UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`Ameri gen Pharmaceuticals Limited and Argentum Pharmaceuticals LLC
`
`Petitioners
`
`v.
`
`Janssen Oncology, Inc.
`
`Patent Owner
`
`U.S. Patent No. 8,822,438 to Auerbach et al.
`Issue Date: September 2, 2014
`Title: Methods and Compositions for Treating Cancer
`
`Inter Partes Review No. 2016-00286'
`
`Declaration of Dr. Mark J. Ratain
`
`I declare that all statements made herein on my own knowledge are true and that
`
`all statements made on information and belief are believed to be true, and
`
`further, that these statements were made with the knowledge that willful false
`
`statements and the like so made are punishable by fine or imprisonment, or
`both,/under Sectioi 10
`f Title 18 of the United States Code.
`
`/ gré /Zea 7
`
`1 Case IPRZOI6-01317 has been joined with this proceeding.
`
`i
`i
`
`
`
`AMG 1091
`AMG 1091
`
`

`
`
`
`Contents
`I.
`Introduction ..................................................................................................... 1
`
`II.
`
`Education and Professional Background ....................................................... 1
`
`III. Legal Standards ............................................................................................ 7
`
`IV. Summary of Opinions ................................................................................... 9
`
`V. Analysis ...................................................................................................... 10
`
`A. There Was A Basis in the Prior Art to Add Prednisone to Abiraterone
`Acetate for Purposes of Glucocorticoid Replacement ....................................... 10
`
`There Was a Clinical Basis for Believing That the Combination of
`B.
`Abiraterone Acetate and Prednisone Would Be Successful in Achieving the
`Results Claimed in the ‘438 Patent ................................................................... 20
`
`There is No Evidence of Unexpected Results Supporting the Non-
`C.
`Obviousness of the Claims of the ‘438 Patent ................................................... 22
`
`1. There Is No Unexpected Difference in Results In Comparison to the
`Closest Prior Art ............................................................................................ 22
`
`2. There is no evidence that AA plus prednisone is superior to AA alone .... 25
`
`3. Unexpected results for prednisone and abiraterone cannot be inferred from
`any results for dexamethasone in combination with abiraterone .................... 30
`
`4. There is No Evidence that Use of Abiraterone in Combination with
`Prednisone in Patients with mCRPC Results in Increased Efficacy by Avoiding
`Clinical Resistance to Abiraterone ................................................................. 33
`
`D. The ‘438 Patent Claims Did Not Fulfil A Long-Felt But Unsolved Need 36
`
`The commercial success of abiraterone was expected based on the
`E.
`disclosures in O’Donnell and Barrie, as well as other prior art .......................... 37
`
`

`
`F. Other Secondary Considerations Are Not Relevant Because There is No
`Nexus Between the Attributes of the ‘438 Patent Claims and the Cited
`Considerations .................................................................................................. 38
`
`
`
`

`
`I, Mark J. Ratain, M.D., do hereby declare:
`
`I.
`
`Introduction
`
`1.
`
`At the request of Petitioners Amerigen Pharmaceuticals, Ltd. and
`
`Argentum Pharmaceuticals, LLC (“Petitioners”) in the matter of the inter partes
`
`review of U.S. Patent No. 8,822,438 (the “’438 Patent” (AMG 1001), requested by
`
`Petitioners and instituted by the Patent Trial and Appeal Board (“PTAB”) of the
`
`United States Patent and Trademark Office in Case No. IPR2016-00286 and Case
`
`No. IPR2016-01317, I have been asked to respond to certain opinions expressed in
`
`the expert declaration and deposition testimony of Matthew B. Rettig, M.D. (JSN
`
`2038) submitted on behalf of Patent Owner Janssen Oncology, Inc. (“Janssen”).
`
`2.
`
`I am being compensated for my work in this matter at the rate of
`
`$800.00 per hour. My compensation in no way depends on the outcome of this
`
`proceeding. The opinions I set forth herein are my own, and are based on the
`
`education, experience, training and skill that I have accumulated in the course of
`
`my career as a physician and researcher, as well as the materials I have reviewed in
`
`connection with this case.
`
`II. Education and Professional Background
`
`3.
`
`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
`
`1
`
`AMG 1091
`
`

