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
`
`___________
`
`
`DECLARATION OF DR. GUIDO TRICOT IN SUPPORT OF
`PETITION FOR INTER PARTES REVIEW OF CLAIMS 1-15
`OF U.S. PATENT NO. 7,968,569
`
`
`
`
`
`
`
`
`
`
`
`ALVOGEN, Ex. 1003, p. 0001
`
`

`

`Declaration of Dr. Guido Tricot in Support of
`Petition for IPR of U.S. Patent No. 7,968,569
`
`TABLE OF CONTENTS
`
`
`
`
`
`I.
`
`BACKGROUND AND QUALIFICATIONS .............................................. 1
`
`II.
`
`LEGAL UNDERSTANDING ....................................................................... 3
`
`A. Obviousness .......................................................................................... 3
`
`B.
`
`Claim Construction ............................................................................. 7
`
`III. THE RELEVANT ART ................................................................................ 9
`
`IV. OVERVIEW OF THE ʼ569 PATENT ....................................................... 14
`
`A.
`
`B.
`
`The Claims of the ʼ569 Patent .......................................................... 14
`
`The Effective Filing Date of the ’569 Patent Can Be No Earlier
`Than November 6, 2002 .................................................................... 16
`
`V. CLAIM CONSTRUCTION ........................................................................ 20
`
`VI. LEVEL OF ORDINARY SKILL IN THE ART ...................................... 20
`
`VII. SUMMARY OF THE PRIOR ART .......................................................... 21
`
`A.
`
`Thalidomide and Thalidomide Analogs (IMiDs) ........................... 21
`
`B. Multiple Myeloma and Thalidomide ............................................... 29
`
`C. Multiple Myeloma and IMiDs .......................................................... 33
`
`D. A POSA Would Understand that “Revimid” is Lenalidomide ..... 39
`
`E.
`
`F.
`
`Drug Cycling in Cancer Treatments ............................................... 41
`
`A POSA Exercising Reasonable Diligence Would Have Located
`the Relevant Art ................................................................................. 45
`
`VIII. THERE IS A REASONABLE LIKELIHOOD THAT THE
`CHALLENGED CLAIMS ARE UNPATENTABLE .............................. 46
`
`
`
`i
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`ALVOGEN, Ex. 1003, p. 0002
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`

`

`Declaration of Dr. Guido Tricot in Support of
`Petition for IPR of U.S. Patent No. 7,968,569
`
`
`
`A. Ground 1: The Combination of Palumbo, the May Press Release,
`and the August Press Release Renders Claims 1-15 Obvious ....... 46
`
`B. Ground 2: Palumbo, Hideshima, and the ʼ230 Patent ................... 58
`
`C.
`
`Secondary Considerations ................................................................ 75
`
`IX. CONCLUSION ............................................................................................ 80
`
`
`
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`
`
`
`
`
`
`ii
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`ALVOGEN, Ex. 1003, p. 0003
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`

`

`Declaration of Dr. Guido Tricot in Support of
`Petition for IPR of U.S. Patent No. 7,968,569
`
`
`Declaration of Guido Tricot
`
`I, Guido Tricot, declare as follows:
`
`
`1.
`
`I make this declaration based on my own personal knowledge and, if
`
`called upon to testify, would testify competently to the matters contained herein.
`
`2.
`
`I have been asked to provide technical assistance in the inter partes
`
`review of U.S. Patent No. 7,968,569 (“the ’569 Patent”).
`
`3.
`
`This declaration is a statement of my opinions on issues related to the
`
`unpatentability of claims 1-15 of the ’569 Patent.
`
`I. BACKGROUND AND QUALIFICATIONS
`
`4.
`
`In forming my opinions, I have relied upon my knowledge, training,
`
`and experience in the relevant art.
`
`5.
`
`I am currently a Professor Emeritus at the University of Iowa
`
`Hospitals and Clinics. Until July 2017, I was the Gary D. Arthur Professor of Adult
`
`Bone Marrow Transplantation, Department of Internal Medicine, Division of
`
`Hematology, Oncology, and Blood & Marrow Transplantation at the University of
`
`Iowa Hospitals and Clinics. In my practice, I treated patients with hematological
`
`conditions, in particular, those with multiple myeloma (>85%). As part of
`
`treatment, I administered therapeutic agents to my patients. I also perform research
`
`to help develop treatments for patients with these conditions, including the
`
`development of drug regimens and dosing schedules.
`
`
`
`1
`
`ALVOGEN, Ex. 1003, p. 0004
`
`

