`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
`Patent 8,741,929 B2
`Issued: June 3, 2014
`
`Title: METHODS USING 3-(4-AMINO-1-OXO-1,3-DIHYDRO-
`ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONE
`FOR TREATMENT OF MANTLE CELL LYMPHOMAS
`
`PETITION FOR INTER PARTES REVIEW
`
`
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`

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`IPR2018-00685 (8,741,929 B2)
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`
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`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION ............................................................................................... 1
`
`II. MANDATORY NOTICES ................................................................................. 5
`
`A. Real Parties-In-Interest ..................................................................................... 5
`
`B. Related Matters ................................................................................................. 5
`
`C. Lead and Back-Up Counsel .............................................................................. 5
`
`D. Service Information .......................................................................................... 5
`
`III. REQUIREMENTS FOR REVIEW ..................................................................... 6
`
`A. Grounds for Standing ....................................................................................... 6
`
`B. Identification of Challenge ............................................................................... 6
`
`IV. LEVEL OF ORDINARY SKILL IN THE ART ................................................. 7
`
`V. THE PRIOR ART AND THE ’929 PATENT .................................................... 7
`
`A. Background ....................................................................................................... 7
`
`B. Thalidomide Was Known to Treat Relapsed and/or Refractory MCL But Had
`Undesired Side Effects; Lenalidomide Was Less Toxic and Suggested for Such
`Treatment ................................................................................................................ 9
`
`C. Lenalidomide Was Known to Be More Potent Than Thalidomide and Was
`Successfully Used in Treating Cancers Related to MCL ....................................... 9
`
`D. Lenalidomide Dosages, Dosage Forms and Cycling Regimens Were Known
`
`11
`
`E. The Claimed Method of Treating Relapsed and/or Refractory MCL Using
`Lenalidomide Was Disclosed by Celgene Prior to Filing .................................... 12
`
`F. ’929 PATENT ................................................................................................. 13
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`IPR2018-00685 (8,741,929 B2)
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`VI. CLAIM CONSTRUCTION .............................................................................. 14
`
`VII. KEY PRIOR ART REFERENCES AND DISCLOSURE DATES ........... 14
`
`VIII. OBVIOUSNESS UNDER 35 U.S.C. § 103(a) ........................................... 16
`
`A. Ground 1: Claims 1-4, 8-9, 15 and 20 Would Have Been Obvious Based on
`Drach in View of Zeldis ........................................................................................ 16
`
`1. Claim 1 Would Have Been Obvious ........................................................... 16
`
`2. Claims 2-4, 8-9, 15 and 20 Would Have Been Obvious ............................. 23
`
`B. Ground 2: Claims 4 and 20 Would Have Been Obvious Based on Drach in
`View of Zeldis and Further in View of Querfeld ................................................. 27
`
`C. There Is No Evidence of Secondary Considerations to Rebut the Strong
`Prima Facie Evidence of Obviousness ................................................................. 28
`
`1. The Efficacy of Lenalidomide in Relapsed and/or Refractory MCL Patients
`Would Have Been Expected .............................................................................. 28
`
`2. The Need for Treatments of Relapsed and/or refractory MCL is Still
`Unmet and Not Satisfied by the ’929 Patent ..................................................... 29
`
`IX. ANTICIPATION UNDER 35 U.S.C. § 102(a) ................................................. 30
`
`A. Ground 3: Claims 1-4, 8-9, 15 and 20 Are Anticipated by the Celgene Press
`Release .................................................................................................................. 30
`
`1. Claim 1 Is Anticipated ................................................................................. 30
`
`2. Claims 2 and 3 Are Anticipated .................................................................. 32
`
`3. Claims 4 and 20 Are Anticipated ................................................................ 33
`
`4. Claim 8 Is Anticipated ................................................................................. 34
`
`5. Claim 9 Is Anticipated ................................................................................. 34
`
`6. Claim 15 Is Anticipated ............................................................................... 35
`ii
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`X. CONCLUSION.................................................................................................. 35
`
`X. CONCLUSION .................................................................................................. 35
`
`IPR2018-00685 (8,741,929 B2)
`IPR2018-00685 (8,741,929 B2)
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`IPR2018-00685 (8,741,929 B2)
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`TABLE OF AUTHORITIES
`
`CASES
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`
` Page(s)
`
`Altana Pharm. AG vs. Teva Pharm. USA Inc.,
`566 F.3d 999 (Fed. Cir. 2009)……………………………………………...20
`
`Bristol-Myers Squibb Co. v. Teva Pharm. USA Inc.,
`752 F.3d 967 (Fed. Cir. 2014)………………………………………….19, 29
`
`Brown v. 3M,
`265 F.3d 1349 (Fed. Cir. 2001)………………………………………...32, 33
`
`Hitachi Koki Co., Ltd. v. Doll,
`620 F. Supp. 2d 4 (D.D.C. 2009) aff'd sub nom. Hitachi Koki Co., Ltd. v.
