On behalf of: Par Pharmaceutical, Inc. et al.
`
`
`
`
`
`
`
`Entered: December 5, 2016
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________________
`
`PAR PHARMACEUTICAL, INC., BRECKENRIDGE PHARMACEUTICAL,
`INC., AND ROXANE LABORATORIES, INC.
`Petitioners
`
`v.
`
`NOVARTIS AG
`Patent Owner
`_______________________
`Case IPR2016-000841
`U.S. Patent No. 5,665,772
`_______________________
`
`Before LORA M. GREEN, CHRISTOPHER L. CRUMBLEY, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`
`DECLARATION OF MARK J. RATAIN, M.D. IN SUPPORT OF
`PETITIONERS’ REPLY IN THE INTER PARTES REVIEW OF U.S.
`PATENT NO. 5,665,772
`
`
`1 Breckenridge Pharmaceutical, Inc. was joined as a party to this proceeding via a
`Motion for Joinder in IPR2016-01023; Roxane Laboratories, Inc. was joined as a
`party via a Motion for Joinder in IPR2016-01102.
`
`
`
`Ex. 1119-0001
`
`

`
`
`
`CONTENTS
`
`I.
`
`II.
`
`INTRODUCTION AND QUALIFICATIONS ............................................... 1
`
`UNDERSTANDING OF THE GOVERNING LAW ..................................... 5
`
`Invalidity by Obviousness ..................................................................... 5
`A.
`Interpreting Claims Before the Patent Office ........................................ 7
`B.
`C. Materials Relied on in Forming My Opinions ...................................... 8
`
`III. The Person of Ordinary Skill in the Art of the ’772 Patent ............................. 8
`
`IV. Scope of Declaration........................................................................................ 9
`
`V.
`
`Summary of Opinions .................................................................................... 11
`
`VI. Everolimus Does Not Have Unexpectedly Different Properties
`Compared to Rapamycin ............................................................................... 13
`
`B.
`
`C.
`
`D.
`
`A. A POSA Would Have Reasonably Expected Rapamycin and
`Everolimus to Have Similar Properties in 1992 .................................. 13
`There Is No Evidence that Rapamycin Cannot Be Co-
`Administered with Cyclosporine ......................................................... 21
`Everolimus’s Shorter Half-Life Does Not Lead to an
`Unexpected Clinical Benefit ............................................................... 23
`FDA Approval Is Not a Difference in Properties Between
`Rapamycin and Everolimus ................................................................ 25
`The Prior Art Taught Rapamycin Had Antitumor Activity ................ 27
`Rapamycin Has Clinical Efficacy in Each Tumor Type for
`Which Everolimus Is Indicated ........................................................... 31
`Everolimus and Rapamycin Have Similar Activity Because
`They Are mTOR Inhibitors ................................................................. 55
`
`E.
`F.
`
`G.
`
`VII. Everolimus Did Not Satisfy Any Long-Felt Needs ....................................... 60
`
`
`
`i
`
`Ex. 1119-0002
`
`

`
`
`
`I, Mark J. Ratain, M.D., resident of Chicago, Illinois, hereby declare as
`
`follows:
`
`I.
`
`INTRODUCTION AND QUALIFICATIONS
`
`1.
`
`I have been retained by Par Pharmaceutical, Inc. (“Par”) to provide
`
`my opinion concerning the validity of U.S. Patent No. 5,665,772 (Exhibit 1001;
`
`“the ’772 patent”) in support of Petitioners’ Petition for Inter Partes Review of the
`
`’772 patent (“the ’772 Petition”).
`
`2.
`
`I graduated from Harvard University magna cum laude in 1976 with
`
`an A.B. in Biochemical Sciences. I obtained my M.D. from Yale University
`
`School of Medicine in 1980. I completed my internship and residency at the Johns
`
`Hopkins Hospital in Baltimore, MD from 1980-1983. I completed a fellowship in
`
`Hematology/Oncology at the Department of Medicine at the University of Chicago
`
`from 1986-1988.
`
`3.
`
`In 1986, I
`
`joined
`
`the Department of Medicine, Section of
`
`Hematology/Oncology at the University of Chicago as an Instructor and was
`
`promoted to Professor in that department in 1995. In 2002, I was appointed as the
`
`first Leon O. Jacobson Professor, an endowed chair, at the University of Chicago.
`
`4.
`
`I have had a secondary appointment on the Committee on Clinical
`
`Pharmacology and Pharmacogenomics (previously Committee on Clinical
`
`Pharmacology) since joining the University of Chicago faculty. I also chaired this
`
`1
`
`Ex. 1119-0003
`
`