`

`Declaration of Dr. Guido Tricot in Support of
`Petition for IPR of U.S. Patent No. 7,968,569
`
`
`
`6.
`
`I completed my MD from the University of Leuven in Belgium in
`
`1975, and a Ph.D. in 1983 from the same university during which I studied the
`
`biology of myelodysplastic syndromes. I was hired to the faculty or the University
`
`of Leuven in 1980 and since that time have held faculty positions at Indiana
`
`University, the University of Arkansas for Medical Sciences, the University of
`
`Utah School of Medicine, and the University of Iowa Hospitals and Clinics.
`
`7.
`
`I have been an author on over 300 peer reviewed publications related
`
`to the treatment of multiple myeloma and other hematological conditions, as well
`
`as an author of over 250 abstracts, book chapters, and other non-peer reviewed
`
`publications. I serve on the editorial boards of Bone Marrow Research, Leukemia,
`
`the Journal of Blood and Lymph, the Journal of Cancer Therapy, and the Journal
`
`of Hematology and Thrombosis. I also review manuscripts for several additional
`
`journals, including the American Journal of Hematology, Blood, the British
`
`Journal of Haematology, Cancer Cell, the Journal of Clinical Oncology, Lancet,
`
`the New England Journal of Medicine, and the Proceedings of the National
`
`Academy of Sciences.
`
`8. My qualifications and experience are stated more fully in my
`
`curriculum vitae attached as Ex. A.
`
`9.
`
`I am being compensated by Alvogen at the rate of $500 per hour for
`
`my work in this matter, including time spent testifying. This rate is my standard
`
`
`
`2
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`ALVOGEN, Ex. 1003, p. 0005
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`

`

`Declaration of Dr. Guido Tricot in Support of
`Petition for IPR of U.S. Patent No. 7,968,569
`
`
`hourly rate for engagements of this nature. I am also being reimbursed for
`
`reasonable fees and expenses, including hotel and travel expenses, incurred as a
`
`result of my work in this matter. My compensation does not depend on the
`
`outcome of the proceedings, and the fact that I am being compensated has not
`
`altered the opinions that I have or will give in this matter.
`
`II. LEGAL UNDERSTANDING
`
`10. My opinions are informed by my understanding of the relevant law. I
`
`understand that the patentability analysis is conducted on a claim-by-claim and
`
`element-by-element basis, and that there are several possible reasons that a patent
`
`claim may be found to be unpatentable.
`
`A. Obviousness
`
`11.
`
`I understand that the prior art may render a patent claim “obvious.” I
`
`understand that two or more prior art references (e.g., prior art articles, patents, or
`
`publications) that each discloses fewer than all elements of a patent claim may
`
`nevertheless be combined to render a patent claim obvious if the combination of
`
`the prior art collectively discloses all elements of the claim and one of ordinary
`
`skill in the art at the time would have been motivated to combine the prior art in
`
`such a way. I understand that this motivation to combine need not be explicit in
`
`any of the prior art, but may be inferred from the knowledge of one of ordinary
`
`skill in the art at the time the patent was filed. I also understand that one of
`
`
`
`3
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`ALVOGEN, Ex. 1003, p. 0006
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`

