`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`BRECKENRIDGE PHARMACEUTICAL, INC., AND
`WEST-WARD PHARMACEUTICALS INTERNATIONAL LIMITED,
`
`Petitioners,
`
`v.
`
`NOVARTIS PHARMACEUTICALS CORPORATION,
`
`Patent Owner.
`
`
`
`
`Case IPR2017-015921
`
`Patent No. 8,410,131
`
`
`
`EXPERT DECLARATION OF DR. KRISHNA V. KOMANDURI
`
`
`1 IPR2018-00507 has been joined to this proceeding.
`
`NOVARTIS EXHIBIT 2080
`Breckenridge v. Novartis, IPR 2017-01592
`Page 1 of 35
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`
`
`TABLE OF CONTENTS
`
`
`
`I.
`
`Qualifications ................................................................................................... 1
`
`II.
`
`Scope Of This Declaration .............................................................................. 5
`
`III. Legal Principles ............................................................................................... 6
`
`IV. The ’131 Patent .............................................................................................. 10
`
`V.
`
`Solid And Liquid Tumors .............................................................................. 12
`
`VI. Wasik Did Not Disclose Solid Kidney Tumors ............................................ 16
`
`VII. Conclusion ..................................................................................................... 28
`
`
`
`
`
`
`i
`
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`
`
`LIST OF EXHIBITS CITED
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`I
`
`I
`
`1002
`
`PCT Published Application No. WO
`01/51049 A1, “O-Methylated Rapamycin
`Derivatives For Alleviation And Inhibition
`Of Lymphoproliferative Disorders,” to
`Wasik et al.
`
`Wasik
`
`1010
`
`Declaration of Allan J. Pantuck, M.D. in
`Support of Petition for Inter Partes Review
`of U.S. Patent No. 8,410,131
`
`Pantuck Decl.
`
`1041
`
`Perez-Atayde, A.R. et al., “Spectrum Of
`Tumor Angiogenesis In The Bone Marrow
`Of Children With Acute Lymphoblastic
`Leukemia,” Am. J. Pathol. 150(3):815-821
`(1997)
`
`1075
`
`Majewski, M. et al., “The
`Immunosuppresive Macrolide RAD Inhibits
`Growth Of Human Epstein-Barr Virus
`Transformed B Lymphocytes In Vitro And
`In Vivo: A Potential Approach To
`Prevention And Treatment Of
`Postrransplant Lymphoproliferative
`Disorders,” Proc. Natl. Acad. Sci.
`97(8):4285-4290 (2000)
`
`Perez-Atayde
`
`Majewski
`
`1101
`
`Motzer, R.J. & Vogelzang, N.J.,
`“Chemotherapy For Renal Cell Carcinoma,”
`Principles And Practice Of Genitourinary
`Oncology, pages 885-896 (Raghavan, D. et
`al. eds., 1997)
`
`Motzer 1997
`
`
`
`
`
`
`
`ii
`
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`
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`I
`
`I
`
`2003
`
`Laughlin, E.H., Coming To Terms With
`Cancer: A Glossary Of Cancer-Related
`Terms, pages 4, 126, 140, 173-174, 188-190
`(2002)
`
`Laughlin
`
`2004
`
`Altman, R. & Sarg, M.J., The Cancer
`Dictionary, 51-52, 278 (1992)
`
`Altman
`
`2005
`
`2006
`
`2007
`
`Sutcliffe, S.B. & Gospodarowicz, M.K.,
`Chapter 25, “Primary Extranodal
`Lymphomas,” The Lymphomas (Canellos,
`G.P. et al. eds., 1998)
`
`Molina, A. & Pezner, R.D., Chapter 30,
`“Non-Hodgkin’s Lymphoma,” Cancer
`Management: A Multidisciplinary
`Approach: Medical, Surgical, & Radiation
`Oncology, 4th Edition (Pazdur, R. et al.
`eds., 2000)
`
`Sutcliffe, S.B. & Gospodarowicz, M.K.,
`“Clinical Features And Management Of
`Localized Extranodal Lymphomas,”
`Haematological Oncology, Volume 2 pages
`189-222 (Keating, A. et al. eds., 1992)
`
`Sutcliffe 1998
`
`Pazdur
`
`Sutcliffe 1992
`
`2027
`
`March 13, 2018 Deposition Testimony of
`Dr. Allan J. Pantuck
`
`Pantuck Tr.
