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
`
`
`DECLARATION OF MICHAEL J. THIRMAN, M.D.
`
`
`
`
`
`
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`Apotex Ex. 1002, p.1
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`Case No. IPR2018-00685
`Attorney Docket No.: 020623-00128
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`TABLE OF CONTENTS
`
`
`
`
`
`I.
`
`INTRODUCTION ............................................................................................... 1
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`II. EXPERIENCE AND QUALIFICATIONS ......................................................... 1
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`III. LEGAL STANDARDS USED IN MY ANALYSIS ....................................... 3
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`A. Prior Art ......................................................................................................... 3
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`B. Person of Ordinary Skill In The Art .............................................................. 3
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`C. Anticipation ................................................................................................... 4
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`D. Obviousness ................................................................................................... 5
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`IV. THE ’929 PATENT .......................................................................................... 7
`
`A. The Alleged Invention ................................................................................... 7
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`B. Challenged Claims ........................................................................................ 7
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`C. Claim Construction ........................................................................................ 9
`
`V. BACKGROUND ................................................................................................. 9
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`VI. PRIOR ART ................................................................................................... 10
`
`A. Drach (Ex. 1003) ......................................................................................... 11
`
`B. Zeldis (Ex. 1004) ......................................................................................... 12
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`C. Querfeld (Ex. 1005) ..................................................................................... 14
`
`D. Celgene Press Release (Ex. 1006) ............................................................... 15
`
`VII. OBVIOUSNESS ............................................................................................. 16
`
`A. Claims 1-4, 8-9, 15 and 20 Would Have Been Obvious Based on Drach in
`View of Zeldis ................................................................................................... 16
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`i
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`Apotex Ex. 1002, p.2
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`Case No. IPR2018-00685
`Attorney Docket No.: 020623-00128
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`a. Claim 1 Would Have Been Obvious ...................................................... 16
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`b. Claim 2 Would Have Been Obvious ...................................................... 22
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`c. Claim 3 Would Have Been Obvious ...................................................... 23
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`d. Claim 4 Would Have Been Obvious ...................................................... 24
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`e. Claim 8 Would Have Been Obvious ...................................................... 25
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`f. Claim 9 Would Have Been Obvious ....................................................... 25
`
`g. Claim 15 Would Have Been Obvious .................................................... 26
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`h. Claim 20 Would Have Been Obvious .................................................... 26
`
`B. Claims 4 and 20 Would Have Been Obvious .............................................. 27
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`C. Lack of Secondary Considerations .............................................................. 28
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`a. The Efficacy of Lenalidomide in Relapsed and/or Refractory MCL
`
`Patients Would Have Been Expected ................................................................ 28
`
`b. The Need for Treatments of Relapsed and/or Refractory MCL Is Still
`
`Unmet ................................................................................................................. 29
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`VIII. ANTICIPATION ............................................................................................ 30
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`A. Claims 1-4, 8-9, 15 And 20 Are Anticipated by the Celgene Press Release
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`30
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`a. Claim 1 Is Anticipated ............................................................................ 30
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`b. Claim 2 Is Anticipated ............................................................................ 32
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`c. Claim 3 Is Anticipated ............................................................................ 32
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`d. Claim 4 Is Anticipated ............................................................................ 33
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`e. Claim 8 Is Anticipated ............................................................................ 33
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`ii
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`Apotex Ex. 1002, p.3
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`f. Claim 9 Is Anticipated ............................................................................ 33
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`g. Claim 15 Is Anticipated .......................................................................... 34
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`h. Claim 20 Is Anticipated .......................................................................... 34
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`IX. CONCLUSION .............................................................................................. 35
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`iii
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`Apotex Ex. 1002, p.4
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`Case No. IPR2018-00685
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`LIST OF EXHIBITS CITED
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`Exhibit No.