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`Declaration of Dr. Guido Tricot in Support of
`Petition for IPR of U.S. Patent No. 7,968,569
`
`
`ordinary skill in the art is not an automaton, but is a person having ordinary
`
`creativity. I further understand that one or more prior art references, articles,
`
`patents or publications that disclose fewer than all of the elements of a patent claim
`
`may render a patent claim obvious if including the missing element would have
`
`been obvious to one of skill in the art (e.g., the missing element represents only an
`
`insubstantial difference over the prior art or a reconfiguration of a known system).
`
`12. Under the doctrine of obviousness, I understand that a claim may be
`
`invalid if the differences between the invention and the prior art are such that the
`
`subject matter as a whole would have been obvious at the time the invention was
`
`made to a person having ordinary skill in the art to which the subject matter
`
`pertains.
`
`13.
`
`I understand that obviousness is based on the scope and content of the
`
`prior art, the differences between the prior art and the claim, the level of ordinary
`
`skill in the art, and “secondary indicia” of non-obviousness to the extent they exist.
`
`14.
`
`I understand that any evidence of secondary indicia of non-
`
`obviousness should be considered when evaluating whether a claimed invention
`
`would have been obvious to one of ordinary skill at the time of invention. These
`
`secondary indicia of non-obviousness may include, for example:
`
` a long felt but unmet need in the prior art that was satisfied by the
`
`claimed invention;
`
`
`
`4
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`ALVOGEN, Ex. 1003, p. 0007
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`

`

`Declaration of Dr. Guido Tricot in Support of
`Petition for IPR of U.S. Patent No. 7,968,569
`
`
`
` commercial success of processes claimed by the patent;
`
` unexpected results achieved by the invention;
`
` praise of the invention by others skilled in the art;
`
` the taking of licenses under the patent by others; and
`
` deliberate copying of the invention.
`
`15.
`
`I understand that there must be a relationship between any such
`
`secondary indicia and the claimed invention.
`
`16.
`
`It is also my understanding that there are additional considerations
`
`that may be used as further guidance as to when the above factors will result in a
`
`finding that a claim is obvious, including the following:
`
` the claimed invention is simply a combination of prior art elements
`
`according to known methods to yield predictable results;
`
` the claimed invention is a simple substitution of one known element
`
`for another to obtain predictable results;
`
` the claimed invention uses known techniques to improve similar
`
`devices or methods in the same way;
`
` the claimed invention applies a known technique to a known device or
`
`method that is ready for improvement to yield predictable results;
`
`
`
`5
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`ALVOGEN, Ex. 1003, p. 0008
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`

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`Declaration of Dr. Guido Tricot in Support of
`Petition for IPR of U.S. Patent No. 7,968,569
`
`
`
` the claimed invention would have been “obvious to try” choosing
`
`from a finite number of identified, predictable solutions, with a
`
`reasonable expectation of success;
`
` there is known work in one field of endeavor that may prompt
`
`variations of it for use in either the same field or a different one based
`
`on design incentives or other market forces if the variations would
`
`have been predictable to one of ordinary skill in the art;
`
` there existed at the time of invention a known problem for which there
`
`was an obvious solution encompassed by the patent’s claims; and
`
` there is some teaching, suggestion, or motivation in the prior art that
`
`would have led one of ordinary skill to modify the prior art reference
`
`or to combine prior art reference teachings to arrive at the claimed
`
`invention.
`
`17. Finally, I understand that a claim may be deemed invalid for
`
`obviousness in light of a single prior art reference, without the need to combine
`
`references, if the elements of the claim that are not found in the reference can be
`
`supplied by the knowledge or common sense of one of ordinary skill in the
`
`relevant art.
`
`
`
`6
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`ALVOGEN, Ex. 1003, p. 0009
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`

`

`Declaration of Dr. Guido Tricot in Support of
`Petition for IPR of U.S. Patent No. 7,968,569
`
`
`
`B. Claim Construction
`
`18.
`
`I have been instructed by counsel on the law regarding claim
`
`construction and patent claims, and understand that a patent may include two types
`
`of claims, independent claims and dependent claims. An independent claim stands
`
`alone and includes only the limitations it recites. A dependent claim can depend
`
`from an independent claim or another dependent claim. I understand that a
`
`dependent claim includes all the limitations that it recites in addition to all of the
`
`limitations recited in the claim from which it depends.
`
`19.
`
`It is my understanding that in proceedings before the USPTO the
`
`claims of an unexpired patent are to be given their broadest reasonable
`
`interpretation in light of the specification from the perspective of one of skill in the
`
`art. It is my further understanding that claim terms of an expired patent are given
`
`the meaning the term would have to a person of ordinary skill in the art at the time
`
`of the invention, in view of the specification and file history. I understand that the
`
`standard used for expired patents is similar to that used in district court litigation,
`
`and that this standard is sometimes referred to as the Phillips standard.
`
`20.
`
`It is my understanding that the broadest reasonable interpretation of a
`
`claim term may be the same as or broader than the construction of a term under the
`
`Phillips standard, but it cannot be narrower.
`
`
`
`7
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`ALVOGEN, Ex. 1003, p. 0010
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`