`
`2028
`
`Truong, L. et al., “The Diagnostic And
`Therapeutic Roles Of Fine-Needle
`Aspiration,” Am. J. Clin. Pathol. 115:18-31
`(2001)
`
`Truong
`
`iii
`
`NOVARTIS EXHIBIT 2080
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`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`I
`
`I
`
`2030
`
`Abbas, Z. et al., “Renal Lymphoma: An
`Unusual Cause Of Extrahepatic Biliary
`Obstruction,” Postgraduate Med. J. 617-
`618 (1996)
`
`Abbas
`
`2081
`
`Curriculum vitae of Dr. Krishna V.
`Komanduri
`
`Komanduri CV
`
`2095
`
`2096
`
`2098
`
`Robbins, S.L. et al., Chapter 15, “Diseases
`Of White Cells, Lymph Nodes, And
`Spleen,” Pathologic Basis Of Disease, 3rd
`Edition, pages 653-704 (1984)
`
`Buzaid, A. & Cadman, E., Chapter 52:
`“Pharmacology Of Antineoplastic Agents
`And Mechanisms Of Multidrug
`Resistance,” Hematology Basic Principles
`And Practice (Hoffman, R. et al. eds., 1991)
`
`Robbins
`
`Buzaid
`
`Molldrem, J.J. et al., “Overexpressed
`Differentiation Antigens As Targets Of
`Graft-Versus-Leukemia Reactions,” Curr.
`Opin. Hematol. 9:503-508 (2002)
`
`Molldrem
`
`
`
`iv
`
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`
`
`I.
`
`Qualifications
`
`1.
`
`I am a physician-scientist with knowledge and experience in the field
`
`of lymphoproliferative disorders, including post-transplant lymphoproliferative
`
`disorders (PTLDs) and lymphomas, as well as the development of cancer therapies,
`
`as of February 2001, February 2002, and up to the present day.
`
`2.
`
`I am currently the Kalish Family Chair in Stem Cell Transplantation,
`
`Professor of Medicine, Microbiology and Immunology, Director of the Adult Stem
`
`Cell Transplant Program, Associate Director for Clinical Innovation, at the
`
`Sylvester Comprehensive Cancer Center, University of Miami Miller School of
`
`Medicine, Miami, Florida.
`
`3.
`
`I obtained my S.B. in biology and literature in 1987 from the
`
`Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts.
`
`Between 1985 and1987, I was also a teaching assistant in the MIT Department of
`
`Biology. I obtained a Doctor of Medicine degree in 1991 from the University of
`
`Minnesota Medical School, Minneapolis, Minnesota. Between 1991 and 1994, I
`
`completed my internal medicine residency at UCLA Center for Health Sciences,
`
`Los Angeles, California. Between 1994 and 1997, I completed my fellowship in
`
`both hematology and medical oncology at UCSF, San Francisco, California.
`
`4.
`
`From 1997 to 1999, I was an Assistant Adjunct Professor, UCSF
`
`Department of Medicine, Division of Hematology/Oncology, as well as an
`
`1
`
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`
`
`
`attending physician in the Hematology & Bone Marrow Transplant Service, San
`
`Francisco, California. From 1999 to 2006, I was an Assistant Professor of
`
`Medicine, University of Texas M.D. Anderson Cancer Center, Section of
`
`Transplantation Immunology, Department of Stem Cell Transplantation and
`
`Cellular Therapy, Houston, Texas. From 2000 to 2008, I served as the Director of
`
`the Bone Marrow Transplantation Fellowship Program, University of Texas M.D.
`
`Anderson Cancer Center, Houston, Texas. From 2005 to 2008, I was also
`
`Associate Director of the Hematology/Oncology Fellowship Program, University
`
`of Texas M.D. Anderson Cancer Center, Houston, Texas, and from 2006 to 2008, I
`
`was Associate Professor of Medicine, M.D. Anderson Cancer Center, Section of
`
`Transplantation Immunology, Department of Stem Cell Transplantation and
`
`Cellular Therapy, Houston, Texas.