`Kappos, 397 F. App'x 660 (Fed. Cir. 2010)…………………………..……29
`
`In re Aller,
`220 F.2d 454 (C.C.P.A. 1955)……………………………………………...24
`
`In re Carey,
`392 F.2d 646 (C.C.P.A. 1968)……………………………………………...19
`
`In re Cavanagh,
`436 F.2d 491 (C.C.P.A. 1971)……………………………………………...29
`
`In re Elsner,
`381 F.3d 1125 (Fed. Cir. 2004)…………………………………………….34
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007)………………………………………………………..19
`
`Ortho-McNeil Pharm., Inc. v. Kali Labs. Inc.,
`482 F. Supp. 2d 478 (D.N.J. 2007), vacated on other grounds, 344 F. App’x
`595 (Fed. Cir. 2009)………………………………………………………..21
`
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007)………………………………………….3, 28
`
`Titanium Metals Corp. v. Banner,
`
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`IPR2018-00685 (8,741,929 B2)
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`778 F.2d 775 (Fed. Cir. 1985)……………………………………………...32
`
`Trivascular, Inc. v. Samuels,
`812 F.3d 1056 (Fed. Cir. 2016)…………………………………………….14
`
`Warner Chilcott Co., LLC v. Teva Pharm. USA Inc.,
`594 F. App’x 630 (Fed. Cir. 2014)…………………………………………24
`
`
`STATUTES
`
`35 U.S.C. § 102(a)………………………………………………………….7, 15, 30
`
`35 U.S.C. § 102(b)………………………………………………………….……. 15
`
`35 U.S.C. § 103(a)……………………………………………………….…..…6, 16
`
`OTHER AUTHORITIES
`
`37 C.F.R. § 42.8(b)…………………………………………………………………5
`
`37 C.F.R. §§ 42.22(a)(1)…………………………………………………………...6
`
`37 C.F.R. § 42.100(b)……………………………………………………………..14
`
`37 C.F.R. § 42.104………………………………………………………………….6
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`37 C.F.R. § 42.104(b)………………………………………………………………6
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`IPR2018-00685 (8,741,929 B2)
`
`LIST OF EXHIBITS
`
`Exhibit No.
`
`Description
`
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`Zeldis, J.B. et al., U.S. Patent No. 8,741,929, “Methods using 3-(4-
`amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione for
`treatment of mantle cell lymphomas” (the “’929 patent”)
`
`Declaration of Michael J. Thirman, M.D.
`In Support of Petition for Inter Partes Review
`
`Drach, J. et al., “Treatment of Mantle Cell Lymphoma: Targeting
`the Microenvironment,” Expert Review of Anticancer Therapy,
`5:477-85 (2005) (“Drach”)
`
`U.S. Patent Application Publication No. 2004/0029832 (“Zeldis”)
`(published Feb. 12, 2004)
`
`Querfeld, C. et al., “Preliminary Results of a Phase II Study of CC-
`5013 (Lenalidomide, Revlimid®) in Patients with Cutaneous T-Cell
`Lymphoma,” Blood, 106:3351 (2005) (“Querfeld”)
`Celgene Press Release, Celgene Corp., Revlimid® (Lenalidomide)
`Clinical Results in Non-Hodgkins Lymphoma Presented at the 11th
`Congress of the European Hematology Association (June 19, 2006)
`(“ Celgene Press Release”)
`
`U.S. Application No. 12/621,502, Response to Office Action dated
`Sept. 19, 2013 (dated Dec. 18, 2013)
`
`U.S. Application No. 12/621,502, Declaration of Lei Zhang, M.D.
`Pursuant to 37 C.F.R. § 1.132 (dated Dec. 18, 2013)
`
`U.S. Application No. 12/621,502, Notice of Allowance and Fees
`Due (issued Jan. 22, 2014)
`
`Harris, N.L. et al., “World Health Organization Classification of
`neoplastic diseases of the hematopoietic and lymphoid tissues:
`report of the clinical advisory committee meeting,” J. Clin. Oncol.
