UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`PAR PHARMACEUTICAL, INC.,
`
`Petitioner,
`
`v.
`
`NOVARTIS AG,
`
`Patent Owner.
`
`
`Case IPR2016-00084
`Patent No. 5,665,772
`
`
`
`
`
`
`
`EXPERT DECLARATION OF
`DR. HOWARD A. BURRIS, III
`
`NOVARTIS EXHIBIT 2095
`Par v Novartis, IPR 2016-00084
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`Contents
`
`D. 
`
`Academic And Professional Qualifications ..................................................... 1 
`I. 
`II.  Applicable Legal Principles ............................................................................. 5 
`III.  Summary Of Opinions ..................................................................................... 7 
`IV.  Renal Cell Carcinoma .................................................................................... 13 
`A.  Overview ............................................................................................. 13 
`In October 1992, There Was A Long-Felt Unmet Need
`B. 
`For Safe And Effective Pharmaceutical Therapies For
`Advanced RCC .................................................................................... 14 
`C.  Others Tried And Failed To Develop New Therapies For
`Advanced RCC .................................................................................... 17 
`Everolimus Satisfied A Long-Felt Unmet Need For A
`Safe And Effective Therapy For Advanced RCC ............................... 21 
`V.  Advanced Breast Cancer ............................................................................... 27 
`A.  Overview ............................................................................................. 27 
`In October 1992, There Was A Long-Felt Unmet Need
`B. 
`For Safe And Effective Pharmaceutical Therapies For
`Advanced Breast Cancer ..................................................................... 30 
`C.  Others Tried And Failed To Develop New Therapies For
`Advanced Breast Cancer ..................................................................... 34 
`Everolimus Satisfied A Long-Felt Unmet Need For A
`Safe And Effective Therapy For Advanced Breast Cancer ................ 35 
`VI.  A POSA In October 1992 Would Not Have Had A Reasonable
`Expectation That Everolimus Would Have Its Antitumor
`Activity .......................................................................................................... 39 
`A.  Overview ............................................................................................. 39 
`The In Vivo Antitumor Activity Of Rapamycin Was
`B. 
`Unpredictable In October 1992 ........................................................... 43 
`
`D. 
`
`
`
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`- i -
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`E. 
`
`F. 
`
`C.  A POSA In October 1992 Would Not Have Reasonably
`Predicted What Effect A Structural Difference Would
`Have On Antitumor Activity ............................................................... 49 
`D.  A POSA In October 1992 Would Not Have Reasonably
`Expected Everolimus To Have Its Observed Antitumor
`Activity ................................................................................................ 51 
`A POSA In October 1992 Would Not Have Reasonably
`Expected The Antitumor Activity Of Everolimus Simply
`Because It Was A Rapamycin Analog ................................................ 58 
`The Absence Of Clinical Testing Of Rapamycin Prior To
`October 1992 Provides Additional Evidence That The
`Antitumor Activity Of Everolimus Would Have Been
`Unexpected .......................................................................................... 62 
`VII.  Everolimus Has Demonstrated Unexpected Properties ................................. 64 
`A.  Overview ............................................................................................. 64 
`The Combination Of FDA Approvals Of Everolimus
`B. 
`Would Have Been Unexpected In October 1992 ................................ 65 
`Rapamycin Has Not Demonstrated The Same Clinical
`Efficacy As Everolimus ...................................................................... 67 
`The Rapamycin Analog Temsirolimus Has Not
`Demonstrated The Same Clinical Efficacy As
`Everolimus ........................................................................................... 88 
`VIII.  Physicians Prescribe Afinitor® (Everolimus) Because Of The
`Clinical Benefits Of Everolimus.................................................................... 90 
`IX.  Everolimus Has Received Industry Praise For Its Use In The
`Treatment Of Advanced RCC and Breast Cancer ......................................... 95 
`
`C. 
`
`D. 
`
`
`
`ii
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`NOVARTIS EXHIBIT 2095
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`I, Dr. Howard A. Burris, III, declare as follows:
`I.
`
`Academic And Professional Qualifications
`1.