`
`Description
`
`1001
`
`1003
`
`1004
`
`1005
`
`1006
`
`1008
`
`1010
`
`1011
`
`1012
`
`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”)
`
`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”)
`
`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, Declaration of Lei Zhang, M.D.
`Pursuant to 37 C.F.R. §1.132 (dated Dec. 18, 2013)
`
`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”)
`
`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, P.H. [sic] et al., “Preliminary Results from a Phase II
`Study of Lenalidomide Monotherapy in Relapsed/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”)
`
`iv
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`Apotex Ex. 1002, p.5
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`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`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/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”)
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`v
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`Apotex Ex. 1002, p.6
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`Case No. IPR2018-00685
`Attorney Docket No.: 020623-00128
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`I, Michael, J. Thirman, M.D., of Chicago, Illinois declare that:
`I.
`
`INTRODUCTION
`
`1.
`
`I have been retained as an expert on behalf of Apotex, Inc.
`
`(“Apotex”). I have been asked to review U.S. Patent No. 8,741,929 (“the ’929
`
`patent”) (Ex. 1001) and opine on whether Claims 1-4, 8-9, 15 and 20 of the ’929
`
`patent would have been obvious as of August 3, 2006 (its earliest possible priority
`
`date).
`
`2. My findings, as explained below, are based on my study, experience,
`
`and background in the field and review of the relevant references cited herein.
`
`3.
`
`I am being compensated for my work as an expert with respect to this
`
`inter partes review, but my compensation is not contingent in any way on the
`
`content of my opinions or the outcome of this proceeding.
`
`II.
`
`EXPERIENCE AND QUALIFICATIONS
`4.
`
`A true and correct copy of my curriculum vitae is attached to this
`
`expert report. Appendix.
`
`5.
`
`I am currently appointed as an Associate Professor and Director of
`
`Leukemia Biology of the Section of Hematology/Oncology at University of
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`Chicago.
`
`6.
`
`I earned a Bachelor of Arts degree from University of Michigan,
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`College of Literature, Science, and the Arts in 1982 and my medical degree (MD)
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`
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`1
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`Apotex Ex. 1002, p.7
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`from University of Michigan Medical School in 1986. After an internship and
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`residency at University of Minnesota Hospitals, Department of Internal Medicine, I
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`was a fellow in the Section of Clinical Pharmacology at Minneapolis VA Medical
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`Center and subsequently was a fellow in the Section of Hematology/ Oncology at
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`University of Chicago.
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`7.
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`I joined the faculty of University of Chicago Medicine in 1996. Since
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`then, I have been a member of the Committee on Cancer Biology and also a
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`member of University of Chicago Cancer Research Center.
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`8.
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`I became board-certified in medical oncology in 1993 and specialize
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`in the medical management of patients with blood cancers including lymphoma,
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`leukemia, myelodysplastic syndromes, and myeloproliferative disorders. I have
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`authored or co-authored at least 60 peer-reviewed publications, 5 book chapters in
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`hematology/oncology and have delivered at least 29 invited talks. I have served on
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`the Editorial Boards of Cancer Biology and Therapy, Leukemia and Lymphoma
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`and Blood Advances.
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`9.
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`I have extensive knowledge and experience in treatment of various
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`types of blood cancers including mantle cell lymphoma. I have treated patients
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`having lymphomas since 1991. I am also familiar with administering therapeutic
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`agents such as immunomodulatory drugs including thalidomide and its analogues.
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`2
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`Apotex Ex. 1002, p.8
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`10. Additionally, throughout my career I have been involved with
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`research and clinical trials related to blood cancers. For example, I have directed
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`clinical trials testing new drugs for chronic lymphocytic leukemia and small
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`lymphocytic lymphoma, both B-cell malignancies. In my laboratory, I am also
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`involved in pre-clinical research.
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`III.
`
`LEGAL STANDARDS USED IN MY ANALYSIS
`11.