`17:3835-49 (1999) (“Harris”)
`
`
`
`vi
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`

`

`1011
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`IPR2018-00685 (8,741,929 B2)
`
`Bartlett, J.B. et al, “The evolution of thalidomide and its ImiD
`derivatives as anticancer agents,” Nature Rev. Cancer 4:314-22
`(2004) (“Bartlett”)
`
`Wiernik, H. [sic] et al., “Preliminary Results from a Phase II Study
`of Lenalidomide Monotherapy in Relapsed and/or refractory
`Aggressive Non-Hodgkins Lymphoma [abstract],” in 11th Congress
`of the European Hematology Association, June 15-18, 2006,
`Amsterdam, the Netherlands, Abstract No. 706 (“Wiernik”)
`Revlimid® (Lenalidomide) Prescription Label published on
`December 27, 2005 (“Revlimid Label 2005”)
`
`Wiernik, P.H. et al., “Lenalidomide Monotherapy in Relapsed or
`Refractory Aggressive Non-Hodgkin’s Lymphoma,” J. Clin. Oncol.
`26: 2952-57 (2008) (“Wiernik 2008”)
`
`Dreyling, M. et al., “Treatment for patients with relapsed and/or
`refractory mantle cell lymphoma: European-based
`recommendations,” Leukemia & Lymphoma (2017) (“Dreyling”),
`DOI: 10.1080/10428194.2017.1403602
`
`Goy, A., “New Directions in the Treatment of Mantle Cell
`Lymphoma: An Overview,” Clinical Lymphoma & Myeloma, Vol.
`7, Suppl. 1, S24-S32 (2006) (“Goy”)
`
`Mark J. Cameron and David J. Kelvin, “Cytokines, Chemokines
`and Their Receptors,” Madame Curie Bioscience Database
`[Internet], Landes Bioscience (2000-2013) (“Cameron”)
`
`
`
`
`
`vii
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`IPR2018-00685 (8,741,929 B2)
`
`I.
`
`INTRODUCTION
`
`Petitioners Apotex Inc. and Apotex Corp. request inter partes review and
`
`cancellation of Claims 1-4, 8-9, 15 and 20 of U.S. Patent No. 8,741,929 (the “’929
`
`patent”), which are directed to methods of treating relapsed and/or refractory
`
`mantle cell lymphoma (“MCL”) by administering certain daily doses of 3-(4-
`
`amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (“lenalidomide”) in a
`
`cycling regimen. Ex. 1001, Claim 1.
`
`The prior art reveals that there was nothing inventive or patentable
`
`whatsoever in the claimed methods of treatment. That is because at the time of
`
`filing, four key facts were already known:
`
`1. Thalidomide was being used to treat relapsed and/or refractory MCL;
`
`2. Thalidomide had undesirable side effects such as birth defects, nerve
`
`issues, drowsiness and constipation;
`
`3. Lenalidomide, which is a structurally similar analog of thalidomide,
`
`was less toxic and more potent than thalidomide and was being
`
`proposed as a treatment for MCL; and
`
`4. Lenalidomide could be used to treat MCL in exactly the same dosages,
`
`dosage forms, and cycling regimens recited by the challenged claims.
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`1
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`IPR2018-00685 (8,741,929 B2)
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`As set forth in the Grounds below, these prior art teachings render the claims at
`
`issue anticipated and/or obvious.
`
`Ground 1: Obviousness based on Drach in View of Zeldis. Drach1 in view
`
`of Zeldis2 (“Ground 1”) renders obvious Claims 1-4, 8-9, 15 and 20. See infra
`
`Section VIII.A. Drach discloses the treatment of relapsed and/or refractory MCL
`
`by thalidomide. Drach also discloses that lenalidomide, a closely related,
`
`structurally similar analog of thalidomide, has fewer side effects and reduced
`
`toxicity. And lenalidomide was known to be more potent than thalidomide
`
`(Zeldis), with clinical trials underway for malignant diseases similar to MCL
`
`(Drach). Thus, the art suggested the use of, or substitution of thalidomide with,
`
`lenalidomide.
`
`Additionally, Zeldis provides a specific motivation to use lenalidomide to
`
`treat relapsed and/or refractory MCL in the specific dosages and treatment cycles
`
`claimed in the ’929 patent. Indeed, it teaches the same exact dosages, dosage
`
`forms and treatment cycles for lenalidomide that are recited in the ’929 patent
`
`claims. See id.
`
`
`1 Drach et al., “Treatment of Mantle Cell Lymphoma: Targeting the
`Microenvironment,” Expert Review of Anticancer Therapy, 5:477-485 (2005)
`(“Drach”).
`2 U.S. Patent Application Publication No. 2004/0029832 (“Zeldis”) (published Feb.
`12, 2004).