`
`I am a board certified Oncologist at the Sarah Cannon Research
`
`Institute in Nashville, Tennessee. I am currently the President of Clinical
`
`Operations, the Executive Director of Drug Development, and the Chief Medical
`
`Officer at Sarah Cannon Research Institute. I am also an Associate at Tennessee
`
`Oncology, PLLC in Nashville. I began working in both the renal cell carcinoma
`
`field and the breast cancer field in 1988. I have been involved in 27 everolimus
`
`clinical trials, including 9 related to renal cell carcinoma and 9 related to breast
`
`cancer. My curriculum vitae, which lists my professional experience and academic
`
`qualifications, is attached hereto as Exhibit 2096.
`
`2.
`
`I obtained my B.S. in chemistry in 1981 at the West Point United
`
`States Military Academy. I obtained a Doctor of Medicine degree at the
`
`University of South Alabama, College of Medicine in 1985. Between 1985 and
`
`1991, I completed my Internship, Residency in Internal Medicine, and Fellowship
`
`in Hematology/Medical Oncology at Brooke Army Medical Center at Fort Sam
`
`Houston in San Antonio, Texas.
`
`3.
`
`From 1990 to 1991, I was a Clinical Instructor in the Department of
`
`Medicine/Oncology at The University of Texas Health Science Center in San
`
`Antonio, Texas. From 1991 to 1997, I was a staff member in
`
`1
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`Hematology/Oncology Service at both the Cancer Therapy and Research Center of
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`South Texas and the Brooke Army Medical Center. Between 1991 and 1996, I
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`was an Assistant Professor in the Department of Medicine/Oncology at The
`
`University of Texas Health Science Center, and from 1996 to 1997, I was an
`
`Associate Professor there. From 1992 to 1995, I was the Associate Director, and
`
`then the Director, of Clinical Research in the Institute for Drug Development at the
`
`Cancer Therapy and Research Center of South Texas. And, from 1990 through
`
`1997, I was the Director of the Drug Development Program at the Brooke Army
`
`Medical Center.
`
`4.
`
`I am a member of the following Professional Associations: American
`
`Society of Hematology; Southwest Oncology Group; Southern Association for
`
`Oncology (Affiliation of Southern Medical Association); and the International
`
`Association for the Study of Lung Cancer. I am also a Board Member of Gilda’s
`
`Club.
`
`5.
`
`I have been involved with the American Society of Clinical Oncology
`
`(ASCO). I am currently on the following ASCO committees: Cancer Education
`
`Committee, Track Leader; Cancer Research Committee; Clinical Trial
`
`Participation Award (CTPA) Review Committee; and the Community Research
`
`Forum Council, Chair. In the past, I have been on the following ASCO
`
`committees: Board of Directors; Nominating Committee, Chair; Clinical Practice
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`2
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`Committee; Sponsorship Sub-Committee; Scientific Program Committee; and the
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`Ethics Committee.
`
`6.
`
`I have received numerous professional honors in my field. For
`
`instance, in 2014, I received the Giant of Cancer Care Award from OncLive.
`
`Giants of Cancer Care are chosen by an exclusive advisory board of 29 oncology
`
`educators, clinicians, and researchers. In evaluating criteria for selection to the
`
`inaugural class of Giants, the Advisory Board considered individuals who have
`
`made a significant contribution to patient care, clinical trials, or translational
`
`research. I was one of 16 luminaries nationwide in 2014 selected for my
`
`achievements in research and clinical practice, which includes specific recognition
`
`for my initiation of one of the largest investigational drug development programs
`
`for cancer. In 2006, I was elected by my peers to serve on the American Society of
`
`Clinical Oncology Board of Directors. In 2008, I was elected by my peers to chair
`
`the American Society of Clinical Oncology nominating committee. From 2001 to
`
`2002, I was the President of the Southern Association for Oncology. I am a fellow
`
`of the American College of Physicians and the editor of The Oncology Report.
`
`7.
`
`I have authored more than 300 published manuscripts and book
`
`chapters, and more than 480 abstracts in the oncology field, including publications
`
`concerning a phase I/II trial in the treatment of advanced renal cell carcinoma with
`
`the combination of bevacizumab/erlotinib/imatinib in 2007, a phase II trial of
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`3
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`bevacizumab and everolimus in patients with advanced renal cell carcinoma in
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`2010 (abstract 2008), a phase II trial of panobinostat in the treatment of patients
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`with refractory metastatic renal cell carcinoma in 2011, and a phase I/II trial of
`
`lenalidomide in combination with sunitinib in patients with advanced or metastatic
`
`renal cell carcinoma in 2014. More than 130 of my manuscripts and abstracts
`
`pertain to breast cancer. I have also co-authored 11 book chapters in the oncology
`
`field. The list of publications and abstracts that I have written or to which I have
`
`contributed is attached to my curriculum vitae, which is attached hereto as Exhibit
`
`2096.