`
`5.
`
`In 2008, I moved to University of Miami Miller School of Medicine,
`
`Miami, Florida, and in addition to the positions I still hold today (see ¶ 2 above),
`
`from 2011 to 2017, I was also Medical Director, cGMP Laboratory,
`
`Interdisciplinary Stem Cell Institute, Miami, Florida.
`
`6.
`
`I am also the immediate past President and a current member of the
`
`Executive Committee and the Board of Directors of the American Society for
`
`Blood and Marrow Transplantation (ASBMT). My recent leadership positions
`
`include serving as 2015-2016 Chair of the American Society of Hematology
`
`2
`
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`
`
`Immunology and Host Defense Scientific Committee, 2015 Scientific Program
`
`Chair for the ASBMT, and Co-Chair (2015-2020) of the Center for International
`
`Blood and Marrow Transplant Research Infection and Immune Reconstitution
`
`Working Committee, which conducts research including on PTLDs.
`
`7. My past honors include election to the American Society of Clinical
`
`Investigation (2009), and receipt of the M.D. Anderson Cancer Center Division of
`
`Cancer Medicine Leadership in Education Award (2008), the University of
`
`California AIDS Research Program Fellowship (1997-1999), the Amgen Research
`
`Fellowship in Medical Oncology (1996), the UCLA Solomon Scholars Medical
`
`Resident Research Award (1994), and a National Merit Scholarship (1983).
`
`8.
`
`From 1998 to the present date, I have served as an ad hoc reviewer on
`
`numerous different journals, including NEJM, Blood, Nature Medicine, J
`
`Immunology, J Exp Medicine, J Infectious Diseases, J Clinical Investigation,
`
`Biology of Blood & Marrow Transplantation, Bone Marrow Transplantation,
`
`British Journal of Cancer, Clinical Cancer Research, BMC Immunology, Clinical
`
`Immunology, International Immunology, J AIDS, Clinical Infectious Diseases,
`
`Clinical Experimental Immunology, Transplant Immunology, and Transplantation.
`
`9.
`
`I have expertise in both normal and abnormal lymphocyte cell biology
`
`and my research in this field has been supported by the NIH as well as many
`
`cancer-related foundations. In particular, prior to February 2001, I conducted
`
`3
`
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`
`
`preclinical studies on transformed lymphocytes, including the generation of
`
`“lymphoblastoid B-cell lines . . . by in vitro infection with EBV of peripheral blood
`
`mononuclear cells,” a method discussed in Wasik. (Ex. 1002, Wasik at 20:23-24,
`
`see also 19:17-22 (describing a method “useful for identifying an agent capable of
`
`inhibiting establishment of a tumor” in which the first step involved “exposing a B
`
`lymphocyte to [EBV], such that a transformed B lymphocyte [was] generated”).) I
`
`also conducted preclinical research on B cell lymphoma cell lines obtained from
`
`lymphoma patients, similar to the 15A and 20A cell lines used in Wasik, as well as
`
`a “peritoneal effusion B-cell lymphoma,” similar to the BC-1 cell line used in
`
`Wasik. (Ex. 1002, Wasik at 20:25-27, 21:3-4.)
`
`10.
`
`I am also a clinical expert in the treatment of patients with
`
`lymphoproliferative disorders, including PTLDs and lymphomas, and have been
`
`treating patients with these conditions since at least 1997. PTLDs are a relatively
`
`rare complication associated with immunosuppressive therapy given to transplant
`
`patients. I have experience in both the treatment of cancer patients with
`
`lymphomas and transplant patients with PTLDs because as of February 2001,
`
`February 2002, and still today, patients with liquid tumors are treated with blood
`
`and marrow transplants. In this regard, liquid tumors were and still are distinct
`
`from solid kidney tumors, such as advanced RCC, which were and still are not
`
`generally treated by transplantation. As of 2001 and 2002, solid kidney tumors,
`
`4
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`
`
`such as advanced RCC, were treated by nephrectomy and systemic therapy, and
`
`were known to respond to different drugs from lymphomas. (Ex. 1101, Motzer
`
`1997 at 885-86, 891; Ex. 2028, Truong at 27; Ex. 2006, Pazdur at 595-606 & Table
`
`5 (lymphomas).)