`
`
`
`2
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`

`

`IPR2018-00685 (8,741,929 B2)
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`Overall, a person of ordinary skill in the art (“POSITA”) would have been
`
`motivated to combine the teachings of Drach and Zeldis to arrive at Claims 1-4, 8-
`
`9, 15 and 20 of the ’929 patent with a reasonable expectation of success. Id.
`
`Ground 2: Obviousness over Drach in View of Zeldis and Querfeld.
`
`Claims 4 and 20 would have additionally been obvious over Drach in view of
`
`Zeldis and Querfeld3 (“Ground 2”). See infra Section VIII.B. Querfeld teaches
`
`treating cutaneous T-cell lymphoma (a related subtype of non-Hodgkin’s
`
`lymphoma (“NHL”), of which MCL is also a subtype) by administering
`
`lenalidomide. Notably, Querfeld teaches treatment with the exact dosages, dosage
`
`forms and cycling regimens that are recited in Claims 4 and 20. Querfeld also
`
`suggests using lenalidomide for relapsed and/or refractory lymphoma. Therefore,
`
`a POSITA would have been motivated to use lenalidomide in the recited dosages
`
`and cycling regimens for treating relapsed and/or refractory MCL, with a
`
`reasonable expectation of success in doing so. Id.
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`Secondary Considerations for Obviousness Are Unavailing. Secondary
`
`considerations, even if argued here, are insufficient to overcome such a strong
`
`prima facie case of obviousness. See, e.g., Pfizer, Inc. v. Apotex, Inc., 480 F.3d
`
`1348, 1372 (Fed. Cir. 2007) (holding that secondary considerations do “not
`
`
`3 Querfeld et al., “Preliminary Results of a Phase II Study of CC-5013
`(Lenalidomide, Revlimid®) in Patients with Cutaneous T-Cell Lymphoma,” Blood,
`106:3351 (2005) (“Querfeld”).
`
`
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`3
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`IPR2018-00685 (8,741,929 B2)
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`overcome [a] strong showing of obviousness”). For example, Patent Owner argued
`
`during prosecution that the clinical results in the alleged invention would have
`
`been unexpected and that there was an unmet need in therapeutic options for MCL
`
`patients. Ex. 1007 at 7. But the alleged unexpected properties would have been
`
`fully expected in light of the disclosures summarized above. And while a need
`
`existed for improved MCL treatments, it was not satisfied by the alleged claimed
`
`invention. See infra Section VIII.C.
`
`Ground 3: Anticipation by Celgene Press Release. Additionally, Claims 1-
`
`4, 8-9, 15 and 20 are anticipated by Celgene Press Release4 (“Ground 3”). See
`
`infra Section IX.A. The Celgene Press Release discloses lenalidomide clinical trial
`
`results relating to relapsed and/or refractory MCL that Celgene presented at a
`
`poster presentation (Ex. 1012) prior to the critical date. Specifically, it was
`
`disclosed that relapsed and/or refractory MCL patients were being treated by
`
`lenalidomide, within the claimed dosages, dosage forms and cycling regimens. Id.
`
`*
`
`*
`
`*
`
`At bottom, the Board should cancel Claims 1-4, 8-9, 15 and 20 of the ’929
`
`patent due to anticipation and/or obviousness.
`
`
`4 Celgene Press Release, Celgene Corp., Revlimid® (Lenalidomide) Clinical
`Results in Non-Hodgkin’s Lymphoma Presented at the 11th Congress of the
`European Hematology Association (June 19, 2006) (“Celgene Press Release”).
`4
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`IPR2018-00685 (8,741,929 B2)
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`II. MANDATORY NOTICES
`
`Pursuant to 37 C.F.R. § 42.8(b), Petitioners state as follows:
`
`A. Real Parties-In-Interest
`
`Petitioners Apotex Inc. and Apotex Corp. are the real parties-in-interest.
`
`Additional real parties-in-interest are Apotex Pharmaceuticals Holdings Inc., and
`
`Apotex Holdings Inc.
`
`B. Related Matters
`
`The ’929 patent is asserted in one litigation: Celgene Corp. v. Apotex Inc.,
`
`C.A. No. 18-cv-00461 (D.N.J filed Jan. 11, 2018).
`
`C. Lead and Back-Up Counsel
`
`Petitioners identify the following:
`
` Lead counsel:
`
`John J. Molenda (Reg. No. 47,804)
`
` Back-up counsel: Vishal Gupta (Reg. No. 67,284)
`
` Back-up counsel: Won Seon Choi (Reg. No. 73,012)
`
`D.