`
`I am not a patent attorney, nor have I independently researched patent
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`law. Counsel for Petitioner has explained certain legal standards to me that I have
`
`relied upon in forming my opinions set forth in this Declaration.
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`A. Prior Art
`12.
` I have been informed that the law provides certain categories of
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`information, known as prior art, that may be used to render patent claims
`
`anticipated or obvious. The reference materials I discuss in this declaration are
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`prior art at least because they would have been available to members of the public
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`as of August 3, 2006 and are relevant to the subject matter of the ’929 patent. The
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`references I discuss herein are from the same field of endeavor as the claimed
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`invention and/or are reasonably pertinent to the problem faced by the inventor.
`
`B. Person of Ordinary Skill In The Art
`13.
`I understand that “a person of ordinary skill in the art (POSITA)” of
`
`the ’929 patent is a hypothetical person at the relevant date who is presumed to be
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`3
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`Apotex Ex. 1002, p.9
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`aware of pertinent art including knowledge in the art, thinks along conventional
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`wisdom in the art, and is a person of ordinary creativity. I understand that this
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`hypothetical person of ordinary skill in the art is considered to have the normal
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`skills and knowledge of a person in the technical field.
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`14. As of August 3, 2006, a POSITA would have been a hematologist
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`and/or oncologist (i.e. a medical doctor with hematology/oncology training) with
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`several years of experience in treating blood cancers.
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`15.
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`I have had exposure to others who met the definition of a POSITA at
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`and around the time of the alleged invention during my work as a faculty member
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`and clinician at University of Chicago.
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`C. Anticipation
`16.
`I have been informed that a claim is not patentable if a single piece of
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`prior art describes every element of the claimed invention, either expressly or
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`inherently, to a POSITA. I understand that this principle is called “anticipation.” I
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`have also been informed that, to anticipate a patent claim, the prior art reference
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`does not need to use the same words as the claim. However, it must describe the
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`requirements of the claim with sufficient clarity that a POSITA would have been
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`able to make and use the claimed invention based on that single prior art reference.
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`17.
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`In addition, I have been informed and understand that when a multiple
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`species are recited in a single claim, disclosure of one of those species by prior art
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`4
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`Apotex Ex. 1002, p.10
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`renders the claim anticipated.
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`18.
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`I also have been informed and understand that a claimed range is
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`anticipated when the prior art discloses a specific example in the claimed range.
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`D. Obviousness
`19.
`I have been informed that the following four factors are considered
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`when determining whether a patent claim would have been obvious to a POSITA:
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`(a) the level of ordinary skill in the art; (b) the scope and content of the prior art;
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`(c) the differences between the prior art and the claim; and (d) any “secondary
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`considerations” tending to prove nonobviousness. These secondary considerations,
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`which I understand are also called “objective indicia” or “objective evidence,” may
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`include factors such as: (i) the invention’s satisfaction of a long-felt unmet need in
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`the art; (ii) unexpected results of the invention; (iii) skepticism of the invention by
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`experts; (iv) teaching away from the invention in the prior art; (v) commercial suc-
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`cess of an embodiment of the invention; and (vi) praise by others for the invention.
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`I have also been informed that there must be an adequate nexus or connection be-
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`tween the evidence that is the basis for an asserted secondary consideration and the
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`scope of the invention claimed in the patent.
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`20. The question of obviousness turns on whether a hypothetical person of
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`ordinary skill in the art would have been motivated to combine prior art teachings
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`to derive the claimed subject matter with a reasonable expectation of success.
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`5
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`Apotex Ex. 1002, p.11
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`Further, I understand that obviousness does not require absolute predictability.
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`Only a reasonable expectation that the beneficial result will be achieved is
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`necessary to show obviousness.
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`21.
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`I have been informed that a claimed invention can be rendered obvi-
`
`ous by the combination of teachings in the prior art even if there is no explicit
`
`teaching to combine them. Instead, any problem known in the field at the time of
`
`the alleged invention can provide a sufficient rationale to combine the elements of
`
`the prior art in the manner claimed in the patent.