`
`
`
`interdepartmental unit from 1992-2010. In 2010, I founded the University’s Center
`
`for Personalized Therapeutics, and still serve as its Director, as well as serving as
`
`the Chief Hospital Pharmacologist at University of Chicago Medicine.
`
`5.
`
`I have also had a number of leadership roles in the University’s
`
`Comprehensive Cancer Center. I served from 1995-1999 as Co-Director of the
`
`Clinical and Experimental Therapeutics Program and in 1999 was appointed as the
`
`Associate Director for Clinical Sciences at the Comprehensive Cancer Center at
`
`the University of Chicago.
`
`6.
`
`I have received numerous honors and awards over my career. These
`
`include election to the Association of American Physicians in 2007, and awards
`
`from multiple institutions (MD Anderson Cancer Center, University of North
`
`Carolina, University of Nebraska, University of Utah),
`
`foundations
`
`(Pharmaceutical Research and Manufacturer’s Association of America Foundation)
`
`and professional societies (American Association of Pharmaceutical Scientists,
`
`American Society for Clinical Pharmacology and Therapeutics, American Society
`
`of Clinical Oncology, American College of Clinical Pharmacology).
`
`7.
`
`I have also had extensive involvement with the American Society of
`
`Clinical Oncology (ASCO), dating back to 1990 when I was appointed Chair of
`
`ASCO’s Audit and Finance Committee. I was subsequently elected to the position
`
`of Secretary-Treasurer of ASCO, and served in that capacity as an Officer and
`
`2
`
`Ex. 1119-0004
`
`

`
`
`
`Director from 1994 to 1997. I also served as the Chair of ASCO’s Continuing
`
`Medical Education Committee from 1997 to 1999. In my capacities as Committee
`
`Chair, Officer, and Director, I participated actively in ASCO Board meetings and
`
`am familiar with ASCO’s policy and lobbying efforts to modify Medicare
`
`reimbursement policies for oral oncology drugs during the period from 1990 to
`
`1999.
`
`8.
`
`I have also had extensive involvement in clinical pharmacology
`
`organizations, including the American Society for Clinical Pharmacology and
`
`Therapeutics (ASCPT) and the American Board for Clinical Pharmacology
`
`(ABCP). ASCPT is the premier international society for clinical pharmacology
`
`and therapeutics, and includes a diverse membership from academia, industry, and
`
`government (especially FDA). I have chaired multiple committees for ASCPT
`
`over the past 25 years, and served as a Director from 1997-2001. ABCP is the
`
`entity
`
`that accredits
`
`training programs and certifies
`
`trainees
`
`in clinical
`
`pharmacology. I served ABCP as a member of its Governing Board from 2002-
`
`2007 and Chair of its Credentials Committee from 2004-2007, and continue to
`
`direct the University’s ABCP-accredited training program, which is funded in part
`
`by a Federal training grant from the National Institute of General Medical Sciences
`
`(part of the National Institutes of Health).
`
`3
`
`Ex. 1119-0005
`
`

`
`
`
`9.
`
`I have served as a research reviewer for a number of committees and
`
`working groups at the National Institutes of Health, as well as for several cancer
`
`societies and state departments of health.
`
`10.
`
`I have served as an editor for both oncology and clinical
`
`pharmacology journals, including Clinical Cancer Research (1996 to 2002,
`
`Associate Editor); Journal of Clinical Oncology (Associate Editor, 2001 to 2007);
`
`Current Pharmacogenomics (2001 to 2004, Editor-in-chief); and Pharmacogenetics
`
`and Genomics (2005 to present; Co-Editor-in-Chief).
`
`11.
`
`I have written more than 400 articles in peer-reviewed journals. I am
`
`additionally a named inventor on five United States and two foreign patents.
`
`12.
`
`I have extensive experience
`
`in clinical pharmacokinetics and
`
`development of cancer therapeutics, including chemotherapeutic agents, other
`
`small molecules (e.g., targeted compounds) and biologics. I have been involved in
`
`the design, conduct and analysis of clinical Phase 1, 2, and 3 trials for cancer
`
`therapeutics, including studies of rapamycin and its derivatives. Many of these
`
`studies have been conducted in our Developmental Therapeutics Clinic (at the
`
`University of Chicago), which was previously known as the Advanced Solid
`
`Tumor Clinic. (I have served as the director of that clinic since its founding more
`
`than 20 years ago.)
`
`4
`
`Ex. 1119-0006
`
`

