Paper No. ___
`Date Filed: March 10, 2016
`
`David T. Pritikin
`Bindu Donovan
`SIDLEY AUSTIN LLP
`787 Seventh Avenue
`New York, NY 10019
`Tel.: (212) 839-5300
`Fax: (212) 839-5599
`ZytigaIPRTeam@sidley.com
`
`
`
`Filed on behalf of Janssen Oncology, Inc.
`By: Dianne B. Elderkin
`Barbara L. Mullin
`Ruben H. Munoz
`AKIN GUMP STRAUSS HAUER
`& FELD LLP
`Two Commerce Square
`2001 Market Street, Suite 4100
`Philadelphia, PA 19103
`Tel: (215) 965-1200
`Fax: (215) 965-1210
`JANS-ZYTIGA@akingump.com
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________________
`
`AMERIGEN PHARMACEUTICALS LIMITED,
`Petitioner
`
`v.
`
`JANSSEN ONCOLOGY, INC.,
`Patent Owner.
`
`_______________________________
`
`CASE No. IPR2016-00286
`U.S. Patent No. 8,822,438 B2
`_______________________________
`
`
`
`JANSSEN ONCOLOGY, INC.’S PATENT OWNER PRELIMINARY
`RESPONSE UNDER 37 C.F.R. § 42.107
`
`
`
`
`
`
`

`
`
`
`TABLE OF CONTENTS
`
`I.
`II.
`
`V.
`
`B.
`C.
`
`C.
`
`Page
`INTRODUCTION ..................................................................................................... 1
`BACKGROUND ....................................................................................................... 7
`A.
`Prostate Cancer Treatment Prior to the Discovery of the ‘438 Patent
`Invention .......................................................................................................... 7
`The Initial Failed Efforts to Develop Abiraterone Acetate .................. 10
`The Discovery of the ‘438 Patent Invention ........................................... 11
`1.
`The Inventors’ Unexpected Discovery That Treatment with
`Abiraterone Acetate and Prednisone Has Therapeutic Effects 11
`The ‘438 Patent .................................................................................. 16
`2.
`ZYTIGA® ..................................................................................................... 17
`D.
`PERSON OF ORDINARY SKILL IN THE ART ............................................ 18
`III.
`IV. CLAIM CONSTRUCTION ................................................................................... 18
`A. Amerigen’s Proposed Constructions ........................................................ 18
`B.
`“Therapeutically Effective Amount of Prednisone” .............................. 18
`THE PRIOR ART CITED BY AMERIGEN ..................................................... 19
`A. O’Donnell (2004) ......................................................................................... 19
`B.
`Gerber et al (1990) ....................................................................................... 23
`C.
`The ‘213 Patent ............................................................................................. 25
`VI. AMERIGEN FAILS TO SHOW A REASONABLE LIKELIHOOD THAT
`ANY CLAIM OF THE ‘438 PATENT WAS OBVIOUS ............................... 27
`Standard for Granting Inter Partes Review ............................................ 28
`A.
`B.
`Amerigen’s Petition Should be Denied Because it Ignores the Claim
`Element “Therapeutically Effective Amount of Prednisone” .............. 29
`Amerigen’s Petition Should Be Denied Because It Admits that the
`Claimed Method of Treatment is Not Obvious ...................................... 30
`D. Amerigen’s Petition Should Be Denied Because Ground 1 Does Not
`Render Obvious Claims 1-20 of the ‘438 Patent .................................... 32
`1.
`The Prior Art Relied On by Amerigen Does Not Teach the
`Problem of Mineralocorticoid Excess ........................................... 32
`Dr. Serels’s Conclusory Assertion That Mineralocorticoid
`Excess Would Be Expected Is Factually Unsupported .............. 33
`There Is Nothing In Amerigen’s Petition That Might Establish
`That Mineralocorticoid Excess Would Be A Problem With
`Abiraterone Acetate .......................................................................... 35
`
`2.
`
`3.
`
`
`
`ii
`
`