`
`11.
`
`I have also been a co-investigator on dozens of clinical trials,
`
`including Phase I, II and III clinical trials in patients with liquid tumors, e.g.,
`
`leukemias and lymphomas. I am also presently serving on an independent data
`
`safety monitoring committee for a Novartis Phase III clinical trial in patients
`
`undergoing hematopoietic stem cell transplants for leukemia. And I have
`
`conducted ad hoc scientific consulting for Novartis, Kite Pharma, Juno/Celgene,
`
`Sanofi, Kyowa Kirin Pharmaceutical Development and Incyte.
`
`12.
`
`I have authored more than 140 journal articles and abstracts, including
`
`publications concerning lymphomas, PTLDs and human immune responses and
`
`therapies for EBV infection in immunocompromised hosts.
`
`13. My curriculum vitae is attached to this declaration as Exhibit 2081.
`
`II.
`
`Scope Of This Declaration
`
`14.
`
`I understand that Breckenridge Pharmaceutical, Inc. and West-Ward
`
`Pharmaceuticals International Limited have challenged the patentability of claims
`
`1-3 and 5-9 of U.S. Patent No. 8,410,131 (“the ’131 Patent”), which relate, inter
`
`alia, to “[a] method for inhibiting growth of solid excretory system tumors in a
`
`5
`
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`subject, said method consisting of administering to said subject a therapeutically
`
`effective amount of [everolimus].”
`
`15.
`
`I have been asked to provide my opinion on whether Wasik (Ex.
`
`1002) disclosed methods of using everolimus for inhibiting growth of solid kidney
`
`tumors. In summary, because a POSA in February 2001 and February 2002 would
`
`have understood Wasik’s disclosure of a “tumor of the . . . kidney” to refer to a
`
`lymphoma of the kidney, and not a solid kidney tumor, Wasik did not disclose
`
`methods of using everolimus for inhibiting growth of “solid excretory system
`
`tumors,” “advanced solid excretory system tumor[s],” or “solid … kidney
`
`tumor[s],” as those terms are used in the ’131 Patent. Accordingly, Wasik did not
`
`disclose all of the claim elements and did not anticipate the challenged claims of
`
`the ’131 Patent.
`
`16.
`
`In forming these opinions, I have considered the declaration of Dr.
`
`Pantuck (Ex. 1010) as it related to the issue I have been asked to consider, as well
`
`as the documents cited in this declaration and my knowledge and experience as a
`
`physician-scientist working in the field of lymphoproliferative disorders, including
`
`PTLDs and lymphomas, as of February 2001, February 2002, and still today.
`
`III. Legal Principles
`
`17.
`
`I understand that a claim is anticipated only if each and every element
`
`of the claim is expressly or inherently described in a single prior art reference.
`
`6
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`What a prior art reference disclosed is determined from the perspective of a person
`
`of ordinary skill in the art (“POSA”).
`
`18.
`
`I have been asked to assume that a POSA with respect to the ’131
`
`Patent would be: a person with (1) a Ph.D. in biology, biochemistry,
`
`pharmaceutical sciences, molecular biology, cancer biology, or other biological
`
`sciences, and/or (2) a medical degree. Such a person would have had at least one
`
`year of relevant training, experience, or research in treating patients with solid
`
`excretory system tumors, including advanced RCC, and would have had
`
`knowledge of the design, implementation, and analysis of preclinical studies of
`
`potential cancer therapies and/or clinical studies involving patients with solid
`
`excretory system tumors, including advanced RCC. The POSA would also have
`
`collaborated with others having skills and expertise in areas pertinent to the above
`
`subject matter, including, for example, pharmacologists, formulators, and
`
`biochemists.
`
`19. As of February 2001 and February 2002, I had the level of education
`
`and experience of a POSA because I had the required qualification, namely, a
`
`medical degree, as well as the experience and knowledge of a POSA in the design,
`
`implementation, and analysis of preclinical studies of potential cancer therapies.
`
`Also, during my medical residency and fellowship in both hematology and
`
`oncology, I trained in the treatment of solid excretory system tumors, such as
`
`7
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`
`advanced RCC. While I do not practice in the field of solid excretory system
`
`tumors, such as advanced RCC, I believe that my knowledge and experience in the
`
`field of lymphoproliferative disorders, including PTLDs and lymphomas, will
`
`assist the Board in understanding the disclosure of Wasik.
