26:31-
`
`30:15; 28:24; 31:1-4].
`
`Since the ʼ842 provisional only discloses methods of treatment involving the
`
`administration of a large molecule (e.g., a protein) in combination with a small
`
`molecule such as lenalidomide, it does not adequately support the claims of the
`
`’569 patent. Ex. 1003 at ¶ 36. Nowhere does the ’842 provisional disclose a
`
`method of treating MM with a combination of lenalidomide and dexamethasone,
`
`nor does it provide “blaze marks” that would allow one of skill in the art to identify
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`Petition for Inter Partes Review of U.S. Patent No. 7,968,569
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`such a method amongst the multitude of other possible methods set forth in the
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`disclosure of the ’842 provisional. Id.; see, e.g., Novozymes A/S v. DuPont
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`Nutrition Biosciences APS, 723 F.3d 1336, 1349 (Fed. Cir. 2013).
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`Thus, for purposes of demarcating the prior art, the earliest priority date for
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`all claims of the ’569 Patent can be no earlier than November 6, 2002, i.e., the
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`filing date of the ’600 Provisional. Art published prior to November 6, 2001, the
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`critical date, is § 102(b) prior art.
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`IV. CLAIM CONSTRUCTION
`In an IPR, claims are given their “broadest reasonable construction in light
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`of the specification.” See 37 C.F.R. § 42.100(b); In re Cuozzo Speed Technologies,
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`LLC, 793 F.3d 1268, 1275-78 (Fed. Cir. 2015). No terms require construction for
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`purposes of this IPR, and the claim terms should be given their plain and ordinary
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`meaning. Ex. 1003 at ¶ 38.
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`V. LEVEL OF ORDINARY SKILL IN THE ART
`A POSA at the time of the alleged invention of the ’569 patent would have
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`several years of experience as a practicing physician in the fields of oncology and
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`hematology. Id. at ¶ 40. The POSA would have had experience with the
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`administration of therapeutic agents and the development of drug regimens and
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`dosing schedules. Id. Typically, such a person would have an M.D. as well as
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`experience in clinical oncology or pharmacology. Id.
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`Petition for Inter Partes Review of U.S. Patent No. 7,968,569
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`VI. SUMMARY OF THE PRIOR ART
`A. Thalidomide and Thalidomide Analogs (IMiDs)
`In the 1950s, thalidomide was used in Europe as a remedy for morning
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`sickness in pregnant women, but was withdrawn from the market because of
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`reports of teratogenicity (birth defects) associated with its use. Id. at ¶ 42 [citing
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`Ex. 1016 at 2943]. Despite its dangers, researchers later discovered that
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`thalidomide possesses immunomodulatory properties, and was therapeutically
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`beneficial in a variety of autoimmune and inflammatory disease states. Id. [citing
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`Ex. 1008 at 1625; Ex. 1009 at 380]. By the 1990s, thalidomide was known to
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`selectively inhibit TNF-α, a cytokine produced by monocytes and macrophages
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`that plays a role in the immune system but is also associated with inflammatory
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`conditions such as arthritis and inflammatory bowel disease. Id. [citing Ex. 1009 at
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`380].
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`In the late 1990s, researchers began synthesizing and investigating structural
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`analogs of thalidomide to develop analogs with increased anti-TNF-α activity and
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`reduced or absent teratogenic potential. Id. at ¶ 43. [citing Ex. 1009 at 383]. In
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`1999, these researchers published several studies in which they identified three
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`thalidomide analogs they referred to as “class I compounds” or “IMiDs” (i.e.,
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`“Immunomodulatory Imide Drugs”). Id. [citing Ex. 1009 at 381; Ex. 1010 at I109].
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`1. Muller
`Muller, et al., “Amino-Substituted Thalidomide Analogs: Potent Inhibitors
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`Petition for Inter Partes Review of U.S. Patent No. 7,968,569
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`of TNF-α Production,” Bioorg. Med. Chem. Lett. 9:1625-1630 (Ex. 1008,
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`“Muller”) was published June 7, 1999 and was publicly available at least as of June
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`16, 1999 as evidenced by its presence at, e.g., the Linda Hall Library in Kansas
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`City, Missouri by that time. Ex. 1055 at ¶¶ 40-49. As such Muller is § 102(b) prior
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`art.
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`Muller disclosed compounds developed from “a program to improve the
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`TNF-α inhibitory activity by structural modification.” Ex. 1003 at ¶ 45 [citing Ex.
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`1008 at 1625]. Muller disclosed the synthesis of several compounds and the
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`measurement of their TNF-α inhibitory activity. Id. [citing Ex. 1008 at 1626-28].