`
`
`
`13. My curriculum vitae is attached as Exhibit 1064. My work in this
`
`matter is currently being billed at my standard rate of $750 per hour, with
`
`reimbursement for necessary and reasonable expenses. My compensation is not in
`
`any way contingent upon the outcome of any Inter Partes Review. I have no
`
`financial interest in the outcome of this proceeding or any related litigation.
`
`II. UNDERSTANDING OF THE GOVERNING LAW
`
`A.
`
`14.
`
`Invalidity by Obviousness
`
`I am informed by counsel that obviousness is analyzed from the
`
`perspective of a hypothetical person of ordinary skill in the art (“POSA”) at the
`
`time of the alleged invention. I am also informed by counsel for Par that a POSA
`
`is presumed to have been aware of all pertinent prior art at the time of the alleged
`
`invention.
`
`15.
`
`I am informed by counsel that 35 U.S.C. § 103 governs the
`
`determination of obviousness. According to 35 U.S.C. § 103:
`
`A patent
`
`for a claimed
`
`invention may not be obtained,
`
`notwithstanding that the claimed invention is not identically disclosed
`
`as set forth in section 102, if the differences between the claimed
`
`invention and the prior art are such that the claimed invention as a
`
`whole would have been obvious before the effective filing date of the
`
`claimed invention to a person having ordinary skill in the art to which
`
`5
`
`Ex. 1119-0007
`
`

`
`
`
`the claimed invention pertains. Patentability shall not be negated by
`
`the manner in which the invention was made.
`
`16.
`
`I am also informed by counsel that the first three factors to be
`
`considered in an obviousness inquiry are: (1) the scope and content of the prior
`
`art; (2) the differences between the prior art and the claims; and (3) the level of
`
`ordinary skill in the pertinent art. I have also been informed by counsel for Par that
`
`when a patent claims a genus, that claim is obvious if a single embodiment falling
`
`within the scope of the claims is obvious.
`
`17.
`
`I am also informed by counsel that when there is some recognized
`
`reason to solve a problem, and there are a finite number of identified, predictable
`
`solutions, a POSA has good reason to pursue the known options within his or her
`
`technical grasp. If such an approach leads to the anticipated success, it is likely the
`
`product not of innovation but of ordinary skill and common sense. In such a
`
`circumstance, when a patent simply arranges old elements with each performing
`
`the same function it had been known to perform and yields no more than one
`
`would expect from such an arrangement, the combination is obvious.
`
`18.
`
`I am also informed by counsel that certain factors, sometimes known
`
`as “secondary considerations,” must be considered, if present, when in an
`
`obviousness determination. These secondary considerations include: (i) long-felt
`
`need, (ii) unexpected results, (iii) skepticism of others of the invention,
`
`6
`
`Ex. 1119-0008
`
`

`
`
`
`(iv) teaching away from the invention, (v) commercial success, (vi) praise by
`
`others for the invention, and (vii) copying by other companies.
`
`19.
`
`I am informed by counsel that “unexpected results” require that (1)
`
`there be a difference in properties between the claimed subject matter and the
`
`closest prior art and (2) that this difference would have been unexpected to a
`
`POSA as of the date of the alleged invention. For the purposes of my analysis
`
`here, I consider the compound rapamycin to be the closest prior art to the claimed
`
`subject matter of the ’772 Patent.
`
`20.
`
`I am also informed by counsel that the earliest claimed priority for the
`
`’772 Patent is October 9, 1992. I have therefore used that day or somewhat before
`
`as the relevant time for a POSA, understanding that as time passes, the knowledge
`
`of a POSA will increase.
`
`B.
`
`Interpreting Claims Before the Patent Office
`
`21.
`
`I understand that Inter Partes Review is a proceeding before the
`
`United States Patent & Trademark Office (“PTO”) for evaluating the validity of
`
`issued patent claims. I understand that in an Inter Partes Review a claim term is
`
`given the broadest reasonable interpretation that is consistent with the patent’s
`
`specification. I understand that a patent’s “specification” includes all the figures,
`
`discussion, and originally filed claims within the patent. I understand that the PTO
`
`will look to the specification to see if there is a definition for a given claim term,
`
`7
`
`Ex. 1119-0009
`
`