`
`20. Dr. Pantuck defined a POSA in his declaration as a person having, at a
`
`minimum: (a) a medical degree (e.g., M.D.) with several years of specific
`
`experience in medical or surgical oncology, which may include board certification,
`
`as well as knowledge of oncology drug development and clinical pharmacology; or
`
`(b) a Ph.D. in cancer biology, molecular biology, medicinal chemistry, or a related
`
`field with several years of experience in oncology drug development and clinical
`
`pharmacology, including evaluating cancer therapeutics in in vitro and/or in vivo
`
`assays, as well as familiarity with the practice of medical oncology. (Ex. 1010,
`
`Pantuck Decl. ¶ 20.)
`
`21. As of February 2001 and February 2002, I had the level of education
`
`and experience of a POSA, as defined by Dr. Pantuck in his declaration, because I
`
`had a medical degree as well as years of specific experience in medical oncology
`
`and knowledge of oncology drug development. (Ex. 2081, Komanduri CV at 1-2.)
`
`Applying Dr. Pantuck’s POSA definition from his declaration does not change my
`
`opinions because that POSA definition does not change how a POSA would have
`
`understood the disclosure of Wasik.
`
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`22.
`
`I understand that, at deposition, Dr. Pantuck testified that a POSA
`
`would have had specific experience in the treatment of solid excretory system
`
`tumors of the urinary system, including kidney tumors and RCC. (Ex. 2027,
`
`Pantuck Tr. at 14:17-20.) As I explained above, prior to February 2001 and
`
`February 2002, during my medical residency and fellowship in both hematology
`
`and oncology, I trained in the treatment of solid excretory system tumors of the
`
`urinary system, such as advanced RCC. While I do not practice in the field of
`
`solid excretory system tumors of the urinary system, such as advanced RCC, I
`
`believe that my knowledge and experience in the field of lymphoproliferative
`
`disorders, including PTLDs and lymphomas, will assist the Board in understanding
`
`the disclosure of Wasik.
`
`23.
`
`I have also been asked to assume that the relevant date for assessing
`
`the validity of the ’131 Patent is February 2001. I understand that Dr. Pantuck
`
`disputed that this is the correct date and opined that the relevant date for assessing
`
`the validity of the ’131 Patent is February 2002. (Ex. 1010, Pantuck Decl. ¶ 147.)
`
`However, applying Dr. Pantuck’s assessment date does not change my opinions
`
`because the date does not change how a POSA would have understood the
`
`disclosure of Wasik.
`
`9
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`IV. The ’131 Patent
`
`24.
`
`I understand that the claims at issue in this inter partes review
`
`proceeding are claims 1-3 and 5-9 of the ’131 Patent.
`
`25. Claim 1 of the ’131 Patent claims: “A method for inhibiting growth of
`
`solid excretory system tumors in a subject, said method consisting of administering
`
`to said subject a therapeutically effective amount of [everolimus].”
`
`26. Claim 2 of the ’131 Patent claims: “The method of claim 1 wherein
`
`the solid excretory system tumor is an advanced solid excretory system tumor.”
`
`27. Claim 3 of the ’131 Patent claims: “The method of claim 1 wherein
`
`the solid excretory system tumor is a kidney tumor.”
`
`28. Claim 5 of the ’131 Patent claims: “The method of claim 1 wherein
`
`[everolimus] is administered orally.”
`
`29. Claims 6 to 9 of the ’131 Patent are dependent claims and claim
`
`specific dose ranges of everolimus.2
`
`
`2 Claim 6 of the ’131 Patent claims: “The method of claim 5 wherein [everolimus]
`
`is administered at a daily dose range of from about 0.1 to 25 mg, as a single dose
`
`or in divided doses.” Claim 7 of the ’131 Patent claims: “The method of claim 5
`
`wherein [everolimus] is administered in a unit dosage form of from about 0.05 to
`
`12.5 mg.” Claim 8 of the ’131 Patent claims: “The method of claim 5 wherein
`
`
`
`10
`
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`30.