`

`Declaration of Dr. Guido Tricot in Support of
`Petition for IPR of U.S. Patent No. 7,968,569
`
`
`
`21.
`
`I understand that to determine how a person of ordinary skill would
`
`understand a claim term, one should look to those sources available that show what
`
`one of skill in the art would have understood disputed claim language to mean.
`
`Such sources include the words of the claims themselves, the remainder of the
`
`patent’s specification, the prosecution history of the patent (all considered
`
`“intrinsic” evidence), and “extrinsic” evidence concerning relevant scientific
`
`principles, the meaning of technical terms, and the state of the art.
`
`22.
`
`I understand that, in construing a claim term, one looks primarily to
`
`the intrinsic patent evidence, including the words of the claims themselves, the
`
`remainder of the patent specification, and the prosecution history.
`
`23.
`
`I understand that extrinsic evidence, which is evidence external to the
`
`patent and the prosecution history, may also be useful in interpreting patent claims
`
`when the intrinsic evidence itself is insufficient.
`
`24.
`
`I understand that words or terms should be given their ordinary and
`
`accepted meaning unless it appears that the inventors were using them to mean
`
`something else. In making this determination, the claims, the patent specification,
`
`and the prosecution history are of paramount importance. Additionally, the
`
`specification and prosecution history must be consulted to confirm whether the
`
`patentee has acted as its own lexicographer (i.e., provided its own special meaning
`
`
`
`8
`
`ALVOGEN, Ex. 1003, p. 0011
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`

`

`Declaration of Dr. Guido Tricot in Support of
`Petition for IPR of U.S. Patent No. 7,968,569
`
`
`to any disputed terms), or intentionally disclaimed, disavowed, or surrendered any
`
`claim scope.
`
`25.
`
`I understand that in general, a term or phrase found in the introductory
`
`words of the claim, the preamble of the claim, should be construed as a limitation
`
`if it recites essential structure or steps, or is necessary to give life, meaning, and
`
`vitality to the claim. Conversely, a preamble term or phrase is not limiting where a
`
`patentee defines a structurally complete invention in the claim body and uses the
`
`preamble only to state a purpose or intended use for the invention. In making this
`
`distinction, one should review the entire patent to gain an understanding of what
`
`the inventors claim they actually invented and intended to encompass by the
`
`claims.
`
`26.
`
`I understand that language in the preamble limits claim scope (i) if
`
`dependence on a preamble phrase for antecedent basis indicates a reliance on both
`
`the preamble and claim body to define the claimed invention; (ii) if reference to the
`
`preamble is necessary to understand limitations or terms in the claim body; or (iii)
`
`if the preamble recites additional structure or steps that the specification identifies
`
`as important.
`
`III. THE RELEVANT ART
`
`27.
`
`In addition to the ’569 Patent, I have considered the following patents
`
`and printed publications:
`
`
`
`9
`
`ALVOGEN, Ex. 1003, p. 0012
`
`

`

`Declaration of Dr. Guido Tricot in Support of
`Petition for IPR of U.S. Patent No. 7,968,569
`
`Ex. 1005
`
`Ex. 1006
`
`Document
`
`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. 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
`Protection For Lead IMiD(TM), REVIMID(TM); Comprehensive
`Patent Protection for REVIMID Includes Coverage of the Active
`Ingredient, Pharmaceutical Compositions, and Therapeutic Uses,”
`
`10
`
`
`
`
`
`ALVOGEN, Ex. 1003, p. 0013
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`

`

`Declaration of Dr. Guido Tricot in Support of
`Petition for IPR of U.S. Patent No. 7,968,569
`
`Document
`
`
`
`Exhibit
`No.
`
`Ex. 1015
`
`Ex. 1018
`
`Ex. 1019
`
`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”)
`Ex. 1024 Cytovene®-IV, Physicians’ Desk Reference 2623-2629 (54th ed.
`2000). (“Cytovene Label”)
`Imashuku et al., “Management of severe neutropenia with
`cyclosporin during initial treatment of Epstein-Barr virus-related
`hemophagocytic
`lymphohistiocytosis,” Leuk. Lymphoma, 36(3-
`4):339-346 (2000). (“Imashuku”)
`
`Ex. 1025
`
`
`
`11
`
`ALVOGEN, Ex. 1003, p. 0014
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`