`
`Service Information
`
`Petitioners identify the following:
`
` Email address:
`
` Mailing address:
`
`
`
`
`
`lenalidomide@steptoe.com
`
`STEPTOE & JOHNSON LLP
`
`1114 Avenue of the Americas
`
`New York, NY 10036
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`IPR2018-00685 (8,741,929 B2)
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` Telephone number:
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`212-506-3900
`
` Fax number:
`
`
`
`212-506-3950
`
`Please address all correspondence to lead counsel at the address shown
`
`above. Petitioners consent to electronic service at the above-listed email address.
`
`III. REQUIREMENTS FOR REVIEW
`
`Pursuant to 37 C.F.R. § 42.104, Petitioners state as follows:
`
`A. Grounds for Standing
`
`Petitioners certify that (1) the ’929 patent is available for inter partes review
`
`and (2) Petitioners are not barred or estopped from requesting review of any claim
`
`on the grounds identified in this Petition. The Office is authorized to charge all
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`fees due in connection with this mater to Deposit Account No. 19-4293.
`
`B.
`
`Identification of Challenge
`
`Pursuant to 37 C.F.R. §§ 42.104(b) and 42.22(a)(1), Petitioners request
`
`review and cancellation of Claims 1-4, 8-9, 15 and 20 of the ʼ929 patent pursuant
`
`to the following statement of precise relief requested:
`
`Ground
`
`Claims
`
`Basis
`
`Reference
`
`1
`
`2
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`1-4, 8-9, 15 and 20
`
`§ 103(a)
`
`Drach in view of Zeldis
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`4, 20
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`§ 103(a) Drach in view of Zeldis and
`Querfeld
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`IPR2018-00685 (8,741,929 B2)
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`3
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`1-4, 8-9, 15 and 20
`
`§ 102(a)
`
`Celgene Press Release
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`IV. LEVEL OF ORDINARY SKILL IN THE ART
`
`Petitioners and declarant Dr. Thirman use August 3, 2006, the filing date of
`
`a prior provisional application, as the relevant date for analyzing the level of skill
`
`and knowledge of a hypothetical person of ordinary skill in the art. Ex. 1002 ¶ 12.
`
`A POSITA would have been a hematologist and/or oncologist, i.e., a medical
`
`doctor with hematology and/or oncology training, with several years of experience
`
`in treating blood cancers. Ex. 1002 ¶ 14.
`
`V. THE PRIOR ART AND THE ’929 PATENT
`A. Background
`
`The ’929 patent claims at issue relate to treating refractory and/or relapsed
`
`MCL by administering lenalidomide in certain doses and cycles of repeating
`
`therapy. See, e.g., Ex. 1001, Claim 1. MCL is a blood cancer that affects the B-
`
`cells of the immune system and is thus classified as a B-Cell lymphoma. Ex. 1002
`
`¶ 37; Ex. 1010 at 3. In many patients, this type of cancer can be resistant to
`
`treatment (i.e. refractory) or can be recurring (i.e. relapsed). Ex. 1002 ¶ 38; Ex.
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`1014 at 1; Ex. 1015, 2.
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`IPR2018-00685 (8,741,929 B2)
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`Lenalidomide is a closely related, structurally similar analog of thalidomide,
`
`within the same class of compounds called immunomodulatory drugs.5 Ex. 1002 ¶
`
`39; Ex. 1011 at 4. Thalidomide had been known for decades prior to the critical
`
`date, and lenalidomide was approved as of 2005 and known far earlier. Ex. 1002 ¶
`
`39; Ex. 1013 at 31; Ex. 1003 at 10. Their structures are presented below: 6
`
`NH2
`
`
`
`
`
` Lenalidomide (REVLIMID™)
`
` Thalidomide
`
`The relevant activity of thalidomide and lenalidomide was attributed to
`
`inhibiting cytokines, which are small proteins involved in cell signaling, or
`
`immunomodulation, i.e., regulating the immune system,7 both of which were
`
`thought to be relevant pathways to address for treating MCL. Ex. 1002 ¶ 42; see
`
`Ex. 1003 at 10.
`
`
`5 Immunomodulatory drugs were synthesized using thalidomide structural
`backbone as a template by chemists to design compounds with increased
`immunological and anticancer properties, but lacking the toxicity associated with
`the parent compound. Ex. 1011 at 4.
`6 Ex. 1011 at 5, FIG. 3.
`7 Ex. 1017 at 1.
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`IPR2018-00685 (8,741,929 B2)
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`B.