`
`I have been asked to assume that the claim term “solid excretory
`
`system tumors” in the context of the ’131 Patent means “tumors and/or metastases,
`
`other than tumors and/or metastases of the blood or lymphatic system, which arise
`
`from the cells of the urinary excretory system.”
`
`31.
`
` I have also been asked to assume that the claim term “advanced solid
`
`excretory system tumor[s]” in the context of the ’131 Patent means “locally
`
`advanced or metastatic tumors, other than tumors and/or metastases of the blood or
`
`lymphatic system, which arise from the cells of the urinary excretory system.”
`
`32.
`
` Finally, I have been asked to assume that “solid . . . kidney tumor” in
`
`the context of the ’131 Patent means “a tumor and/or metastasis, other than a tumor
`
`and/or metastasis of the blood or lymphatic system, which arises from the cells of
`
`the kidney.”
`
`33. Based on those understandings, I have considered whether Wasik
`
`disclosed methods of using everolimus for inhibiting growth of “solid excretory
`
`system tumors,” “advanced solid excretory system tumor[s],” and/or “solid . . .
`
`kidney tumor[s],” as those terms are used in the ’131 Patent.
`
`
`[everolimus] is administered in a unit dosage form of from about 0.25 to 10 mg.”
`
`And claim 9 of the ’131 Patent claims: “The method of claim 8 wherein
`
`[everolimus] is administered in a unit dosage form of 10 mg.”
`
`11
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`
`
`V.
`
`Solid And Liquid Tumors
`
`34. As of both February 2001 and February 2002, a POSA would have
`
`known that solid tumors and liquid tumors arose from different types of cells.
`
`Liquid tumors, including blood cancers, arose from cells of the lymphatic system
`
`and bone marrow, whereas solid tumors arose from cells other than cells from the
`
`lymphatic system and bone marrow. (Ex. 2003, Laughlin at 126; Ex. 1041, Perez-
`
`Atayde at 816.) As of February 2001 and February 2002, liquid tumors, such as
`
`lymphomas, were usually treated by hematologists and solid kidney tumors, such
`
`as advanced RCC, were generally treated by medical oncologists, particularly
`
`urologic oncologists. Likewise, when a PTLD or lymphoma arose in a transplant
`
`patient, they were generally referred to a hematologist for treatment, and not a
`
`urologic oncologist. Accordingly, the overlap of cancer and transplant patients in
`
`my clinical practice is due to my expertise in the treatment of liquid cancers, and a
`
`POSA working in the field of solid excretory system tumors, including solid
`
`kidney tumors, such as advanced RCC, would have been unlikely to have
`
`experience treating transplant patients with immunosuppressive therapies.
`
`35. A POSA would have understood that the term “tumor” in a
`
`publication or patent could refer to (i) solid tumors (e.g., Ex. 2004, Altman at 51
`
`(“CARCINOMA—a cancerous tumor or lump, originating in the surface tissue of
`
`body organs”), (ii) liquid tumors (e.g., Ex. 2004, Altman at 51 (“MYELOMA—a
`
`12
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`cancerous tumor originating in the plasma cells of the BONE MARROW” and
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`“LYMPHOMA—a cancerous tumor originating in the lymph system”), or (iii)
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`both solid and liquid tumors (e.g., Ex. 2003, Laughlin at 140 (“Literally a swollen
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`area”); Ex. 2096, Buzaid at, e.g., 669 (noting that the pattern of “Tumor Growth”
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`depends in part on “the type of tumor,” with different proportions of the cells in a
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`tumor in some adenocarcinomas (i.e., solid tumors) versus some lymphomas (i.e.,
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`liquid tumors))).
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`36. Accordingly, a POSA would have understood that it was always
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`necessary to consider the context of the use of the word “tumor.” For example,
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`Sutcliffe 1998 was a chapter in the textbook, The Lymphomas, and a POSA would
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`have understood that, throughout the chapter, the term “tumor” was used to refer
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`exclusively to “lymphomas.” (Ex. 2005, Sutcliffe 1998 at, e.g., 449 (stating that
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`“indolent tumors constitute a substantial proportion of presentations” of
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`lymphomas), 450 (discussing “tumor bulk” and “primary tumor control with
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`therapy” for lymphomas), 456 (stating that “resection of the primary tumor may
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`be helpful” in the context of local treatment methods for lymphomas), 468
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`(describing “lymphoma[s] of the ovary” as tumors and that “[m]ost tumors were
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`of B-cell type,” i.e., liquid tumors that arose from B cells, a type of lymphocyte or
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`white blood cell of the immune system), 473 (stating that, of “lymphoma[s] of the
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`13
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`liver,” [e]ighty percent of tumors [were] of B-cell type” and “T cell lesions are
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`rarely recorded”) (emphases added).)