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`In particular, Muller identified three compounds as potent inhibitors of TNF-α and
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`designated them as 5a, 8a, and 14. Id. [citing Ex. 1008 at 1629]. Muller disclosed
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`the structure of each of these compounds, which are represented below:
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`
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`
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`Compound 5a
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`Compound 8a
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`Compound 14
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`Thalidomide
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`Id. at ¶ 46. Compound 8a of Muller is now called lenalidomide and is the active
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`ingredient in Celgene’s Revlimid® product. Id. at ¶ 47 [citing Ex. 1026 at 25].
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`Lenalidomide is referred to in the ’569 patent as 3-(4-amino-1-oxo-1,3- dihydro-
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`isoindol-2-yl)-piperidine 2,6-dione and
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`is also known as 1-oxo-2-(2,6-
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`dioxopiperidin-3-yl)-4-aminoisoindoline. Id.
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`Compound 5a of Muller is now called pomalidomide and is the active
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`ingredient in Celgene’s Pomalyst® product. Id. at ¶ 48 [citing Ex. 1027 at 19].
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`Revlimid® and Pomalyst® are both indicated for the treatment of patients with
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`MM in combination with dexamethasone. Id. [citing Ex. 1026 at 1; Ex. 1027 at 1].
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`2.
`Corral I and II
`Corral et al., “Differential Cytokine Modulation and T Cell Activation by
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`Two Distinct Classes of Thalidomide Analogues That Are Potent Inhibitors of
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`TNF-α,” J. Immunol., 163:380-86 (1999) (Ex. 1009, “Corral I”) was published
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`July 1, 1999 and was publicly available at least as of June 25, 1999 as evidenced
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`by its presence at, e.g., Health Sciences Library, University of Wisconsin by that
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`time. Ex. 1055 at ¶¶ 60-69. As such, Corral I is § 102(b) prior art.
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`Corral I disclosed additional studies of thalidomide analogs that were
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`discovered through a program to “develop analogs of thalidomide with increased
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`anti-TNF-α potency and reduced or absent teratogenic potential[.]” Ex. 1003 at ¶
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`50 [citing Ex. 1009 at 383]. Corral I designated two classes of analog compounds:
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`class I and class II. Id. [citing Ex. 1009 at 381-383]. Corral I identified analogues
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`5a, 8a, and 14 from Muller as the three class I compounds CI-A, CI-B and CI-C,
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`respectively, and disclosed that these class I compounds inhibit TNF-α and
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`described other properties of these compounds. Id. [citing Ex. 1009 at 381-383].
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`Given their activity, Corral I predicted that the class I compounds could be useful
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`in “boosting anti-tumor immunity.” Id. [citing Ex. 1009 at 385].
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`The structures of the IMiDs, including lenalidomide, were also disclosed in
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`Corral and Kaplan, “Immunomodulation by
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`thalidomide and
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`thalidomide
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`analogues,” Ann. Rheum. Dis., 58(Suppl I):1107-13 (1999) (Ex. 1010, “Corral
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`II”). Ex. 1003 at ¶ 52; Ex. 1010 at Figure 1. Corral II was publicly available at least
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`as of December 1999. Ex. 1055 at ¶¶ 70-79. As such, Corral II is § 102(b) prior art.
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`3.
`The ’230 Patent
`U.S. Patent No. 6,281,230 (Ex. 1028, “the ʼ230 Patent”) entitled
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`“Isoindolines, method of use, and pharmaceutical compositions” was issued on
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`August 28, 2001. Ex. 1028 at 1. As such, the ’230 patent is § 102(b) prior art.
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`The ’230 Patent disclosed methods for preparation of several isoindoline
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`compounds, including lenalidomide, by hydrogenation of the corresponding nitro-
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`compounds, and crystallization and recrystallization of the residues. Ex. 1003 at
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`¶ 54 [citing Ex. 1028 at 8:62-9:30, Example 1 and 17:26-18:61, Example 16].
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`The ʼ230 Patent described methods of treating oncogenic or cancerous
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`conditions using a class of TNF-α-reducing compounds that includes lenalidomide.
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`Id. at ¶ 55 [citing Ex. 1028 at Abstract, 4:17-25, and 4:37-39]. The ʼ230 Patent
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`cited TNF-α inhibition as the mechanism of action underlying the claimed
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`inventions, stating that “TNFα production [] has been associated with cancerous
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`conditions, particularly induced tumors,” and that the “present invention is based
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`on the discovery that certain classes of non-polypeptide compounds more fully
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`described herein decrease the levels of TNFα.” Id. [citing Ex. 1028 at 2:7-9, 4:37-
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`39]. Lenalidomide is highlighted in the Abstract as one of two “typical
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`embodiments” of the invention, and claim 22 is directed to a method of treating an
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`oncogenic or cancerous co