`
`Thalidomide Was Known to Treat Relapsed and/or Refractory
`MCL But Had Undesired Side Effects; Lenalidomide Was Less
`Toxic and Suggested for Such Treatment
`
`
`Drach teaches that thalidomide was being used clinically to treat relapsed
`
`and/or refractory MCL. Ex. 1002 ¶ 41; Ex. 1003 at 10. This was viewed as an
`
`important advance in relapsed and/or refractory MCL therapy at the time. Ex.
`
`1002 at ¶ 41. But thalidomide had associated undesired side effects such as birth
`
`defects, nerve issues, drowsiness and constipation. Ex. 1002 at ¶ 65; Ex. 1003 at
`
`10; Ex. 1011 at 8.
`
`Analogs such as lenalidomide were generated to exploit thalidomide’s anti-
`
`cancer activity but reduce its side effects. Ex. 1002 at ¶ 66; Ex. 1003 at 10.
`
`Indeed, Drach teaches that lenalidomide has a far more favorable toxicity profile
`
`than thalidomide and therefore reduces side effects. Id. at 10; Ex. 1011 at 8.
`
`Drach further suggests that lenalidomide should be an important new potential
`
`agent for treating MCL. Id.; see also Ex. 1002 ¶¶ 42-43.
`
`C. Lenalidomide Was Known to Be More Potent Than Thalidomide
`and Was Successfully Used in Treating Cancers Related to MCL
`
`
`Zeldis teaches that lenalidomide has a higher potency than thalidomide in
`
`properties relevant to MCL treatment. In pharmacological studies, lenalidomide
`
`was 50 to 2000 times more potent than thalidomide in inhibiting production of
`
`TNF-α, a cytokine thought to be involved with cancer progression. Ex. 1002 ¶ 50;
`
`
`
`9
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`IPR2018-00685 (8,741,929 B2)
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`Ex. 1004 ¶ 0220. This is relevant and informative for several reasons. First, it was
`
`well established that increases in TNF-α in cancer patients were often associated
`
`with advanced disease. Ex. 1002 ¶ 72; Ex. 1011 at 3. Second, inhibition of TNF-α
`
`was also thought to inhibit angiogenesis, i.e., new blood vessel formation often
`
`associated with cancers. Ex. 1002 ¶ 73; Ex. 1003 at 10. Additionally, inhibition of
`
`TNF-α was associated with immunomodulatory effects thought to be beneficial for
`
`MCL treatment. Ex. 1002 ¶ 74; Ex. 1003 at 10.
`
`Moreover, Zeldis teaches that lenalidomide was more potent than
`
`thalidomide in inhibition of multiple myeloma (“MM”) cell proliferation. Ex.
`
`1002 ¶ 51; Ex. 1004 ¶¶ 0221- 0222, FIG. 1. This is relevant because MM and
`
`MCL were known to be related B-cell cancers (malignancies) that involved at least
`
`one common pathway. Ex. 1002 ¶ 51; Ex. 1003 at 11; Ex. 1010 at 3; Ex. 1011 at
`
`4.
`
`Zeldis also discloses that lenalidomide is 50-100 times more potent than
`
`thalidomide in stimulating the proliferation of T-cells following primary induction
`
`by T-cell receptor activation (Ex. 1004 ¶ 0220), which is relevant for
`
`immunomodulatory activity (a potential biochemical pathway for MCL treatment).
`
`Ex. 1011 at 2; see also Ex. 1002 ¶ 52.
`
`Additionally, lenalidomide was successful in treating multiple myeloma in
`
`clinical studies. Ex. 1002 ¶ 53; see e.g. Ex. 1003 at 10; Ex. 1004 ¶¶ 0238-0243.
`
`
`
`10
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`IPR2018-00685 (8,741,929 B2)
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`And, as Drach discloses, before the priority date of the ’929 patent, various public
`
`clinical trials were in progress for lenalidomide, including those related to
`
`lymphomas. Ex. 1003 at 10.
`
`D. Lenalidomide Dosages, Dosage Forms and Cycling Regimens
`Were Known
`
`
`
`Zeldis discloses methods of treating B-cell lymphomas and NHLs (both of
`
`which MCL is a subtype of) in humans by administering lenalidomide in dosages,
`
`dosage forms and treatment cycles recited in the challenged claims. Ex. 1002 ¶¶
`
`45-48; see, e.g., Ex. 1004, Claims 1-6 & 11, ¶¶ 0081-0082, 0106-0107, 0112,
`
`0139, 0150, 0170-0176, 0187-0188, 0218; Ex. 1010 at 3.