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`37. Other prior art publications similarly used the term “tumor” to refer
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`exclusively to liquid tumors. (Ex. 2007, Sutcliffe at, e.g., 190 (discussing “sites
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`[with] a highly skewed representation of intermediate and high grade tumors e.g.
`
`extradural, brain, testis and bone lymphomas”), 190-191 (“In certain sites where
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`low grade tumors occur, localized or more conservative treatment options may be
`
`applicable. In other sites where virtually all tumors are of diffuse, aggressive
`
`type, initial systemic therapy [was] a mandatory component of potentially curative
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`treatment.”), 197 (“The overwhelming majority of tumors [were] of B-cell origin
`
`although there [was] a distinct, small subset of T-cell tumors of pleomorphic type
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`ranging from low to high grade.”) (emphases added); Ex. 2006, Pazdur at 588
`
`(discussing non-Hodgkin’s lymphoma diagnosis by biopsy of “tumor tissue”),
`
`593-594 (discussing prognostic factors for lymphomas including the “tumor’s
`
`growth and invasive potential,” and “the patient’s response to the tumor”), 608
`
`(discussing poor-risk factors including “large tumor bulk”) (emphases added); Ex.
`
`2095, Robbins at, e.g., 667 (classifying non-Hodgkin’s lymphomas based in part
`
`on “[t]he histologic appearance of the tumors”), 668 (“[S]ince lymphomas are
`
`neoplasms of the immune system, certain special features that apply to these
`
`tumors will be discussed here.”) (emphases added); Ex. 2096, Buzaid at 678,
`
`14
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`Table 52-9 (reporting the frequency of a drug resistant phenotype in liquid tumors
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`as “Number of Tumors Positive/Total”) (emphasis added).)
`
`38.
`
`In particular, relevant to the disclosure of Wasik, the term “tumor”
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`was used in the literature as of February 2001 and February 2002 to refer to renal
`
`lymphomas, i.e., lymphomas of the kidney. (Ex. 2030, Abbas at Summary
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`(describing a “lymphoma arising in a kidney” as a “tumour [that] had invaded the
`
`pancreas and duodenum”), 617 (discussing the “reduction of the tumour” in
`
`response to lymphoma therapy) (emphases added); Ex. 2028, Truong at 20, Table 1
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`(reporting that “the renal tumor in many patients responded well to therapy” in
`
`the context of renal lymphoma) (emphasis added).)
`
`39. Also, in particular, relevant to the disclosure of Wasik, the term
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`“tumor” was used in the literature as of February 2001 and February 2002 to refer
`
`to a lymphoma metastasis, that is, a second tumor derived from a lymphoma that
`
`had spread from its primary site to other sites in the body. (Ex. 2005, Sutcliffe
`
`1998 at, e.g., 456 (discussing “tumor bulk” in the context of stage II lymphomas,
`
`which are second tumors that have spread from the primary site of the lymphoma),
`
`462 (reporting that, for paranasal sinus and nasal cavity lymphomas, “most tumors
`
`are stage I-IIE,” where stage IIE tumors referred to second tumors that have spread
`
`from the primary site of the lymphoma) (emphases added); Ex. 2007, Sutcliffe at
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`15
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`213 (discussing “multiple tumor masses” in the liver in the context of lymphoma
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`of the liver) (emphasis added).)
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`VI. Wasik Did Not Disclose Solid Kidney Tumors
`
`40. As of February 2001 and February 2002, it was known that PTLDs
`
`were “a life-threatening complication of the immunosuppressive therapy necessary
`
`to inhibit graft rejection.” (Ex. 1002, Wasik at 1:8-11.) PTLDs “usually
`
`involve[d] expansion of B lymphocytes infected with Epstein–Barr virus (EBV).”