`
`
`
`and if not, will apply the broadest reasonable interpretation from the perspective of
`
`a POSA at the time in which the alleged invention was made.
`
`C. Materials Relied on in Forming My Opinions
`
`22.
`
`In forming my opinions, I have relied on the declaration of Dr.
`
`Jorgensen that was submitted in support of the ’772 Petition, the other materials
`
`cited in this declaration, and my own experience, expertise, and knowledge of the
`
`person of ordinary skill in the art in the relevant timeframe.
`
`III. THE PERSON OF ORDINARY SKILL IN THE ART OF THE ’772
`PATENT
`23. The claims of the ’772 patent are directed to derivatives of rapamycin
`
`modified at the C40 position, including compositions and methods of using such
`
`derivatives.
`
`24.
`
`I have reviewed Dr. Jorgensen’s definition of a POSA as of the
`
`earliest claimed priority date, October 1992, and have been asked to use that
`
`definition in conducting my analysis. (Ex. 1003 ¶¶ 44-45.) Although I am not a
`
`medicinal chemist, I have expertise in pharmacology and oncology that gives me a
`
`similar perspective on the interpretation of the activities and properties of drugs,
`
`particularly in regard to addressing the properties of putative anticancer agents. I
`
`have also reviewed the definition of a POSA used by Dr. Burris in his declaration,
`
`and my opinions would not change if I adopted that definition.
`
`8
`
`Ex. 1119-0010
`
`

`
`
`
`IV. SCOPE OF DECLARATION
`25.
`I have been asked to respond to certain opinions of Dr. Burris and Dr.
`
`Roush related to Novartis’s allegations that the claims of the ’772 patent are not
`
`obvious.
`
`26. Dr. Roush alleges that a POSA would not have reasonably expected
`
`that (1) everolimus would have a shorter half-life than rapamycin (Ex. 2093 ¶ 151),
`
`(2) everolimus could be co-administered with “cyclosporin A” (id. ¶¶ 152-54), and
`
`(3) everolimus would have the “combination of approved anti-tumor indications”
`
`(id. ¶¶ 155-56). In addition to stating that a POSA would not have reasonably
`
`expected these properties, Dr. Roush further states that everolimus’s half-life, co-
`
`administration with “cyclosporin A,” and “combination of approved anti-tumor
`
`indications” represent unexpected results (id. ¶¶ 226-229).
`
`27. Dr. Burris states that a POSA would not have had a reasonable
`
`expectation or be able to “predict” that everolimus would have antitumor activity
`
`or would be safe and effective for advanced renal cell carcinoma (RCC) or
`
`advanced breast cancer. (Ex. 2095 ¶¶ 23, 86-97.) Dr. Burris also states that
`
`everolimus satisfied a long-felt but unmet need for safe and effective therapies for
`
`RCC and a long-felt but unmet need for safe and effective therapies for advanced
`
`breast cancer. (Id. ¶¶ 42-51 (RCC), 65-72 (breast cancer).) He further offers
`
`opinions that the combination of FDA approvals for everolimus “is unique and
`
`9
`
`Ex. 1119-0011
`
`

`
`
`
`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.” (Id. ¶ 25; see also id. ¶¶ 101-104.)
`
`28.
`
`I understand from counsel that whether or not a POSA has a
`
`“reasonable expectation” relates to the prima facie case of obviousness, rather than
`
`secondary considerations. I understand that neither Par nor Dr. Jorgensen argued
`
`that a POSA would have been motivated to modify rapamycin (1) to achieve a
`
`derivative with shorter half-life, (2) to affect the co-administration with
`
`“cyclosporin A,” or (3) to achieve a derivative that would result in a specific
`
`“combination of approved anti-tumor indications.” I also understand that Dr.
`
`Burris testified at his deposition that for his opinions related to reasonable
`
`expectation of success that he did not consider the motivation of the POSA. (Ex.
`
`1035, Burris Dep. Tr. at 19:19-24 (“Q. Okay. So you didn’t consider – you didn’t
`
`consider a motivation in coming to your conclusions on whether or not a person of
`
`ordinary skill in the art would have had a reasonable expectation of success? A.
`
`Correct.”).) For that reason, I have been asked to respond to these statements by
`
`Dr. Roush and similar statements by Dr. Burris as to what a POSA would have
`
`expected only in the context of whether these were “unexpected results,” as
`
`defined above.
`
`10
`
`Ex. 1119-0012
`
`