`
`For example, Zeldis discloses that lenalidomide can be administered from
`
`about 5 to 25 mg per day in a preferred embodiment. Ex. 1002 ¶ 46; Ex. 1004 ¶
`
`0113. Zeldis also discloses that lenalidomide can be administered for 21 to 28
`
`days, followed by seven to 14 days of rest in a 28 or 42 day cycle, with repeating
`
`cycles. Ex. 1002 ¶ 48; Ex. 1004 ¶ 0173. Querfeld additionally teaches treating a
`
`subtype of NHL by administering 25 mg of lenalidomide per day for 21 days with
`
`7 days rest in a 28-day cycle. Ex. 1002 ¶ 55; Ex. 1005 at 2.
`
`And it was known that a drug such as lenalidomide could be administered
`
`orally in tablet or capsule form. Ex. 1002 ¶ 47; see, e.g., Ex. 1004 ¶¶ 0178, 0188.
`
`
`
`11
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`IPR2018-00685 (8,741,929 B2)
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`E.
`
`The Claimed Method of Treating Relapsed and/or Refractory
`MCL Using Lenalidomide Was Disclosed by Celgene Prior to
`Filing
`
`
`
`A Celgene Press Release dated June 19, 2006 summarized a poster
`
`presentation by Dr. Peter Wiernik, at the 11th Congress of the European
`
`Hematology Association on June 17, 2006.8 Ex. 1002 ¶ 57; Ex. 1006 at 1. The
`
`Celgene Press Release discloses initial clinical trial results related to evaluating
`
`lenalidomide in patients with relapsed and refractory NHL.9, Ex. 1002 ¶ 59; Ex.
`
`1006 at 1, 2. It specifically discloses treating MCL by orally administering 25 mg
`
`of lenalidomide per day for 21 days with 7 days rest in a 28-day cycle. Ex. 1002 ¶
`
`59; Ex. 1006 at 2. Moreover, the Celgene Press Release discloses that, of the 16
`
`patients evaluable for response, 3 had relapsed and/or refractory aggressive MCL
`
`and one of them “achieved partial response with progression free survival for more
`
`than 57 days.” Ex. 1002 ¶ 60; Ex. 1006 at 2. It also discloses repeating therapy,
`
`i.e. a 28-day cycle therapy was continued for 52 weeks as tolerated or until disease
`
`progression. Ex. 1002 ¶ 59; Ex. 1006 at 2. Id. Thus, the claimed subject matter
`
`
`8 The abstract submitted for the presentation lists 7 total authors including: P.
`Wiernik (first author), J.B. Zeldis (the sole inventor of the ’929 patent) and T.
`Habermann (last author). Ex. 1012 (Wiernik).
`9 Those results were initially presented by Dr. Peter Wiernik in a poster at the 11th
`Congress of the European Hematology Association on June 17, 2006. Ex. 1006 at
`1.
`
`
`
`12
`
`

`

`was disclosed before the priority date of the ’929 patent. See also Ex. 1002 ¶¶ 57-
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`IPR2018-00685 (8,741,929 B2)
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`61.
`
`F.
`
`’929 PATENT
`
`Despite the foregoing prior art disclosures, Celgene nonetheless sought
`
`patent protection for a method of treating MCL using lenalidomide. The ’929
`
`patent, which issued on June 3, 2014, claims its earliest priority date from U.S.
`
`Provisional Patent Application No. 60/835,752, filed on August 3, 2006 (“Priority
`
`Date”). According to the Orange Book, which lists 26 other patents related to
`
`lenalidomide, the ’929 patent expires on March 8, 2028.10
`
`Claim 1 of the ’929 patent is the only independent claim at issue in this
`
`Petition and recites as follows:
`
`A method of treating mantle cell lymphoma [MCL] in a human,
`which comprises (a) administering to a human having [MCL]
`from about 5 mg to about 25 mg per day of [lenalidomide] or a
`pharmaceutically acceptable salt or hydrate thereof for 21 days
`followed by seven days rest in a 28 day cycle; and (b) repeating
`step (a), wherein the [MCL] is relapsed, refractory, or relapsed
`and refractory to conventional therapy.
`
`Ex. 1001, col. 23, ln. 62 – col. 24, ln. 4.
`
`
`10 Orange Book: Approved Drug Products with Therapeutic Equivalence
`Evaluations, available at
`https://www.accessdata.fda.gov/scripts/cder/ob/patent_info.cfm?Product_No=005
`&Appl_No=021880&Appl_type=N (last accessed Jan. 25, 2018).
`
`
`
`
`13
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`

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`IPR2018-00685 (8,741,929 B2)
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`Claims 2, 3, 4, 8, 9, 15 and 20 depend directly or indirectly from Claim 1.
`
`Claims 2, 3, 4 and 20 require that specific doses of lenalidomide be administered.