`
`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.
`
`4.
`
`In 1986, I joined the Department of Medicine, Section of
`
`Hematology/Oncology and Committee on Clinical Pharmacology at the University
`
`of Chicago as an Instructor and became a Professor in that department in 1995. In
`
`2002, I was appointed as the inaugural Leon O. Jacobson Professor in the
`
`Department of Medicine at The University of Chicago.
`
`5.
`
`I have had a number of leadership roles in the University of Chicago’s
`
`Cancer Center, dating back to 1991 when I became the Director of the
`
`Developmental Therapeutics Program. Since 1999, I have been the Associate
`
`Director for Clinical Sciences, with responsibility for strategic oversight of all
`
`oncology clinical trials.
`
`6.
`
`I have also had a number of leadership roles in clinical pharmacology
`
`at the University of Chicago. In 1992, I was appointed Chairman of the
`
`University’s interdepartmental unit in clinical pharmacology, then known as the
`
`Committee on Clinical Pharmacology, whose main purpose was postdoctoral
`
`training in clinical pharmacology, primarily supported by a training grant from the
`
`National Institutes of Health (“NIH”). In 2010, my role changed, as I founded a
`
`

`
`new University Center for Personalized Therapeutics, focused on implementation
`
`of genomic prescribing, and was also appointed the first Chief Hospital
`
`Pharmacologist at the University of Chicago Medical Center, interacting closely
`
`with senior management, pharmacists, and the medical staff.
`
`7.
`
`I have 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
`
`Director from 1994 to 1997. I also chaired a Subcommittee on Phase I Clinical
`
`Trials for ASCO’s Public Issues Committee in 1996, and led the publication of
`
`ASCO’s position paper on this topic. ASCO, Critical Role of Phase I Clinical
`
`Trials in Cancer Treatment, J. CLIN. ONCOL., Vol. 15, No. 2, 853-59 (Feb. 1997)
`
`(“ASCO 1997”).
`
`8.
`
`I have also had extensive involvement with the American Society of
`
`Clinical Pharmacology and Therapeutics (“ASCPT”), an international organization
`
`comprised of clinical pharmacologists from academics, industry, and government
`
`(including FDA). Among other roles, I have served as a Director from 1997-2001,
`
`and also chaired ASCPT’s Program Committee for its 2003 meeting.
`
`9.
`
`I have received numerous honors and awards over my career. I
`
`received the 2011 Translational Research Professorship from ASCO, for my
`
`

`
`pioneering work in the pharmacogenomics of anti-cancer agents. I have also been
`
`recognized for my work in clinical pharmacology by the Pharmaceutical Research
`
`and Manufacturer’s Association of America Foundation (2015 Award in
`
`Excellence in Clinical Pharmacology), the American Association of
`
`Pharmaceutical Scientists (2009 Research Achievement Award in Clinical
`
`Pharmacology and Translational Research), ASCPT (2010 Rawls-Palmer Progress
`
`in Medicine Award), and the American College of Clinical Pharmacology (2011
`
`Honorary Fellow). I was one of approximately 60 physicians across the country
`
`elected to the Association of American Physicians in 2007, and have received
`
`awards from multiple institutions for my research accomplishments in medical
`
`oncology and clinical pharmacology, including MD Anderson Cancer Center
`
`(2008 Emil J. Freireich Award for Clinical Research), the University of North
`
`Carolina (2008 Institute for Pharmacogenomics and Individualized Therapy
`
`Clinical Service Award), the University of Nebraska (2011 Robert Hart Waldman,
`
`M.D. Annual Lecture), and the University of Utah (2012 Special Recognition,
`
`Department of Pharmaceutics and Pharmaceutical Chemistry, College of
`
`Pharmacy).
`
`10.
`
`I have served as a research reviewer for a number of committees and
`
`working groups at the NIH, as well as for several cancer societies and state
`
`departments of health.
`
`