`
`8.
`
`9.
`
`I have treated hundreds of renal cell carcinoma patients since 1988.
`
`I have treated thousands of breast cancer patients since 1988, and
`
`served as Principal Investigator on more than 100 breast cancer studies.
`
`10.
`
`I have been involved in more than 1000 cancer clinical trials,
`
`including phase I, II and III trials.
`
`11. On the basis of my education and experience described above, I
`
`believe I am qualified to give the opinions set out in this declaration. I am being
`
`compensated at my current customary rate of $550 per hour for consulting, $1000
`
`per hour for testifying or in-person meetings, and $250 per hour for travel. This
`
`compensation is paid to the Sarah Cannon Research Institute, LLC, and not to me
`
`4
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`personally. This compensation does not affect the content of this declaration and
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`does not depend on the outcome of these proceedings.
`
`12. The materials I considered in forming my opinions are referenced in
`
`this declaration. I also relied upon my knowledge and professional experience as a
`
`practicing physician in the oncology field.
`
`II. Applicable Legal Principles
`13. Counsel for Novartis AG (“Novartis”) has informed me that the
`
`claims of U.S. Patent No. 5,665,772 (“the ’772 patent”) are “obvious” only if their
`
`subject matter, as a whole, would have been obvious to a “person of ordinary skill
`
`in the art” (“POSA”) as of the invention date, here, October 9, 1992. I have been
`
`asked to assume that a POSA would have had a Ph.D. in medicinal or organic
`
`chemistry, or alternatively, a POSA could have had a bachelor’s or master’s degree
`
`in medicinal or organic chemistry with practical experience in the field.
`
`Additionally, the POSA here would be working in the field of drug discovery and
`
`would have access to individuals with knowledge and skills that he or she did not
`
`possess through formal training or personal experience, including someone with
`
`experience in antitumor agents.
`
`14.
`
`I understand that the Patent Trial and Appeal Board (the “Board”) of
`
`the United States Patent and Trademark Office will determine whether an
`
`invention is obvious by assessing: (i) the level of ordinary skill in the art; (ii) the
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`scope and content of the prior art; (iii) the differences between the prior art and
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`subject matter claimed; and (iv) the existence of any objective evidence of non-
`
`obviousness (“secondary considerations”), such as unexpected results, commercial
`
`success, long-felt but unmet needs, failure of others, and/or industry praise.
`
`15.
`
`In determining obviousness in cases involving new chemical
`
`compounds, like everolimus, I understand that first, the Board will consider
`
`whether a POSA would have selected the asserted prior art compound as a lead
`
`compound, or starting point, for further development and chemical modification.
`
`The Board will next consider whether the prior art would have supplied a POSA
`
`with a reason or motivation to modify a lead compound to make the claimed
`
`compound with a reasonable expectation of success. I further understand that in
`
`determining whether there would have been a reasonable expectation of success,
`
`the Board will consider whether there would have been a reasonable expectation of
`
`achieving the unique combination of properties possessed by the claimed
`
`compound; absolute predictability of the results is not required. Finally, the Board
`
`will consider the existence of any objective evidence of non-obviousness or
`
`secondary considerations where there is a causal relationship or “nexus” between
`
`the claimed compound and the objective evidence.
`
`16.
`
`I understand that unexpected results of a claimed compound are one
`
`type of objective evidence that show that a claimed compound would not have
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`been obvious. I understand that the Board will consider whether the claimed
`
`compound possesses beneficial properties that a POSA, as of the invention date,
`
`would have found surprising or unexpected. To be evidence of non-obviousness,
`
`the results must be shown to be unexpected as compared to the closest prior art.
`
`However, there is no requirement that the claimed compound’s properties were
`
`fully known as of the invention date, or that the patent contain all of the work done
`
`in studying the claimed compound.