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`(Ex. 1002, Wasik at 1:8-10.) However, “PTLDs comprise[d] a whole spectrum of
`
`lymphoproliferative disorders,” and included malignant B-cell lymphomas, a type
`
`of tumor, but were not limited to disorders that resulted in the formation of tumors.
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`(Ex. 1002, Wasik at 1:12-14.) Some PTLDs could be effectively treated by
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`lowering the dose of immunosuppressant used in the transplant patients, but this
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`put the transplanted organ at risk of rejection. (Ex. 1002, Wasik at 1:17-21.) And
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`lowering the dose of immunosuppressive therapy was not effective against
`
`malignant, lymphoma-type PTLDs. (Ex. 1002, Wasik at 1:21-23.)
`
`41. Furthermore, as of February 2001 and February 2002, lymphomas,
`
`which could be derived from B and T cells, were known to cause significant
`
`morbidity and mortality. (Ex. 1002, Wasik at 1:24-27.) The prognosis for
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`immunocompromised lymphoma patients, e.g., AIDS patients or post-transplant
`
`patients (i.e., patients with malignant, lymphoma-type PTLDs), was poor. (Ex.
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`16
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`1002, Wasik at 1:29-2:2.) And lymphomas were not limited to post-transplant
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`settings. (Ex. 1002, Wasik at 1:24-2:2.)
`
`42. Accordingly, there was a need for new treatment options for the
`
`prevention and treatment of lymphoproliferative disorders, such as PTLDs and
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`lymphomas. (Ex. 1002, Wasik at 2:2-3, 18-20, 32:10-19.) A POSA would have
`
`understood that the invention, as defined in the Wasik specification, aimed to
`
`address this need, and not any need for treatments for solid tumors, which were not
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`mentioned in the “background of the invention” section of the Wasik specification
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`(Ex. 1002, Wasik at 1:7-2:20) or anywhere else in Wasik.
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`43.
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`Indeed, a POSA would have recognized that Wasik defined “the
`
`invention” in the specification as related to the treatment of lymphoproliferative
`
`disorders, e.g., PTLDs and lymphatic cancers, such as lymphomas. (Ex. 1002,
`
`Wasik at 2:23-3:2, 5:13-18.) Wasik also stated that “[n]ot previously recognized
`
`by others [was] the fact that O-alkylated rapamycin derivatives such as those
`
`described [t]herein [could] be used to alleviate or prevent lymphoma.” (Ex. 1002,
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`Wasik at 5:25-27, see also 2:29-30 (“Lymphoproliferative disorders that can be
`
`alleviated using this method include, for example, PTLDs and lymphatic cancers
`
`such as lymphomas.”).) A POSA also would have recognized that all the
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`experiments in Wasik used lymphoma cell lines, not any solid tumor cell lines.
`
`(Ex. 1002, Wasik at 3:30-5:10, 20:14-32:9.) A POSA would not have understood
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`17
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`NOVARTIS EXHIBIT 2080
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`“the invention” in the Wasik specification to relate to solid tumors, as such solid
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`tumors were never mentioned in Wasik.
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`44. A POSA also would have understood Wasik to use the term “tumor”
`
`to refer to lymphomas. For example, Wasik stated that “[i]f one or more of tumor
`
`regression, tumor eradication, and absence of a second tumor [was] observed in
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`the mouse, then this [was] an indication that the agent [was] useful for alleviating
`
`or inhibiting a post-transplant lymphoproliferative disorder in a mammal.”
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`(Ex. 1002, Wasik at 3:24-27 (emphases added).) A POSA would have understood
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`that these references to tumors were to liquid tumors derived from a transformed B
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`lymphocyte. (Ex. 1002, Wasik at 3:19-24.) In fact, Wasik repeatedly used the
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`term “tumor” and in each instance, a POSA would have understood from the
`
`context of Wasik that it referred to a liquid tumor. (Ex. 1002, Wasik at, e.g., 4:26
`
`(discussing “treatment of established tumors”), 18:23 (discussing “[i]nhibition of
`
`tumor growth”), and 19:15-16 (discussing “tumor growth (i.e., an increase in
`
`tumor size) or the development of a second
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