`
`11.
`
`I have served as an editor for numerous journals, including Clinical
`
`Cancer Research (1996 to 2002, Associate Editor); Journal of Clinical Oncology
`
`(2001 to 2007; Associate Editor); Current Pharmacogenomics (2001 to 2004;
`
`Editor-in-Chief); and Pharmacogenetics and Genomics (2005 to present; Co-
`
`Editor-in-Chief).
`
`12.
`
`I have consulted extensively to the pharmaceutical industry for over
`
`25 years, primarily in the area of the development and commercialization of
`
`oncology drugs. This includes consulting services in regard to both investigational
`
`and marketed drugs. I have also interacted extensively with the pharmaceutical
`
`industry as an investigator. Thus, I am familiar with the decision-making process
`
`of the pharmaceutical industry.
`
`13.
`
`I have written more than 400 articles in peer-reviewed journals. I am
`
`additionally a named inventor on five United States patents and two foreign
`
`patents.
`
`14.
`
`I have extensive experience in the 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 many Phase 1, 2, and 3 trials of investigational and approved anti-
`
`cancer agents. This experience included membership on the Investigational Drug
`
`Steering Committee of the National Cancer Institute from 2005-2016, including
`
`

`
`leadership of that Committee from 2005-2008 and of its Clinical Trials Design
`
`Task Force from 2012-2016.
`
`15.
`
`I have specific experience in the development of drugs for the
`
`treatment of hormone-refractory prostate cancer. As one example, I participated in
`
`the design and conduct of multiple studies of suramin that were conducted and
`
`funded by the National Cancer Institute. Kobayashi et al., Phase I Study of
`
`Suramin Given by Intermittent Infusion Without Adaptive Control in Patients With
`
`Advanced Cancer, J. CLIN. ONCOL., Vol. 13, No. 9, 2196-207 (Sept. 1995); Small
`
`et al., Randomized Study of Three Different Doses of Suramin Administered With
`
`A Fixed Dosing Schedule in Patients With Advanced Prostate Cancer: Results of
`
`Intergroup 0159, Cancer and Leukemia Group B 9480, J. CLIN. ONCOL., Vol. 20,
`
`No. 16, 3369-375; Vogelzang et al., A Phase II Trial of Suramin Monthly x3 for
`
`Hormone-Refractory Prostate Carcinoma, CANCER, Vol. 100, No. 1, 65-71 (Jan.
`
`2004). I continue to be an active investigator in this area, and have recently been
`
`involved in a randomized dose-ranging trial of abiraterone acetate (“AA”) for this
`
`disease, comparing the activity of the labeled dose (1000 mg fasting) versus a
`
`lower dose (250 mg) administered with food. See, Szmulewitz, Playing Russian
`
`Roulette with Tyrosine Kinase Inhibitors, CLIN. PHARMACOL. THER., Vol. 93, No.
`
`3, 242-44 (Mar. 2013).
`
`

`
`16.
`
`In preparing this declaration, I have relied on my knowledge, training
`
`and expertise, and the documents cited herein, including the documents listed in
`
`Exhibit A, as well as the materials discussed in the Declaration of Matthew B.
`
`Rettig (“Rettig Declaration”) (JSN 2038), the Declaration of Richard Auchus
`
`(“Auchus Declaration”) (JSN 2040) and the Declaration of Gerald Walter Chodak
`
`(“Chodak Declaration”) (JSN 2042).
`
`17. A copy of my curriculum vitae, providing a list of my publications
`
`(including those for the last ten years) and describing my education, training and
`
`experience in greater detail, is attached as AMG 1092.
`
`III. Legal Standards
`
`18.
`
`I have been asked to adopt Dr. Serels’ definition of a person of
`
`ordinary skill in the art (“POSA”) at the effective filing date for purposes of this
`
`declaration. (AMG 1002 (Serels Decl.) ¶ 8.) I understand that the earliest possible
`
`effective filing date is August 25, 2006, and have used this date for my analysis.
`
`19.
`
`I understand that Patent Owner’s experts (Drs. Rettig and Auchus)
`
`have proposed a different definition of the POSA. My opinions offered here would
`
`not change if I used Patent Owner’s experts’ definition of a POSA.
`
`20.
`
`I understand that the obviousness inquiry is a question of law based
`
`on four factual predicates: (1) "the scope and content of the prior art," (2) the
`
`"differences between the prior art and the claims at issue," (3) "the level of
`
`