`
`22.
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`I have been informed that examples of sufficient rationales for estab-
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`lishing obviousness include the following:
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`• combining prior art elements according to known methods to yield
`
`predictable results;
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`• substituting known elements for other known elements to obtain
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`predictable results;
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`• using a known technique to improve similar devices, methods, or
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`products in the same way;
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`• choosing from a finite number of identified, predictable solutions that
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`would be obvious to try; and
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`• providing some teaching, suggestion, or motivation to modify the prior
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`6
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`Apotex Ex. 1002, p.12
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`art reference or to combine teachings in prior art references to arrive at
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`the claimed invention.
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`23.
`
`In my opinion, Claims 1-4, 8-9, 15 and 20 of the ’929 patent are
`
`anticipated by or would have been obvious over the prior art at the time of its
`
`filing.
`
`IV.
`
`THE ’929 PATENT
`A. The Alleged Invention
`24. The ’929 patent is entitled “Methods using 3-(4-amino-1-oxo-1,3-
`
`dihydro-isoindol-2-yl)-piperidine-2,6-dione for treatment of mantle cell
`
`lymphomas,” and generally claims methods of treating mantle cell lymphoma
`
`using lenalidomide in certain dosages and cycles. Ex. 1001.
`
`B. Challenged Claims
`25. Claim 1 of the ’929 patent is directed to a method of treating mantle
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`cell lymphoma in a human, which comprises (a) administering to a human having
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`mantle cell lymphoma from about 5 mg to about 25 mg per day of 3-(4-amino-1-
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`oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione or a pharmaceutically
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`acceptable salt or hydrate thereof for 21 days followed by seven days rest in a 28
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`day cycle; and (b) repeating step (a), wherein the mantle cell lymphoma is
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`relapsed, refractory, or relapsed and refractory to conventional therapy.
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`7
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`Apotex Ex. 1002, p.13
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`26. Claim 2 depends from Claim 1 and further requires that the amount of
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`3-(4-amino-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione administered is
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`about 5, 10, 15, 20 or 25 mg per day.
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`27. Claim 3 depends from Claim 2 and further requires that the amount of
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`3-(4-amino-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione administered is
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`about 10, 15, 20, or 25 mg per day.
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`28. Claim 4 depends from Claim 3 and further requires that wherein the
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`amount of 3-(4-amino-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
`
`administered is about 25 mg per day.
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`29. Claim 8 depends from Claim 2 and further requires that 3-(4-amino-
`
`oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione is administered orally.
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`30. Claim 9 depends from Claim 8 and further requires that 3-(4-amino-
`
`oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione is administered in the form of
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`a capsule or tablet.
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`31. Claim 15 depends from Claim 1 or 11 and further requires that the
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`amount of 3-(4-amino-oxo-1,3-dihydro-isoindol-2-y1)-piperidine-2,6-dione
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`administered is about 5 mg to about 25 mg per day.
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`32. Claim 20 depends from Claim 15 and further requires that the amount
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`of 3-(4-amino-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione administered is
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`about 25 mg per day.
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`8
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`Apotex Ex. 1002, p.14
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`C. Claim Construction
`33.
`I understand that “claim construction” is the interpretation of the
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`meaning of patent claims. I understand that claims in this inter partes review
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`proceeding are given their broadest reasonable construction.
`
`34.
`
`I understand that many sources can be used to assist in understanding
`
`the meaning of a claim including the claims themselves, the specification, the
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`prosecution history, and extrinsic evidence concerning scientific principles, the
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`meaning of technical terms, and the state of the art.
`
`35.
`
`I have been asked to review the claims and ascertain the meaning of
`
`the claims from the perspective of one of ordinary skill in the art. Any opinions on
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`claim construction expressed in this declaration are from the perspective of a
`
`person of ordinary skill in the art as of August 2006, and are consistent with my
`
`understanding as stated above with regards to this inter partes review.