`

`Declaration of Dr. Guido Tricot in Support of
`Petition for IPR of U.S. Patent No. 7,968,569
`
`Document
`
`Exhibit
`No.
`Ex. 1026 Revlimid Label
`Ex. 1027
`Pomalyst Label
`Ex. 1028 U.S. Patent No. 6,281,230 (“the ʼ230 Patent”)
`idarubicin and
`Ex. 1029
`Parameswaran et al., “CCNU
`(lomustine),
`dexamethasone (CIDEX): an effective oral regimen for the treatment
`of refractory or relapsed myeloma,” Br. J. Haematol., 109(3):571-
`575 (2000). (“Parameswaran”)
`etoposide,
`paclitaxel,
`Ex. 1030 Bilgrami
`et
`al.,
`“Dexamethasone,
`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,
`Time
`to Progression, and Survival With Lenalidomide Plus
`Dexamethasone in Newly Diagnosed Myeloma,” Mayo Clin. Proc.
`
`Ex. 1035
`
`Ex. 1038
`
`12
`
`
`
`
`
`ALVOGEN, Ex. 1003, p. 0015
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`

`

`Declaration of Dr. Guido Tricot in Support of
`Petition for IPR of U.S. Patent No. 7,968,569
`
`Document
`
`
`
`Exhibit
`No.
`
`Ex. 1043
`
`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. 1049 Bell et al., “Chapter 5. The Hematopoietic System and Development
`of Blood Cells,” The Johns Hopkins Atlas of Human Functional
`
`Ex. 1047
`
`
`
`13
`
`ALVOGEN, Ex. 1003, p. 0016
`
`

`

`Declaration of Dr. Guido Tricot in Support of
`Petition for IPR of U.S. Patent No. 7,968,569
`
`Exhibit
`No.
`
`Document
`
`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. 1059 Malpas and Rohatiner, “Principles of Cancer Chemotherapy,”
`Advances in Oncology 1:317-350 (1996) (“Malpas 1996”)
`
`
`
`
`
`IV. OVERVIEW OF THE ʼ569 PATENT
`
`A. The Claims of the ʼ569 Patent
`
`1.
`
`Independent Claims 1 and 13
`
`28. Two of the fifteen claims of the ʼ569 patent are independent claims.
`
`Independent claim 1 reads as follows:
`
`1.
`
`A method of
`
`treating multiple myeloma, which
`
`comprises cyclically administering to a patient having multiple
`
`myeloma about 5 to about 25 mg per day of a compound of the
`
`formula:
`
`
`
`14
`
`ALVOGEN, Ex. 1003, p. 0017
`
`

`

`Declaration of Dr. Guido Tricot in Support of
`Petition for IPR of U.S. Patent No. 7,968,569
`
`
`
`
`
`or a pharmaceutically acceptable salt
`
`thereof,
`
`for 21
`
`consecutive days followed by seven consecutive days of rest
`
`from administration of said compound during a 28 day cycle, in
`
`combination with 40 mg per day of dexamethasone.
`
`Independent claim 13 reads as follows:
`
`13. A method of
`
`treating multiple myeloma, which
`
`comprises administering, on a 28 day cycle, to a patient having
`
`multiple myeloma:
`
`(a)
`
`about 25 mg per day of a compound of the formula:
`
`
`
`or a pharmaceutically acceptable salt
`
`thereof,
`
`for 21
`
`consecutive days followed by seven consecutive days of rest
`
`from administration of said compound, and; (b) 40 mg per day
`
`of dexamethasone on days 1-4 every 28 days.
`
`
`
`15
`
`ALVOGEN, Ex. 1003, p. 0018
`
`