`
`ordinary skill in the pertinent art," and (4) “secondary considerations” such as
`
`commercial success, long-felt but unsolved needs, failure of others, and
`
`unexpected results. I also understand that the combination of familiar elements
`
`according to known methods is likely to be obvious when it does no more than
`
`yield predictable results. I understand that the motivation to combine may be
`
`found in many different places and forms.
`
`21.
`
`I have been informed that secondary considerations of non-
`
`obviousness include commercial success, satisfaction of a long-felt unmet need,
`
`unexpected results, prior failure of others, industry praise, licensing, and copying.
`
`I understand that evidence of such secondary considerations is only relevant to the
`
`obviousness analysis if the patentee can show a direct link, or nexus, between the
`
`secondary consideration and the claims of the patent, and that the evidence must be
`
`commensurate in scope with the challenged claims. I also understand that for
`
`results to be considered unexpected for these purposes, there must be a substantial
`
`difference from the prior art that would have been unexpected to a POSA at the
`
`effective date of filing. I also understand that for results to be unexpected that
`
`there must be a difference in kind, and not merely in degree.
`
`22.
`
`I am informed that the PTAB has construed the claim terms “treat,”
`
`“treating,” and “treatment” to “include the eradication, removal, modification,
`
`management or control of a tumor or primary, regional, or metastatic cancer cells
`
`

`
`or tissue and the minimization or delay of the spread of cancer.” See, Paper 14 at
`
`5; Paper 23 at 2-3. I understand that under the broadest reasonable interpretation
`
`standard that applies in this proceeding, claim terms are given their ordinary and
`
`customary meaning in view of the specification, as would be understood by one of
`
`ordinary skill in the art at the time of the invention. I also understand that while
`
`Patent Owner initially agreed with this construction of the terms “treat,” “treating,”
`
`and “treatment” (see, e.g., Paper 12 at 18), Patent Owner later argued for a
`
`narrower construction of the terms “treat,” “treating,” and “treatment” where the
`
`claims of the ‘438 patent would require “an anti-cancer effective amount of
`
`prednisone.” Request for Reconsideration at 2. Although the PTAB declined to
`
`adopt this narrower construction, see Paper 23 at 2-3, my opinions offered here
`
`would not change if instead of the construction adopted by the PTAB, the narrower
`
`definition subsequently proposed by Patent Owner applied.
`
`IV. Summary of Opinions
`
`23.
`
`I disagree with Dr. Rettig’s opinion that there was no scientific basis
`
`in the prior art to add prednisone to AA for purposes of glucocorticoid
`
`replacement.
`
`24.
`
`I disagree with Dr. Rettig’s opinion that there was no scientific or
`
`clinical basis for believing that the combination of AA and prednisone could be
`
`successful in achieving the inventions claimed in the ‘438 patent.
`
`