`
`36.
`
`In my opinion, the meaning of the claims to a person of ordinary skill
`
`in the art can be ascertained by referring to the language of the claims themselves
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`and do not require any special redefinition, in other words, their ordinary meaning
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`is understood by reading the claims in view of the specifications.
`
`V.
`
`BACKGROUND
`
`9
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`Apotex Ex. 1002, p.15
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`37. Mantle cell lymphoma (MCL) is a blood cancer that affects B-cells of
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`the immune system and is classified as a B-Cell lymphoma. Ex. 1010 at 3. It is
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`also classified as a type of non-Hodgkin’s lymphoma (NHL). Ex. 1003 at 6.
`
`38.
`
`In many patients, this type of cancer can be resistant to treatment (i.e.
`
`refractory) or can be recurring (i.e. relapsed). Ex. 1014 at 1; Ex. 1015 at 2.
`
`39. Lenalidomide is a closely related, structurally similar analog of
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`thalidomide, within the same class of compounds called immunomodulatory drugs.
`
`1 Ex. 1003 at 10; Ex. 1011 at 4. Thalidomide had been known for decades prior to
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`the critical date, and lenalidomide was approved as of 2005 and known far earlier.
`
`See Ex. 1013 at 31; Ex. 1003 at 10. Their structures are presented below: 2
`
`NH2
`
`
`
`
`
` Lenalidomide (REVLIMID™)
`
` Thalidomide
`
`
`VI.
`
`PRIOR ART
`
`
`1 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.
`2 Ex. 1011 at 5, FIG. 3.
`
`10
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`
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`Apotex Ex. 1002, p.16
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`A. Drach (Ex. 1003)
`40. Drach is a review article relating to MCL treatments and was
`
`published in June 2005, prior to the ’929 patent’s filing. Ex. 1003 at 1, 3.
`
`41. Notably, Drach discloses clinical treatment of MCL with thalidomide
`
`(i.e. remissions in patients with relapsed and refractory MCL with thalidomide).
`
`Id. at 10. This was viewed as an important advance in relapsed and/or refractory
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`MCL therapy at the time. Id.
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`42. Drach teaches thalidomide and its analogues inhibit adhesion of
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`tumors cells to stromal cells (reducing adhesion-induced cytokine3 production),
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`inhibit angiogenesis by inhibiting cytokine production and have
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`immunomodulatory properties that enhance T- and natural killer cell activity. Id.
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`Drach goes on to suggest that thalidomide and its analogues (e.g. lenalidomide) are
`
`therefore important agents for the new treatment paradigm of targeting both the
`
`tumor cell and its microenvironment (pathways then thought to be involved in
`
`MCL).4 Id.
`
`
`3 Cytokines are small proteins involved in cell signaling and are essential in
`generating and regulating the immune system. Ex. 1017 at 1.
`4 Indeed, at the relevant time, “a supporting role of the microenvironment for
`proliferation and survival of malignant B-cells” was established. Ex. 1003 at 11.
`And, evidence was developing for “similar interactions in B-cell lymphomas.” Id.
`Drach taught that, based “upon these observations, agents that target not only
`11
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`Apotex Ex. 1002, p.17
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`43.
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`In the same section of the reference, Drach calls further attention to
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`lenalidomide as a potential treatment for MCL. Drach discusses that lenalidomide
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`has a more favorable toxicity profile than thalidomide and that clinical trials of
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`lenalidomide were underway for various conditions including lymphomas. Id.
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`Drach authors even disclosed their thought that such developing treatments would
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`improve upon then-existing MCL treatments. Id. at 11.
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`B. Zeldis (Ex. 1004)
`44. Zeldis was published on February 12, 2004, prior to the ’929 patent’s
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`filing. Ex. 1004 at 1.