`
`
`
`V.
`
`SUMMARY OF OPINIONS
`29.
`
`I disagree with Dr. Roush and Dr. Burris that everolimus has any
`
`property that is unexpectedly different from rapamycin. First, I disagree that a
`
`POSA would not have reasonably expected that rapamycin and its derivative
`
`everolimus would have similar activities. Second, I disagree with Dr. Roush that
`
`the difference in labeling regarding co-administration with cyclosporine is a
`
`difference in properties between everolimus and rapamycin. Third, I disagree that
`
`a short half-life is an unexpected difference between everolimus and rapamycin. A
`
`POSA would not be surprised that an analog would have a different half-life
`
`compared to its parent. Given that the goal of the POSA would have been to
`
`increase water solubility, a shorter half-life is not unexpected, and a two-fold
`
`difference in half-life would not be unexpectedly different. Furthermore, longer
`
`half-lives allow for less frequent dosing, which improves adherence and therefore
`
`efficacy of a therapy. Thus, the longer half-life of rapamycin provides a potential
`
`clinical benefit as compared to everolimus. Fourth, I disagree that the FDA-
`
`approved antitumor indications represent a property of the compound everolimus.
`
`As such, the fact that Novartis has been able to obtain these indications for
`
`everolimus does not indicate that everolimus has any different property than
`
`rapamycin. Further, there have been no clinical studies directly comparing the
`
`activity of these two drugs. Fifth, rapamycin was reported to have antitumor
`
`11
`
`Ex. 1119-0013
`
`

`
`
`
`activity in preclinical assays as of 1992 and has since been shown to have clinical
`
`efficacy in a variety of tumors, including in each of the tumors for which
`
`everolimus has been approved. Therefore, the clinical efficacy of everolimus in
`
`these tumor types does not represent a difference in properties from rapamycin.
`
`30.
`
`I further disagree with Dr. Burris that everolimus satisfied a long-felt
`
`but unmet need in the treatment of RCC or advanced breast cancer. Rapamycin
`
`was known to have antitumor properties as of October 1992 and has since been
`
`shown to have clinical efficacy in the treatment of both RCC and breast cancer.
`
`Rapamycin was approved by the FDA in 1999 and is available for physicians to
`
`prescribe in treating their patients. And temsirolimus, whose active metabolite is
`
`rapamycin, is FDA-approved for the treatment of RCC, indicating that it has been
`
`shown to be clinically effective in randomized, placebo-controlled Phase 3 clinical
`
`studies in this tumor type. Thus, any need for a treatment for RCC or breast cancer
`
`was first met by rapamycin. Further, everolimus has not satisfied a need for
`
`treatments for RCC or breast cancer. Additional treatments for RCC and breast
`
`cancer have been developed since 1992. In fact, other treatments have been
`
`explicitly found to be superior to everolimus in the treatment of RCC in head-to-
`
`head direct comparative studies. For at least these reasons, I disagree that
`
`everolimus satisfied any long-felt need.
`
`12
`
`Ex. 1119-0014
`
`