`
`25.
`
`I disagree with Dr. Rettig’s opinion that the invention claimed in the
`
`‘438 patent resulted in “unexpected clinical efficacy”, when compared to the
`
`closest prior art.
`
`26.
`
`I disagree with Dr. Rettig’s implied opinion that the invention claimed
`
`in the ‘438 patent resulted in unexpected commercial success, when compared to
`
`the closest prior art.
`
`27.
`
`I disagree with Dr. Rettig’s implied opinion that the invention claimed
`
`in the ‘438 patent fulfilled any long felt but unsolved need that was not met by the
`
`prior art.
`
`28.
`
`I disagree with Dr. Rettig’s implied opinion that any skepticism and
`
`failure of others is attributable to the claimed combination of AA and prednisone.
`
`V. Analysis
`
`A. There Was A Basis in the Prior Art to Add Prednisone to
`Abiraterone Acetate for Purposes of Glucocorticoid Replacement
`
`29.
`
`I first note that Dr. Rettig admitted in his deposition that he did not
`
`perform a review of any literature other than that provided to him by counsel for
`
`Janssen. Thus, Dr. Rettig ignored the abundance of prior art that would have
`
`provided a motivation for a POSA to add prednisone to AA. Had Dr. Rettig done a
`
`review of the literature, he would have immediately recognized that there were a
`
`

`
`number of reasons why a POSA would have been motivated to add prednisone to
`
`AA.
`
`30. First, a POSA would have been aware that adrenal toxicity can occur
`
`with drugs, including drugs that had undergone testing for prostate cancer, such as
`
`ketoconazole and suramin. (AMG 1004 (Gerber); AMG 1097 (Trachtenberg
`
`1984); (AMG 1098 (Kobayashi (1996))). Thus, a POSA reading O’Donnell would
`
`interpret the abnormal ACTH stimulation tests as a concern and be motivated to
`
`administer low-dose glucocorticoids, including prednisone 5 mg twice daily, to
`
`prevent the complications of adrenal insufficiency. A POSA would also
`
`understand that the clinical data reported in O’Donnell provided limited
`
`information about the toxicities of AA, since only three patients received a dose
`
`reported to be optimal (800 mg daily) and for only 12 days. Despite this short
`
`duration of dosing, there was evidence of adrenal toxicity, as manifested by
`
`consistent abnormalities in the “Synacthen test,” a British term for the test referred
`
`to in the United States as the adrenocorticotrophic hormone (ACTH) stimulation
`
`test. This was specifically characterized in a 2005 publication, (AMG 1023
`
`(Attard 2005)), coauthored by Dr. Belldegrun (one of the named inventors of the
`
`‘438 patent), and Dr. de Bono (also claimed to be an inventor of the ‘438 patent,
`
`according to papers filed by the Patent Owner in the co-pending district court
`
`litigation, see AMG 1099, as evidence of “reduced adrenocortical reserve.” (AMG
`
`

`
`1023 (Attard 2005) at 1245.) Furthermore, a POSA would understand that this test
`
`had been used to evaluate the adrenal toxicities of other drugs, including drugs
`
`under development for prostate cancer. See, e.g., (AMG 1098 (Kobayashi 1996)),
`
`(AMG 1100 (De Coster 1987)), (AMG 1101 (Feldman 1986)).
`
`31. Dr. Rettig also failed to recognize that O’Donnell (AMG 1003)
`
`reported the results of a clinical pharmacology study that provided very limited
`
`information regarding the toxicities of AA. Most Phase 1 trials of new anti-cancer
`
`agents are conducted in cancer patients seeking treatment, usually aiming to define
`
`the maximally tolerated dose and the toxicities occurring over the first 1-2 months.
`
`(AMG 1102 (Ratain 1993); AMG 1103 (Sawyer 2003); (AMG 1104 (Ryan 2004)).
`
`In contrast, O’Donnell reports only the short-term results of three studies of AA in
`
`patients with metastatic castrate-resistant prostate cancer (“mCRPC”). Two of
`
`these studies involved administration of only a single dose of AA (Studies A and
`
`B) and the third study involved administration of only 12 doses over 12 days
`
`(Study C). Although the subjects of these three studies were all patients with
`
`prostate cancer, the studies were not designed to provide treatment for the patients,
`
`since the duration was so limited. Furthermore, the duration of administration
`
`would preclude identification of side effects developing with chronic
`
`administration of AA. Thus, as of August 2006, a POSA would have understood
`
`that the preliminary data in patients with mCRPC reported in O’Donnell would
`
`