`
`17. Commercial success of a claimed compound is another type of
`
`objective evidence that a claimed compound would not have been obvious. I
`
`understand that it is not necessary for the claimed compound to be solely
`
`responsible for the commercial success.
`
`18. A long-felt but unmet need for the claimed compound is another type
`
`of objective evidence that a claimed compound is not obvious. Failure of others to
`
`solve the problem addressed by the claimed compound is also objective evidence
`
`that a claimed compound is not obvious.
`
`19. Acclaim or praise for the claimed compound is another type of
`
`objective evidence that a claimed compound is not obvious.
`
`III. Summary Of Opinions
`20.
`I have been asked by counsel for Novartis to provide my opinions
`
`regarding whether (a) a POSA in October 1992 would have had a reasonable
`
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`expectation that everolimus would have antitumor activity and/or would be a safe
`
`and effective treatment for advanced renal cell carcinoma (“RCC”) and/or
`
`advanced breast cancer, (b) the existence of any objective evidence of non-
`
`obviousness (“secondary considerations”) of everolimus, such as unexpected
`
`results, long-felt but unmet needs, failure of others, and/or industry praise related
`
`to the efficacy and use of everolimus in the treatment of advanced RCC or
`
`advanced breast cancer, and (c) whether there is a causal relationship or “nexus”
`
`between Afinitor® (everolimus) and its commercial success.
`
`21. RCC is the most common type of kidney cancer in adults. As of
`
`October 9, 1992, there were very few options for the treatment of advanced RCC,
`
`and the outlook for patients with metastatic disease was poor. The therapies that
`
`were being used for advanced RCC, interleukin-2 (“IL-2”) and interferon-α (“IFN-
`
`α”), had low response rates and high toxicities. Numerous other therapies had
`
`been tried and failed; for the most part, advanced RCC had proved to be resistant
`
`to chemotherapy, hormonal therapies, and immunotherapies. Therefore, as of
`
`October 1992, there was an urgent need for safe and effective therapies for
`
`advanced RCC, including a need for safe and effective therapies that could be used
`
`after failure of other therapies. Everolimus satisfied that long-felt but unmet
`
`medical need.
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`22. Breast cancer is the largest cause of cancer death in women
`
`worldwide. In October 1992, the two classes of drugs available for advanced
`
`breast cancer were hormonal therapies and chemotherapy. However, it was
`
`recognized in October 1992 that there was a need for safe and effective therapies
`
`for advanced breast cancer, including therapies to overcome resistance to hormonal
`
`therapy. Although many clinical studies had been completed by October 1992,
`
`numerous therapies had failed, and a need still remained. Everolimus satisfied that
`
`long-felt but unmet medical need.
`
`23. A POSA in October 1992 would not have had a reasonable
`
`expectation that everolimus would have antitumor activity and/or would be a safe
`
`and effective therapy for advanced RCC or advanced breast cancer. First, as of
`
`October 1992, it was not known (a) why rapamycin was active in some tumor
`
`models but not others, (b) what cellular protein(s) rapamycin bound to exert its
`
`antitumor activity, or (c) what part(s) of the rapamycin molecule bound to the
`
`unknown cellular protein(s) to exert antitumor activity. Accordingly, a POSA
`
`would not have been able to reasonably predict what effect the difference in
`
`structure at the C40 position between rapamycin and everolimus would have on
`
`antitumor activity. Second, the tumor models against which rapamycin was active
`
`in vivo were notoriously overpredictive of antitumor activity such that the
`
`probability of predicting true-positive results was “very low.” As of October 1992,
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`rapamycin had not been tested in any in vivo animal models of RCC, or in any
`
`patients with advanced RCC or advanced breast cancer. A POSA in October 1992
`
`would not have reasonably predicted that rapamycin would have antitumor activity
`
`in humans. Because the mechanism of rapamycin’s in vivo antitumor activity was
`
`unknown, the uncertainty with respect to the antitumor activity of everolimus in
`
`humans would have been even greater. Accordingly, a POSA in October 1992
`
`would not have reasonably expected that everolimus would have the antitumor
`
`properties it has demonstrated, including in advanced RCC and advanced breast
`
`cancer. Third, in October 1992, it was known that immunosuppressants increased
`
`the rate of malignancy in patients, e.g., following transplant. As of October 1992,
`
`a POSA would not have reasonably expected everolimus to have antitumor activity
`
`simply because everolimus is a rapamycin analog. And the fact that rapamycin
`
`was not in clinical trials by October 1992 provides further support for my opinion
`
`that a POSA in October 1992 would not have had a reasonable expectation that
`
`everolimus would have its observed antitumor activity, including its efficacy in
`
`advanced RCC and advanced breast cancer.