`
`
`
`VI. EVEROLIMUS DOES NOT HAVE UNEXPECTEDLY DIFFERENT
`PROPERTIES COMPARED TO RAPAMYCIN
`A. A POSA Would Have Reasonably Expected Rapamycin and
`Everolimus to Have Similar Properties in 1992
`31. Dr. Burris states that “a POSA would not have reasonably expected
`
`everolimus and rapamycin to have antitumor activity simply because everolimus
`
`was a rapamycin analog.” (Ex. 2095 ¶ 95.) Dr. Burris identifies a handful of
`
`examples in which certain analogs of chemotherapeutic agents were shown to have
`
`“disappointing” results in clinical trials, “lack[] ‘significant activity’” in certain
`
`tumors, or found to be “significantly inferior” compared to their parents. (Id.) Dr.
`
`Burris further states that “it was also known that analogs and their parent drugs
`
`might have different toxicities.” (Id. ¶ 96.) He concludes that a POSA would not
`
`have expected that rapamycin and its analog everolimus would have similar
`
`activity and toxicity. (Id. ¶ 97.) I disagree.
`
`32. First of all, by 1992, rapamycin had already been demonstrated to
`
`have antitumor activity, as discussed below. (Section VI.E.) Second, the purpose
`
`of analog development is to make improvements to a compound, either in terms of
`
`increasing beneficial properties or decreasing harmful properties. (Ex. 1036,
`
`Robert C. Young et al., The Anthracycline Antineoplastic Drugs, 305 NEW ENG. J.
`
`MED. 139, 149 (1981) (discussing anthracyclines as “premier agents” and that
`
`“[a]nalogue development has been active, primarily to identify new agents with
`
`13
`
`Ex. 1119-0015
`
`

`
`
`
`reduced toxicity”); Ex. 1037, S. K. Carter The Clinical Evaluation of Analogs – III.
`
`Anthracyclines, 4 CANCER CHEMOTHERAPY PHARMACOLOGY 5, 5 (1980)
`
`(describing Adriamycin as “an analog that is superior to its parent” and “caused a
`
`flurry of investigation” such that “[a]nalog development work increased in many
`
`countries”).) I understand from Dr. Jorgenson’s declaration that C40 modifications
`
`to rapamycin (e.g., everolimus) would have reasonably been expected to preserve
`
`the pharmacological activity of rapamycin. (Ex. 1003 ¶¶ 141-145.) Therefore, it is
`
`my opinion that a POSA would have expected everolimus to have antitumor
`
`properties, similar to those previously demonstrated for rapamycin.
`
`33. Dr. Burris states that “the literature suggested that the mechanism of
`
`rapamycin’s observed in vivo antitumor activity was different from the mechanism
`
`by which it caused immunosuppression in vivo.” (Ex. 2095 ¶ 87, citing ¶ 85.) In
`
`¶ 85, Dr. Burris states that for rapamycin’s antitumor activity “Houchens suggested
`
`that rapamycin was ‘an inhibitor of DNA synthesis.’” (Id. ¶ 85, citing Ex. 2157 at
`
`803.) Dr. Burris further states that “it has been suggested that rapamycin exerted
`
`its immunosuppressive effect before DNA synthesis.” (Id., citing Ex. 2160 at 4.) I
`
`disagree that these references demonstrate that the prior art suggested that the
`
`mechanism of
`
`rapamycin’s antitumor activity was different
`
`from
`
`its
`
`immunosuppressant activity.
`
`14
`
`Ex. 1119-0016
`
`

`
`
`
`34. First, Houchens (Ex. 2157), which Dr. Burris relies on to support his
`
`opinion regarding the expectations of a POSA in 1992, was published in 1985,
`
`before rapamycin’s immunosuppressant activity was known, which was first
`
`reported in 1989. (Ex. 1005 at 42 (Table 1).)
`
`35. Second, as Dr. Burris acknowledged, the purpose of the research in
`
`Houchens was not directed to understanding the mechanism of rapamycin’s
`
`antitumor activity, but describes the use of a novel brain tumor model for drug
`
`screening, one of which included rapamycin. In discussing their results, the
`
`authors
`
`included a bare statement purportedly attributed
`
`to a personal
`
`communication from a pharmaceutical scientist (Randall K. Johnson) that
`
`rapamycin is a DNA synthesis inhibitor, without any supportive data. (Ex. 1035,
`
`Burris Dep. Tr. 67:25-68:19.) In my opinion, a POSA in 1992 would not have
`
`considered this unsupported statement from 1985 as reliable evidence that the
`
`mechanisms of action differ for rapamycin’s antitumor and immunosuppressant
`
`activity.
`
`36. Third, Dr. Burris states that “it had not been suggested that FKBP-
`
`binding was involved in antitumor activity.” (Ex. 2095 ¶ 88.) Dr. Burris did not
`
`and was not able to identify any references that suggested that rapamycin’s binding
`
`to FKBP was not related to its antitumor activity. (Id.; Ex. 1035, Burris Dep. Tr. at
`
`72:15-74:4, 84:3-22.) But, rapamycin’s binding to FKBP was identified from
`
`15
`
`Ex. 1119-0017
`
`