`
`require further clinical investigation of abiraterone acetate in such patients in Phase
`
`1 and 2 studies of AA to assess its safety over a period of weeks to months (rather
`
`than days) in a larger group of patients, as exemplified by the post-filing
`
`publications. Attard 2008 (JSN 2014), Attard 2009 (JSN 2015).
`
`32. Dr. Rettig did not consider the findings reported in O’Donnell in the
`
`context of the objectives and methods of that study. As one example, Dr. Rettig
`
`failed to distinguish the positive teachings of O’Donnell as based on its stated
`
`primary endpoint (i.e., the stated purpose of a study that supports the methods and
`
`sample size), from what can be gleamed from the limited information regarding its
`
`secondary endpoints (i.e., endpoints that collect additional information and may
`
`generate hypotheses to be studied further). O’Donnell notes that the primary
`
`endpoints of studies A, B, and C were as follows:
`
`A) “to determine the dose of abiraterone acetate that was sufficient to
`
`cause suppression of testosterone synthesis to undetectable levels
`(< 0.14 nmol l-1)”;
`
`B) “to determine the dose of abiraterone acetate that was sufficient to
`
`cause suppression of testosterone synthesis to castrate levels < 2.0
`nmol l-1”; and
`
`C) “to determine the dose of abiraterone acetate that was sufficient to
`
`cause persistent suppression of testosterone synthesis to castrate
`
`levels.”
`
`

`
`33. O’Donnell reports that the primary results of studies A, B, and C
`
`were as follows:
`
`A) a dose of 500 mg was required to achieve the target testosterone
`
`level;
`
`B) the maximal administered dose was 500 mg (to three patients), but
`
`no dose was indicated to cause castrate levels; and
`
`C) a dose of 800 mg daily was determined to be necessary.
`
`34. O’Donnell also notes that all three studies included multiple
`
`secondary endpoints, including “safety and tolerability” and “any other endocrine
`
`effects especially suppression of cortisol synthesis.” A POSA would understand
`
`the distinction between primary and secondary endpoints, in that the latter
`
`endpoints – while included to be maximally informative – are inconclusive,
`
`particularly in regard to information not collected (e.g., long-term safety).
`
`35. Dr. Rettig also failed to recognize that, not surprisingly, all patients
`
`treated for 12 days developed biochemical evidence of adrenal insufficiency, given
`
`the abnormal “Synacthen test.” As discussed above, the Synacthen test is more
`
`generally referred to an ACTH stimulation test. The authors of O’Donnell called
`
`out this result, noting that “[s]ome impact on adrenal reserve was predictable from
`
`the steroid synthesis pathway.” This was also characterized in a subsequent
`
`publication coauthored by Dr. Belldegrun and Dr. de Bono as evidence of “reduced
`
`adrenocortical reserve.” (AMG 1023 (Attard 2005) at 1245.) Thus, there is no
`
`

`
`dispute that an impact on adrenal reserve was predictable based on the known
`
`target of AA and the cited prior experience with ketoconazole discussed in
`
`O’Donnell. While I understand that Dr. Dorin, an endocrinologist, will be
`
`responding to Dr. Auchus’s opinions on this topic, a POSA who is a medical
`
`oncologist would also be concerned about the risks of latent adrenal insufficiency,
`
`particularly in frailer, older men with metastatic prostate cancer. A POSA would
`
`also recognize that a drug may have unrecognized targets, see AMG 1098
`
`(Kobayashi 1996), AMG 1105 (Ron 2002), AMG 1106 (Wilhelm 2004), and that
`
`the effects of a drug on adrenal function may be more complex than initially
`
`appreciated. (AMG 1098 (Kobayashi 1996)). Thus, a POSA would consider that
`
`abiraterone might inhibit other steroid biosynthetic enzymes, especially since there
`
`was no evidence to the contrary. (Notably, such studies were eventually performed
`
`and recently published. (AMG 1107 (Udhane 2016)).)
`
`36. Therefore, the findings of O’Donnell of the abnormal ACTH
`
`stimulation tests would have motivated a POSA to be concerned about the need for
`
`glucocorticoid replacement, contrary to the opinions of Dr. Rettig. This was also
`
`acknowledged by Dr. Belldegrun and Dr. de Bono in Attard 2005 (AMG 1023) at
`
`1245: “[p]atients will closely be monitored for the development of glucocorticoid
`
`insufficiency or hypertension.” Given the common use of prednisone at a dosage
`
`of 5 mg twice daily in conjunction with chemotherapy for prostate cancer, see
`
`