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`45. Zeldis claims and discloses treating NHL and various B-cell
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`lymphomas in humans using lenalidomide or a pharmaceutically acceptable salt or
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`hydrate thereof. See, e.g., Ex. 1004 at Claims 1, 5 & 11, ¶¶ 0081- 0082, 0107,
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`0112, 0139, 0150, 0176, 0218.
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`46. Zeldis also discloses that various doses of lenalidomide applicable to
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`NHL. See, e.g., id. ¶¶ 0113-0114, 0173, 0186. Specifically, Zeldis discloses
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`lenalidomide may be administered from about 5 mg to 25 mg per day in a preferred
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`embodiment. Id. ¶ 0113.
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`
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`lymphoma cells but also their interactions with the microenvironment,” such as
`thalidomide, represented novel treatment approaches to MCL at the time. Id.
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`47. Zeldis further discloses dosage forms of lenalidomide. See, e.g., id. ¶¶
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`0175-0215. Specifically, Zeldis teaches that lenalidomide can be administered in
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`oral dosage forms such as capsules and tablets, which are the most advantageous
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`oral dosage forms due to ease of administration. Id. ¶¶ 0178, 0187- 0190.
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`48. Like the ’929 patent, Zeldis discloses cycling therapy of lenalidomide.
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`See, e.g., id. ¶¶ 0170-0174. Specifically, Zeldis teaches administering
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`lenalidomide for 21 days to 28 days, followed by 7 days or 14 days rest in a 28-day
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`or 42-day cycle, in a particular embodiment. Id. ¶ 0173.
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`49. Zeldis discloses non-clinical and clinical studies evaluating/
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`characterizing lenalidomide. Id. ¶¶ 0217-0260. Moreover, Zeldis discloses that
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`lenalidomide has a pharmacological activity profile that is more potent than
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`thalidomide. Id. ¶¶ 0218 - 0222.
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`50. One in vitro study relates to evaluating the inhibition of TNF-α
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`production by lenalidomide. Id. ¶ 0219. TNF-α is a cytokine then thought to have
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`a role in new blood vessel formation (angiogenesis) and immunomodulation. Ex.
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`1003 at 10, Ex. 1011 at 4. Zeldis shows that lenalidomide is 50 to 2000 more
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`potent than thalidomide for inhibition of TNF-α production. Ex. 1004 ¶ 0219.
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`51. Zeldis discloses another in vitro study showing that lenalidomide
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`inhibited multiple myeloma (MM) cell proliferation much more effectively than
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`thalidomide. Id. ¶¶ 0221-0222, FIG. 1. In my opinion, a study with MM cells is
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`relevant to MCL because both MM (Ex. 1011 at 4) and MCL (Ex. 1010 at 3) are
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`B-cell derived malignancies, and it was known at the relevant time that therapies
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`targeting the microenvironment supporting the growth of tumor cells could be
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`effective for both diseases. Ex. 1011 at 3.
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`52. Zeldis also discloses that lenalidomide is 50-100 times more potent
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`than thalidomide in stimulating the proliferation of T-cells following primary
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`induction by T-cell receptor activation (Ex. 1004 ¶ 0220), which is relevant for
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`immunomodulatory activity (a potential biochemical pathway for MCL treatment).
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`Ex. 1011 at 2.
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`53. Additionally, Zeldis discloses lenalidomide was successful in treating
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`multiple myeloma in clinical studies. Ex. 1004 ¶¶ 0238-0243. Zeldis discloses that
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`in these clinical studies patients started lenalidomide treatment at 5 mg/day with
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`subsequent escalation to 10, 25, and 50 mg/day (id. ¶ 0239) or treated for 28 days
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`at 5 mg/day or 10 mg/day (id. ¶ 0243).
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`C. Querfeld (Ex. 1005)
`54. Querfeld was published in November 2005 and is prior art against the
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`’929 patent. Ex. 1005 at 1.