`
`
`
`cellular extracts not limited to any particular activity. (Ex. 1012 at 284 (“FKBP
`
`was shown to be the predominant rapamycin-binding protein in yeast, calf thymus,
`
`and human T cells (Jurkat).”).) Furthermore, it had been suggested that FKBP
`
`(and cyclophilin) “have a more general function, perhaps assisting in protein
`
`folding in vivo by acting as foldases” and “may have some general cellular
`
`functions,” which would suggest that its binding would impact functions other than
`
`T-cell activation. (Ex. 1012, Schreiber at 286.) I am not aware of any prior art
`
`references that analyzed and concluded that rapamycin’s mechanism of action for
`
`its antitumor activity and its immunosuppressant activity were different or that
`
`FKBP binding was not involved in rapamycin’s antitumor activity. In my opinion,
`
`a POSA in 1992 would not have concluded that a close derivative of rapamycin,
`
`such as everolimus, would not have rapamycin’s antitumor activity based on these
`
`references cited by Dr. Burris.
`
`37. Further, Dr. Burris cites several examples of drugs where analog
`
`development was not successful. (Ex. 2095 ¶¶ 95-97.) First of all, the fact that a
`
`sponsor would expend the resources to move an analog into clinical trials
`
`demonstrates an expectation that the analog would not be inferior to the parent
`
`compound. Given this expectation, it is not surprising that there would be
`
`disappointment when that expectation was not met, as cited by Dr. Burris for
`
`esorubicin (also known as 4-deoxydoxorubicin), a drug that is similar in structure
`
`16
`
`Ex. 1119-0018
`
`

`
`
`
`to its parent drug, doxorubicin (also known as Adriamycin). (Ex. 1038, Harinder
`
`S. Garewal et al., Phase I Trial of Esorubicin (4’Deoxydoxorubicin), 2. J. CLINICAL
`
`ONCOLOGY 1034 (1984).) While esorubicin was demonstrated to be quite active in
`
`lymphoma, it had disappointing activity in breast cancer. (Ex. 2162, Muggia at 57;
`
`Ex. 1039, Elaine M. Rankin et al., A Phase II Study of 4-Deoxydoxorubicin in
`
`Advanced Breast Cancer, 23 EUR. J. CANCER CLINICAL ONCOLOGY 1979 (1987);
`
`Ex. 1040, Thomas P. Miller et al., Activity of Esorubicin in Recurrent Malignant
`
`Lymphoma: A Southwest Oncology Group Study, 9 J. CLINICAL ONCOLOGY 1204
`
`(1991).)
`
`38.
`
`In some cases, analogs have been studied that “differed substantially
`
`in structure,” such as aclacinomycin, a natural product discovered in 1975. (Ex.
`
`2162 Muggia at 44-45, 56; Ex. 1041, S. T. Crooke et al., Structure-Activity
`
`Relationships of Anthracyclines Relative to Effects on Macromolecular Syntheses,
`
`14 MOLECULAR PHARMACOLOGY 290, 297 (1978); Ex. 1042, Toshikazu Oki et al.,
`
`New Antitumor Antibiotics, Aclacinomycins A and B, 28 J. ANTIBIOTICS 830, 830
`
`(1975).) While there are some structural similarities between aclacinomycin and
`
`doxorubicin, the differences between these two compounds are much greater than
`
`between doxorubicin and esorubicin, or between rapamycin and everolimus.
`
`Indeed, Dr. Burris admitted that he did not take into account the structural
`
`differences between aclacinomycin and doxorubicin in considering their different
`
`17
`
`Ex. 1119-0019
`
`