`

`Declaration of Dr. Guido Tricot in Support of
`Petition for IPR of U.S. Patent No. 7,968,569
`
`
`
`2.
`
`Dependent Claims 2-12 and 14-15
`
`29. Dependent claims 2-12 and 14-15 depend from claim 1. The
`
`dependent claims include additional limitations regarding dosage form, strength,
`
`route of administration, or the form of MM being treated. In particular, claims 2
`
`and 4 specify that the MM being treated is one of several possible forms, including
`
`relapsed or refractory myeloma. Claim 3 is directed to the method of treatment
`
`wherein lenalidomide is a pharmaceutically acceptable salt. Claims 5 and 15
`
`require that dexamethasone (and, in the case of claim 5, lenalidomide) be
`
`administered orally. Claim 6 requires that the orally administered lenalidomide of
`
`claim 5 is in the form of a capsule or tablet, and claim 14 requires that a
`
`lenalidomide capsule further comprises lactose anhydrous, microcrystalline
`
`cellulose, croscarmellose sodium and magnesium stearate. Finally, claims 7-12 are
`
`directed to methods of treatment wherein lenalidomide is administered in a
`
`particular daily amount, or within a particular range per day.
`
`B.
`
`The Effective Filing Date of the ’569 Patent Can Be No Earlier
`Than November 6, 2002
`
`30.
`
`I understand that 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. I understand that the ’213 application claims the benefit of
`
`Provisional Application No. 60/380,842 (Ex. 1052, “the ’842 provisional”), filed
`
`
`
`16
`
`ALVOGEN, Ex. 1003, p. 0019
`
`

`

`Declaration of Dr. Guido Tricot in Support of
`Petition for IPR of U.S. Patent No. 7,968,569
`
`
`on May 17, 2002, and Provisional Application No. 60/424,600 (“the ’600
`
`provisional”), filed on November 6, 2002.
`
`31.
`
`I understand that, for claims 1-15 of the ’569 patent to benefit from
`
`the filing date of the ’842 provisional, the ’842 provisional must describe the
`
`subject matter of the claims. I understand that to satisfy the written description
`
`requirement the original disclosure must convey to one of skill in the art that the
`
`inventor had possession of the claimed subject matter as of the priority date. I
`
`understand that the extent of disclosure necessary to satisfy the written description
`
`requirement varies depending on the nature and scope of the claims and the
`
`complexity and predictability of the relevant technology. I understand that the
`
`following factors are relevant to the determination of whether the disclosure of a
`
`patent sufficiently describes the claims: existing knowledge in the particular field,
`
`the extent and content of the prior art, the maturity of the science or technology,
`
`and the predictability of the aspect at issue.
`
`32.
`
`In my opinion, the claims of the ’569 are not adequately described by
`
`the specification of the ’842 provisional for two reasons. First, the ’842 provisional
`
`does not describe a 28-day treatment cycle. All of the claims of the ’569 Patent are
`
`directed to methods of treating multiple myeloma that involve administering
`
`lenalidomide to a patient on a 28-day cycle, wherein lenalidomide is administered
`
`for 21 consecutive days followed by seven consecutive days of rest from
`
`
`
`17
`
`ALVOGEN, Ex. 1003, p. 0020
`
`

`

`Declaration of Dr. Guido Tricot in Support of
`Petition for IPR of U.S. Patent No. 7,968,569
`
`
`administration of lenalidomide. 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.
`
`33. Second, the ’842 provisional does not disclose the combination of
`
`lenalidomide and dexamethasone to treat MM, or any cancer. The claims of the
`
`’569 patent each require the co-administration of the steroid dexamethasone.
`
`34. 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.” ’842 provisional at 1:6–9. The ʼ842 provisional
`
`defines large molecules as “preferably biological molecules, such as naturally
`
`occurring or artificially made proteins” (Id. 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 only
`
`examples of large molecules provided in the specification include IL-2, IL-10,
`
`IL-18, G-CSF, GM-CSF, and EPO. Id. at 24:10-11; see also 1:9-11; 8:15-17; and
`
`10:7-9. Moreover, every claim and each specific embodiment described in the ʼ842
`
`provisional is directed to the combination of a small molecule with one of the
`
`proteins listed above. See id. at 10:33-11:37.
`
`35. The ʼ842 provisional does not state or suggest that dexamethasone is a
`
`“large molecule” as used in the specification. Instead, dexamethasone is a small
`
`
`
`18
`
`ALVOGEN