`
`AMG 1032 (docetaxel and prednisone); AMG 1006 (mitoxantrone and
`
`prednisone), this dosage would be the first consideration.
`
`37. O’Donnell also discloses that in the clinical use of ketoconazole to
`
`treat a patient with mCRPC, it was common practice to administer glucocorticoid
`
`replacement therapy. Based on this clinical evidence, O’Donnell teaches that
`
`supplementary glucocorticoid therapy “may prove necessary” with abiraterone
`
`acetate. O’Donnell (AMG 1003) at 2323 (emphasis added). To this end and
`
`acknowledging the limitations of the reported toxicity data, O’Donnell expressly
`
`teaches that “further studies with abiraterone acetate will be required to ascertain if
`
`concomitant therapy with glucocorticoid is required on a continuous basis, at times
`
`of physiological stress, if patients become symptomatic or indeed at all.” Id. at
`
`2323 (emphasis added).
`
`38.
`
`I disagree with Dr. Rettig that the statements in O’Donnell regarding
`
`the tolerability of AA would be reassuring to a POSA who wished to use AA to
`
`treat patients. To the contrary, a POSA would understand that treatment of patients
`
`with mCRPC would require continuous dosing of AA at a therapeutic dose over
`
`the course of many months – if not years. Thus, a POSA could not draw reliable
`
`conclusions about the spectrum, severity or frequency of toxicities of AA from
`
`O’Donnell. The limited clinical experience reported in O’Donnell at the
`
`recommended dose of 800 mg daily would only lead a POSA to hypothesize that
`
`

`
`such a dose might be tolerable over a longer period, but as expressly taught by
`
`O’Donnell (and Attard 2005 (AMG 1023)), that dosing may require supplemental
`
`glucocorticoid therapy. In fact, since only 3 patients received that dose for 12
`
`days, the total reported experience at that dose was 36 patient-days. (In contrast, a
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`typical Phase 1 trial in cancer patients would generate toxicity data for a larger
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`group of patients over a much longer duration. See AMG 1104 (Ryan 2004)
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`(2,045 days of exposure); AMG 1103 (Sawyer 2003) (128 cycles, each consisting
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`of 14-28 days of treatment, followed by a 14-day break).
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`39. Dr. Rettig also did not compare O’Donnell to the seminal 1984
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`publication by Trachtenberg (AMG 1097) reporting the results of high-dose
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`ketoconazole in 15 men with advanced prostate cancer. In contrast to O’Donnell,
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`13 of the 15 patients completed at least 6 months of therapy. Like O’Donnell,
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`there was no suggestion of any problems with toxicities during the first 12 days,
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`noting that “the side-effects did not require that therapy be stopped in any patient.”
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`(AMG 1097 at page 435.) Trachtenberg did report that after 3 months of
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`ketoconazole therapy that two patients developed darkening skin and weakness,
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`associated with borderline low urinary cortisol and an increase in ACTH
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`(corticotropin), consistent with “mild Addison’s disease”, which was treated with
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`prednisone 5 mg daily. Thus, a POSA considering the teachings of both
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`O’Donnell and Trachtenberg would immediately understand that any adrenal
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`