`
`24. Everolimus is FDA-approved for the treatment of (1) adults with
`
`advanced RCC after failure of treatment with sunitinib or sorafenib, and (2)
`
`postmenopausal women with advanced hormone receptor-positive, HER2-negative
`
`(HR+/HER2-) breast cancer in combination with exemestane after failure of
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`treatment with letrozole or anastrozole, (3) adults with progressive neuroendocrine
`
`tumors of pancreatic origin (PNET) that are unresectable, locally advanced or
`
`metastatic, (4) adults with progressive, well-differentiated, non-functional
`
`neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin that are
`
`unresectable, locally advanced or metastatic, (5) pediatric and adult patients with
`
`tuberous sclerosis complex (TSC) (a genetic disease that causes the formation of
`
`benign tumors in different organs) who have subependymal giant cell astrocytoma
`
`(SEGA), a type of brain tumor, that requires therapeutic intervention but cannot be
`
`curatively resected, and (6) adults with renal angiomyolipoma, a type of kidney
`
`tumor, and TSC, not requiring immediate surgery.
`
`25. The above combination of FDA approvals of everolimus is unique and
`
`represents clinical benefits of everolimus that would have been unexpected in
`
`October 1992 over the observed in vivo antitumor properties of rapamycin reported
`
`in the prior art. As of October 1992, rapamycin was not approved by the FDA for
`
`any indication and as of today, rapamycin is still not approved for any of the same
`
`indications as Afinitor® (everolimus). Rapamycin has not demonstrated the same
`
`clinical efficacy in the everolimus FDA-approved antitumor indications and
`
`temsirolimus, a rapamycin analog, has failed to demonstrate clinical efficacy in
`
`phase II or III clinical trials in PNET and breast cancer patients.
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`26. Based on my experience and expertise, there is a causal connection
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`between the commercial success of Afinitor® (everolimus) and everolimus because
`
`physicians prescribe Afinitor® (everolimus) for the treatment of advanced RCC and
`
`advanced HR+/HER2- breast cancer because of the clinical benefits of everolimus
`
`and not because of Novartis’s marketing and promotion.
`
`27.
`
`In fact, Afinitor® (everolimus) has received industry praise for its use
`
`in the treatment of patients with advanced RCC and advanced breast cancer.
`
`28.
`
`In connection with Novartis v. Breckenridge, Par and Roxane, C.A.
`
`Nos. 14-1043-RGA, 14-1196-RGA and 14-1289-RGA (D. Del. August 2016),
`
`Mark J. Ratain submitted an expert report on behalf of Petitioner Par
`
`Pharmaceutical, Inc., in which Dr. Ratain disagreed with some of my opinions
`
`regarding secondary considerations.1 Dr. Ratain was both deposed in connection
`
`with the litigation and testified at trial. At both deposition and trial, Dr. Ratain
`
`either agreed with or failed to dispute many of my opinions. I have noted those
`
`uncontested issues in this declaration.
`
`
`1 See Ex 2145, Transcript of Trial Testimony of Dr. Ratain, Novartis v.
`
`Breckenridge, Par and Roxane (C.A. Nos. 14-1043-RGA, 14-1196-RGA and 14-
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`1289-RGA) (D. Del. August 31, 2016) (“Ratain Trial Tr.”) at 957:7-958:1.
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`IV. Renal Cell Carcinoma
`A. Overview
`29.
` RCC is the most common type of kidney cancer in adults. As
`
`discussed below (paragraphs 32-35), as of October 9, 1992, there were very few
`
`options for the treatment of advanced RCC, and the therapies that were being used
`
`had low response rates and high toxicities. There was a recognized need for safe
`
`and effective therapies for advanced RCC, including a need for safe and effective
`
`treatments that could be used after failure of other therapies. Many others had tried
`
`and failed to meet that need.