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`55. Querfeld relates to preliminary results of a Phase II study of
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`lenalidomide. Ex. 1005 at 2. It specifically discloses treating cutaneous T-cell
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`lymphoma (one type of NHL) by administering orally 25 mg per day of
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`lenalidomide for 21 days with 7 days rest in a 28-day cycle. Id.
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`56. Querfeld also suggests treatment with lenalidomide for relapsed
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`disease that is refractory to standard treatment options. Id.
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`D. Celgene Press Release (Ex. 1006)
`57. Celgene Press Release was dated June 19, 2006 and is prior art against
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`the ’929 patent. Ex. 1006 at 1.
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`58. Celgene Press Release is a report by Celgene regarding a poster
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`presentation by Dr. Peter Wiernik, at the 11th Congress of the European
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`Hematology Association on June 17, 2006. Id.
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`59. Celgene Press Release relates to a Phase II clinical study evaluating
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`lenalidomide in patients with relapsed and refractory aggressive NHL. Id. It
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`specifically discloses treating by administering orally 25 mg per day of
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`lenalidomide for 21 days with 7 days rest in a 28-day cycle and continuing therapy
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`for 52 weeks as tolerated or until disease progression. Id. at 2.
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`60. Celgene Press Release disclosed that 3 patients of 16 patients
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`evaluated for response had relapsed and refractory aggressive MCL and one of
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`them “achieved partial response with progression free survival for more than 57
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`days.” Id.
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`Apotex Ex. 1002, p.21
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`61. This poster presentation was pursuant to an abstract submitted for the
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`above-mentioned conference. Ex. 1012 at 9. The abstract was published in June
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`2006. Id. at 4. This abstract lists 8 authors, including Peter H. Wiernik as the first
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`author and T. Habermann as the last author. Id. J.B. Zeldis (the sole inventor of
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`the ’929 patent), K. Takeshita and D. Pietronigro from Celgene are listed as middle
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`authors.5 Id.
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`VII.
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`OBVIOUSNESS
`62.
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`It is my opinion that all challenged claims of the ’929 patent would
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`have been obvious to a POSITA based on Drach (Ex. 1003) in view of Zeldis (Ex.
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`1004). Alternatively and independently, Claims 4 and 20 would have been
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`obvious over Drach in view of Zeldis and further in view of Querfeld (Ex. 1005).
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`As discussed below, at the relevant time, a POSITA would have been motivated to
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`use lenalidomide to treat relapsed and/or refractory MCL in the claimed dosage,
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`dosage forms and cycling regimen and would have reasonably expected success in
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`doing so.
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`A. Claims 1-4, 8-9, 15 and 20 Would Have Been Obvious Based on
`Drach in View of Zeldis
`a. Claim 1 Would Have Been Obvious
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`5 See also Goy (discussing that lenalidomide showed activity as a single agent in
`NHL, including in MCL based on European Hematology Association 2006). Ex.
`1016 at 6.
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`63. Claim 1 of the ’929 patent recites a method of treating mantle cell
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`lymphoma in a human, which comprises (a) administering to a human having
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`mantle cell lymphoma from about 5 mg to about 25 mg per day of 3-(4-amino-1-
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`oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione or a pharmaceutically
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`acceptable salt or hydrate thereof for 21 days followed by seven days rest in a 28
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`day cycle; and (b) repeating step (a), where the mantle cell lymphoma is relapsed,
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`refractory, or relapsed and refractory to conventional therapy.
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`64.
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`In my opinion, Claim 1 would have been obvious to a POSITA as of
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`August 2006 based on Drach in view of Zeldis.
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`65. As of August 2006, those in the art were looking for improved
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`treatments for relapsed and/or refractory MCL. See, e.g., Ex. 1003 at 6. Drach
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`discloses that thalidomide was being clinically used to treat relapsed and/or
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`refractory MCL. Id. at 10. Indeed, at the time, thalidomide was viewed as