`
`Claim 8 requires that the lenalidomide be administered orally. Id. col. 24, ll. 24-
`
`26. Claim 9 requires that the lenalidomide be administered in the form of a
`
`capsule or tablet. Id. col. 24, ll. 27-29. Claim 15 depends from Claims 1 and 11
`
`(not challenged in the petition) and recites the same limitations as Claim 1. Id. col.
`
`24, ln. 53-55.
`
`VI. CLAIM CONSTRUCTION
`
`An unexpired claim subject to inter partes review receives the “broadest
`
`reasonable construction in light of the specification of the patent.” 37 C.F.R.
`
`§ 42.100(b). The words of the claims at issue here should be given their plain
`
`meanings, because such a construction would be consistent with the specification
`
`and prosecution history. Trivascular, Inc. v. Samuels, 812 F.3d 1056, 1062 (Fed.
`
`Cir. 2016).
`
`VII. KEY PRIOR ART REFERENCES AND DISCLOSURE DATES
`
`The ’929 patent did not advance in any way what was already known in the
`
`prior art, and various combinations of four prior art references render the subject
`
`matter recited in the challenged claims anticipated and/or obvious.
`
`
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`IPR2018-00685 (8,741,929 B2)
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`Drach, attached as Ex. 1003, was published in June 2005, more than one
`
`year before the Priority Date, and is prior art under 35 U.S.C. § 102(b)11. Drach
`
`was not considered by the examiner during prosecution of the ’929 patent. Ex.
`
`1003.
`
`Zeldis was published on February 12, 2004, more than one year before the
`
`Priority Date, and is prior art under 35 U.S.C. § 102(b).12 Ex. 1004.
`
`Querfeld was published on November 16, 2005, before the Priority Date,
`
`and is prior art under 35 U.S.C. § 102(a). Like Drach, Querfeld was not
`
`considered by the examiner during prosecution of the ’929 patent. Ex. 1005.
`
`Celgene Press Release published on June 19, 2006, before the Priority Date,
`
`and is prior art under 35 U.S.C. § 102(a). The clinical study disclosed in the
`
`Celgene Press Release has numerous investigators listed as authors in the study
`
`(see Ex. 1012) other than the sole inventor of the ’929 patent. Ex. 1012 at 10. The
`
`Celgene Press Release was not considered by the examiner during prosecution of
`
`the ’929 patent. Ex. 1006.
`
`
`
`
`11 References to Title 35 herein are pre-AIA.
`12 The inventor listed on the Zeldis publication, Jerome Zeldis, is also the sole
`inventor of the ’929 patent.
`
`
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`IPR2018-00685 (8,741,929 B2)
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`VIII. OBVIOUSNESS UNDER 35 U.S.C. § 103(a)
`
`A. Ground 1: Claims 1-4, 8-9, 15 and 20 Would Have Been Obvious
`Based on Drach in View of Zeldis
`1.
`Claim 1 Would Have Been Obvious
`
`Claim 1 of the ’929 patent recites a method of treating MCL in a human,
`
`which comprises (a) daily administration of about 5 mg to about 25 mg of
`
`lenalidomide, or a pharmaceutically acceptable salt or hydrate thereof, for 21 days
`
`followed by seven days rest in a 28 day cycle; and (b) repeating step (a), where the
`
`MCL is relapsed, refractory, or relapsed and refractory to conventional therapy.
`
`With respect to claim limitations for treating refractory and/or relapsed MCL
`
`with lenalidomide, Drach and/or Zeldis disclose(s):
`
`• thalidomide’s use in treatment of relapsed and refractory MCL for human
`
`patients (Ex. 1003 at 10) (describing “remissions in three patients with
`
`relapsed and chemotherapy-refractory MCL”);
`
`• an explicit suggestion for using lenalidomide in MCL treatment (Ex. 1003 at
`
`10) (“Thalidomide and its analogs (e.g. lenalidomide) are therefore
`
`important agents for the new treatment paradigm” of treating MCL);
`
`• lenalidomide’s use in treating relapsed and/or refractory cancers related to
`
`MCL (Ex. 1003 at 10; Ex. 1004 ¶¶ 0238-0243) (describing clinical studies
`
`using lenalidomide for MM and lymphomas); and
`
`
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`IPR2018-00685 (8,741,929 B2)
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`• lenalidomide as one of the “most preferred” immunomodulatory compounds
`
`for treating cancers that are refractory or resistant to conventional
`
`chemotherapy. Ex. 1004 ¶¶ 0081-0082; see also ¶¶ 0017, 0034.
`
`With