`
`30. Everolimus satisfied a long-felt unmet need that existed in October
`
`1992; it is FDA-approved for the treatment of adults with advanced RCC after
`
`failure of treatment with sunitinib and sorafenib. Everolimus was the first drug to
`
`demonstrate confirmed clinical efficacy in the treatment of advanced RCC after
`
`failure of prior therapy.
`
`31. Even though rapamycin was known in October 1992, it did not satisfy
`
`the need because it had not been shown to be safe and effective for the treatment of
`
`advanced RCC. Moreover, while other drugs have been FDA-approved for the
`
`treatment of advanced RCC since October 1992, is my understanding that the
`
`Board will look to the invention date of the ’772 patent to assess the presence of a
`
`long-felt and unmet need, and that the need does not have to be unmet at the time
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`everolimus became available on the market and satisfied the need for there to be
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`evidence of non-obviousness. Thus the subsequent development of the new
`
`advanced RCC therapies does not detract from the fact that everolimus satisfied a
`
`long-felt but unmet medical need that existed in October 1992.
`
`B.
`
`In October 1992, There Was A Long-Felt Unmet Need For
`Safe And Effective Pharmaceutical Therapies For Advanced RCC
`32. As of October 1992, there were very few options for the treatment of
`
`advanced RCC, and the outlook for patients with metastatic disease was poor, with
`
`a median survival of only 10 months.2 “In spite of numerous efforts to develop an
`
`effective systemic treatment for advanced RCC, the prognosis of this tumor [had]
`
`not essentially changed during the [previous] 20 years.”3 It was “unquestionable
`
`that none of the available systemic approaches [could] be recommended as
`
`
`2 Ex 2063, Wersäll. “Interleukin-2 and Interferon in Renal Cell Carcinoma.” Med
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`Oncol & Tumor Pharmacother. (1992) 9(4):71-76 (“Wersäll”) at p. 71.
`
`3 Ex 2064, Stahl et al. “Cytokines and Cytotoxic Agents in Renal Cell Carcinoma a
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`Review.” Seminars in Oncology (1992) 19(2)(suppl. 4):70-79 (1992) (“Stahl”) at
`
`p. 75.
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`standard treatment for advanced RCC.”4 Therefore, as of October 1992, “there
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`[was] an urgent need for an effective treatment of [advanced RCC].”5
`
`33. The only FDA-approved pharmaceutical therapy for advanced RCC
`
`by October 1992 was IL-2 (Proleukin® (aldesleukin)).6 Proleukin® (aldesleukin)
`
`was approved based on clinical studies showing an objective response rate of only
`
`15% (37 patients responded out of 255).7 Additionally, Proleukin® (aldesleukin)
`
`was associated with serious adverse events, including capillary leak syndrome
`
`(“CLS”), which could be fatal and resulted in black box warnings on the
`
`Proleukin® (aldesleukin) label.8 In addition to toxicity giving rise to the black box
`
`warnings, Proleukin® (aldesleukin) had severe side effects, including hypotension,
`
`tachycardia, nausea, vomiting, diarrhea, fever and/or chills, anemia, and mental
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`4 Ex 2064, Stahl at p. 76.
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`5 Ex 2063, Wersäll at p. 71; see also Ex 2145, Ratain Trial Tr. at 991:23-992:7
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`(Par’s oncology expert agreeing that, “as of October 1992, there was a long-felt,
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`unmet need for a safe and effective therapy for advanced RCC” and that “included
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`a need for therapies that could be used after failure of other therapies”).
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`6 Ex 2146, 1993 Physician’s Desk Reference for Proleukin® (“Proleukin® PDR”).
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`7 Ex 2146, Proleukin® PDR at p. 875.
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`8 Ex 2146, Proleukin® PDR at p. 874, Black Box Warning.
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`status changes, all of which occurred in over 70% of patients.9 Accordingly,
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`physicians were reluctant to prescribe Proleukin® (aldesleukin) because it was very
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`toxic, and only had a positive effect on a small subset of those who received it.
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`34.