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`toxicities of abiraterone would potentially occur after several months of treatment,
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`and thus would consider the use of prednisone to prevent such problems, especially
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`given the abnormal ACTH stimulation test reported in O’Donnell, consistent with
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`the known effects of ketoconazole, AMG 1100 (De Coster 1987), in a similar
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`population. This same approach was used in Gerber to prevent adrenal toxicities.
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`Gerber (AMG 1004) at 1179 (reporting that, based on results of ketoconazole as
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`monotherapy, “ketoconazole as a single agent has limited use” in patients with
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`mCRPC, but that “in contrast,” a subgroup of patients with mCRPC may “derive
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`significant benefit” from the “combination of ketoconazole and physiological
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`glucocorticoid replacement therapy”).
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`40. Dr. Rettig also opines that a POSA would be concerned about the side
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`effects of glucocorticoids. Rettig (JSN 2038) at ¶¶ 123-134. While such side
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`effects might be of concern for patients without a terminal illness, patients treated
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`with docetaxel and prednisone were known to have a median survival of 18.9
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`months. Tannock 2004 (AMG 1022). Thus, the long-term side effects of
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`prednisone would not be a concern for a physician concerned about the risks of
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`latent adrenal insufficiency. Furthermore, low-dose glucocorticoids were
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`commonly prescribed to palliate symptoms in patients with metastatic terminal
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`cancer. AMG 1108 (Twycross 1992).
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`

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`41.
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`I also disagree with Dr. Rettig’s opinion that a POSA in August 2006
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`would have deemed glucocorticoids as likely to worsen the cancer. The articles
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`cited by Dr. Rettig do not support his conclusions. One article Dr. Rettig cites as
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`support for his argument is a 1996 paper by Marini (JSN 2060) focused on the use
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`of low-dose prednisone in conjunction with chemotherapy in the curative treatment
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`of breast cancer. In my opinion, a POSA in 2006 would not have considered such
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`a paper to be relevant to the common use of prednisone in the treatment of
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`mCRPC, particularly since the underlying hypothesis stated in Marini was that
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`steroids would block the microsomal hepatic activation of cyclophosphamide (an
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`inactive chemotherapy prodrug), to its active metabolite. Thus the conclusions of
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`Marini, which were to conduct further investigations of the interactions of steroids
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`and cyclophosphamide-based chemotherapy as used in the adjuvant treatment of
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`breast cancer, are not relevant to the issue of whether or not to combine steroids
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`with abiraterone for the treatment of prostate cancer. My opinion that this paper
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`would not have been relevant to a POSA in 2006 (or now) in regard to the
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`controversial use of corticosteroids in patients with prostate cancer is supported by
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`its lack of citation in any papers on this important topic. Dr. Rettig also cites a
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`preclinical study by Krishnan (JSN 2024), published in 2002. Importantly, this
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`paper does not teach that all glucocorticoids fuel prostate cancer in patients.
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`Instead, it simply teaches that some glucocorticoids stimulated the growth of a
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`

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`single prostate cancer cell line. In this context, Krishnan provides motivation to
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`study the use of triamcinolone as a treatment for prostate cancer, as well as
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`providing motivation to study whether or not prednisone is detrimental, which is
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`now an area of ongoing investigation.
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`42.
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`In contrast to Dr. Rettig’s opinions, a POSA would understand that
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`corticosteroids, including prednisone 5 mg twice daily, were specifically approved
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`by the FDA for the treatment of prostate cancer – in combination with docetaxel.
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`AMG 1032.
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`B.
`There Was a Clinical Basis for Believing That the Combination of
`Abiraterone Acetate and Prednisone Would Be Successful in Achieving
`the Results Claimed in the ‘438 Patent
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`43. As noted above, Dr. Rettig acknowledged at his deposition that he did
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`not review the prior art. Thus, it is not surprising that he appears not to be aware
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`of the extensive literature regarding the treatment of mCRPC with corticosteroids,
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`including both prednisone and dexamethasone. I first note that the ‘438 patent
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`specification discusses the combination of AA with many other anti-cancer agents,
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`including dexamethasone, and the use of such combinations for many different
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`cancers. However, the issued claims are focused on the treat