`
`
`
`activities. (Ex. 1035, Burris Dep. Tr. at 117:23-118:6, 120:2-12, 120:22-121:10,
`
`126:3-14.)
`
`Doxorubicin
`
`Aclacinomycin
`
`
`
`39.
`
`In this context, a POSA would not have a reasonable expectation that
`
`aclacinomycin would be comparable or superior to doxorubicin. Furthermore,
`
`aclacinomycin was not intentionally synthesized based on doxorubicin; they both
`
`are natural products. Thus, the negative results regarding aclacinomycin cited by
`
`Dr. Burris are not relevant to a POSA’s expectations regarding everolimus.
`
`40. Dr. Burris also cites the inferiority of carminomycin to doxorubicin to
`
`support his opinions. (Ex. 2095 ¶ 95.) I disagree, and if anything, these studies
`
`support my opinions regarding the expectations of a POSA. First of all,
`
`carminomycin is a natural product, not an analog synthesized for the purpose of
`
`improving a parent compound. Second, carminomycin was hypothesized by an
`
`experienced group of European investigators (the EORTC) to be comparable or
`
`superior to doxorubicin, as the EORTC randomized patients with advanced
`
`18
`
`Ex. 1119-0020
`
`

`
`
`
`sarcomas to carminomycin or doxorubicin. (Ex. 1043, Vivien H. Bramwell et al.,
`
`Carminomycin vs Adriamycin in Advanced Soft Tissue Sarcomas: an EORTC
`
`Randomised Phase II Study, 19 EUR. J. CANCER CLINICAL ONCOLOGY 1097
`
`(1983).) Since it would be unethical to randomize patients to a treatment expected
`
`to be inferior, the design of this study demonstrates that the researchers expected
`
`carminomycin to be comparable or superior to doxorubicin.
`
`41. Dr. Burris also quotes a 1989 study by Vorobiof. (Ex. 2095 ¶ 95,
`
`citing Ex. 2164.) Vorobiof (incorrectly) predicted that it was “improbable that
`
`[epirubicin] will be of significant value” for patients with gastric and colorectal
`
`cancer. (Ex. 2164 at 564.) It is unclear why Dr. Burris relied on this study, which
`
`included only 6 patients with gastric cancer, too small a sample size to conclude
`
`that a drug is ineffective for this disease. Furthermore, it is unclear why Dr. Burris
`
`is not aware that epirubicin has become one of the standard drugs used in the
`
`treatment of gastric cancer, demonstrating that the prediction that he cited in
`
`Vorobiof was clearly incorrect. (Ex. 1044, European Soc’y for Med. Oncology &
`
`Anticancer Fund, Stomach Cancer: A Guide for Patients (2012) at 16, 18, available
`
`at https://www.esmo.org/content/download/6635/115239/file/EN-Stomach-Cancer-
`
`Guide-for-Patients.pdf (identifying epirubicin as a drug “often” used in stomach
`
`cancer); Ex. 1045, Nat’l Comprehensive Cancer Network, Clinical Practice
`
`Guidelines in Oncology (NCCN Guidelines): Gastric Cancer – Version 3.2016, at
`
`19
`
`Ex. 1119-0021
`
`

`
`
`
`33 (2016) (describing epirubicin as part of “First-Line Therapy,” available at
`
`https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf;
`
`Ex.
`
`1046,
`
`British Columbia Cancer Agency, Drug Manual - Epirubicin (Jan. 1, 2015),
`
`available
`
`at
`
`http://www.bccancer.bc.ca/drug-database-
`
`site/Drug%20Index/Epirubicin_monograph_1Jan2015.pdf; compare Ex. 1035,
`
`Burris Dep. Tr. at 131:3-10 (“Q. Is it your opinion that epirubicin does not have
`
`clinical activity in gastric cancer? A. It’s my opinion that epirubicin doesn’t have
`
`sufficient clinical activity as demonstrated by traditional endpoints to warrant
`
`further study in stomach cancer.”).) Dr. Burris incorrectly relies on a difference in
`
`regulatory approval status to support his opinion that a POSA would not
`
`reasonably expect analogs to have similar properties, even though these analogs
`
`have both been approved by regulatory agencies. (See id. at 131:22-132:6.)
`
`42. Finally, Dr. Burris did not consider the structural differences between
`
`any of the analogs and their putative parents that he discussed in ¶¶ 95-97 in
`
`forming his opinions on the differences in their antitumor activity. (Ex. 1035,
`
`Burris Dep. Tr. at 122:12-24.) Nor did he consider the greater structural
`
`differences between the anthracycline analogs he cited relative to the structural
`
`differences between rapamycin and everolimus. (Id. at 127:23-128:14.)
`
`43. Pr