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`In October 1992, physicians sometimes used interferon (“IFN”) to
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`treat advanced RCC, despite its lack of FDA approval for this indication, because
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`there were so few options available. It was thought that IFN treatment may
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`increase the ability of cells to induce an immune response, which would increase
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`the tumor’s susceptibility to attack the immune system.10 Analysis of studies using
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`IFN-α therapy showed an overall remission rate of only 14% (95% confidence
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`interval, 11% to 17.5%).11 Despite some remissions, IFN-α was quite toxic,
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`causing flu-like symptoms (fever, fatigue, headache, anorexia), which were dose
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`dependent.12 This treatment related toxicity could lead to decreased dosage
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`intensity, as it could cause the need for dosing delays or dose reductions.
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`9 Ex 2146, Proleukin® PDR at p. 876, Table III.
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`10 Ex 2147, Belldegrun et al. “Immunotherapy for Renal Cell Carcinoma.”
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`Seminars in Urology (1992) X(1):23-27 (“Belldegrun”) at p. 24.
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`11 Ex 2064, Stahl at p. 71.
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`12 Ex 2148, 1992 Physician’s Desk Reference for Intron® A at p. 2101.
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`35. As of October 1992, tumor progression while on systemic therapy or
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`shortly after discontinuing such treatment was also a recognized problem in
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`advanced RCC.13 Accordingly, the long-felt need that existed at that time
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`encompassed a need for more than one safe and effective therapy for advanced
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`RCC and a need for safe and effective therapies that could be used after failure of
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`other therapies.14
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`C. Others Tried And Failed To Develop
`New Therapies For Advanced RCC
`36. Prior to 1992 (and after), it was thought that immune mechanisms
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`played an important role in regulating tumor growth and this had fostered
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`extensive study of immunotherapy for advanced RCC.15 Immunotherapy is
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`treatment that uses the patient’s own immune system to try to fight the cancer.
`
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`13 See Ex 2065, Merimsky and Chaitchik. “Our experience with interferon alpha:
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`renal cell carcinoma.” Mol. Biother. 4(3):130-134 (1992) (“Merimsky”) at p. 133.
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`14 See Ex 2145, Ratain Trial Tr. at 991:23-992:7 (Par’s oncology expert agreeing
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`that, “as of October 1992, there was a long-felt, unmet need for a safe and effective
`
`therapy for advanced RCC” and that “included a need for therapies that could be
`
`used after failure of other therapies”).
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`15 Ex 2064, Stahl at p. 70.
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`Both lymphokine-activated killer (LAK) cells and tumor-infiltrating lymphocytes
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`(TILs) had been tested by October 1992, but were no more successful than IL-2 or
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`IFN monotherapy.16 And LAK therapy was complicated by severe and partially
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`life-threatening side effects that required treatment of many of the patients in
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`intensive care units.17
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`37. A further study was also performed to explore tumor necrosis factor
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`(“TNF”)18 as a potential therapy for advanced RCC patients “[i]n view of the low
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`objective response rate to IFN . . . and the considerable reported toxicity of
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`interleukin-2 plus LAK cells.”19 TNF is another type of immunotherapy. In the
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`phase II study, however, researchers found TNF to cause moderate to severe
`
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`16 Ex 2064, Stahl at p. 74.
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`17 Ex 2064, Stahl at p. 74.
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`18 TNF is a cytokine, i.e., a substance produced by white blood cells that acts upon
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`other cells, which had been implicated in tumor regression.
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`19 Ex 2149, Skillings et al. “A Phase II Study of Recombinant Tumor Necrosis
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`Factor in Renal Cell Carcinoma: A Study of the National Cancer Institute of
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`Canada Clinical Trials Group.” Journal of Immunology (1992) 11(1):67-70
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`(“Skillings”) at p. 67.
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`18
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`toxicity with a low response rate of only 8%.20 Because of this toxicity and
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`minimal activity, researchers determined TNF was not worth pursuing further for
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`advanced RCC.21
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`38. Extensive attempts had also been made to develop a chemotherapeutic
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`treatment for advanced RCC. But by October 1992, advanced RCC was seen as
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`resistant to chemotherapies.22 Yagoda et al. summarized 139 publications from
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`1983-1992 using 77 different chemotherapies and hormonal therapies (alone or in
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`combination with immunotherapy) to treat advanced RCC, including in numerous
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`patients who had received at least one prior therapy.23 These studies showed
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`“dismal” results.24 Drugs and drug combin