`
`4.
`
`b.
`
`Amerigen Has Not Shown a Motivation to Combine O’Donnell
`(2004) with Gerber (1990) .............................................................. 37
`a.
`The prior art demonstrated that abiraterone acetate does
`not cause side effects relating to cortisol suppression. ... 38
`It is only with hindsight that Amerigen can argue that the
`prior art taught that prednisone should be administered
`with abiraterone acetate. ................................................. 39
`Ground 2 Does Not Render Obvious Claims 1-4 and 6-11 of the '438
`Patent .............................................................................................................. 44
`VII. OBJECTIVE INDICIA SUPPORT THE NON-OBVIOUSNESS OF THE
`‘438 PATENT .......................................................................................................... 46
`A. Unexpected Results Of The ‘438 Patent Method ................................... 47
`B.
`Long-Felt Need For The ‘438 Patent Method ......................................... 48
`C.
`Commercial Success Of The ‘438 Patent Method ................................. 48
`VIII. ADDITIONAL FLAWS IN AMERIGEN’S PETITION WARRANT
`DENYING INSTITUTION OF INTER PARTES REVIEW ........................... 52
`A. Amerigen Fails to Meet the Requirements of 35 U.S.C. § 311(b) ...... 52
`B.
`Amerigen’s Obviousness Arguments Are Redundant ........................... 52
`C.
`The Petition Should be Rejected Under 35 U.S.C. § 325(d) ................ 54
`D.
`The Petition Is an Improper Use of the IPR Proceeding and/or an
`Abuse of Process Under AIA, §§ 316(a)(6) & 316(b) .......................... 55
`IX. CONCLUSION ........................................................................................................ 56
`
`E.
`
`
`
`iii
`
`
`
`
`
`

`
`LISTING OF EXHIBITS PURSUANT TO 37 C.F.R. § 42.63(e) AND TABLE
`OF ABBREVIATIONS
`
`
`
`Exhibit
`
`JSN 2003
`
`Description
`
`Remington – The Science and Practice of Pharmacy, 20th ed., pp.
`
`1363-1370 (2000)
`
`JSN 2004
`
`Rumohr and Chang, “Current chemotheratpeutic approaches for
`
`androgen-independent prostate cancer,” Current Opinion in
`
`Investigational Drugs, 7(6):529-533 (2006)
`
`JSN 2005
`
`Declaration of Professor Ian Judson, dated June 29, 2015, cited in
`
`the Opposition of European Patent 2 061 561
`
`JSN 2006
`
`Clinical Cancer Research Peer Review letter to Judson, dated May
`
`12, 2003
`
`JSN 2007
`
`Burgess and Roth, “Changing Perspectives of the Role of
`
`Chemotherapy in Advanced Prostate Cancer,” Urol. Clin. N. Am.,
`
`33:227-236 (2006)
`
`JSN 2008
`
`Strother et al., “Novel cytotoxic and biological agents for prostate
`
`cancer: Where will the money be in 2005?,” European Journal of
`
`Cancer, 41:954-964 (2005)
`
`JSN 2009
`
`Hadaschik et al., “Novel targets and approaches in advanced
`
`
`
`iv
`
`

`
`Exhibit
`
`Description
`
`prostate cancer,” Current Opinions Urology, 17:182-187 (2007)
`
`JSN 2010
`
`Papatsoris et al., Novel Biological Agents for the Treatment of
`
`Hormone-Refractory Prostate Cancer (HRPC), Current Medicinal
`
`Chemistry, 12:277-296 (2005)
`
`JSN 2011
`
`Armstrong and Carducci, “New drugs in prostate cancer,” Current
`
`Opinions Urology, 16:138-145 (2006)
`
`JSN 2012
`
`Duc et al., “In vitro and in vivo models for the evaluation of potent
`
`inhibitors of male rat 17α-hydroxylase/C17,20-lyase,” Journal of
`
`Steroid Biochemistry & Molecular Biology, 84:537-542 (2003)
`
`JSN 2013
`
`Boehringer-Ingelheim-BTG Press Release – “NEW TREATMENT
`
`FOR PROSTATE CANCER UNDER DEVELOPMENT,” dated
`
`May 22, 1996
`
`JSN 2014
`
`Attard et al., “Phase I Clinical Trial of a Selective Inhibitor of
`
`CYP17, Abiraterone Acetate, Confirms That Castration-Resistant
`
`Prostate Cancer Commonly Remains Hormone Driven,” Journal of
`
`Clinical Oncology, 26(28):4563-4571 (2008)
`
`JSN 2015
`
`Attard et al., “Selective Inhibition of CYP17 With Abiraterone
`
`Acetate Is Highly Active in the Treatment of Castration-Resistant
`
`
`
`v
`
`

`
`Exhibit
`
`Description
`
`Prostate Cancer,” Journal of Clinical Oncology, 27(23):3742-3748
`
`(2009)
`
`JSN 2016
`
`Danila et al., “Phase II Multicenter Study of Abiraterone Acetate
`
`Plus Prednisone Therapy in Patients With Docetaxel-Treated
`
`Castration-Resistant Prostate Cancer,” Journal of Clinical
`
`Oncology, 28(9):1496-1501 (2010)
`
`JSN 2017
`
`Ryan et al., “Phase II Study of Abiraterone in Chemotherapy-Naïve
`
`Flare Discordant with Serologic Response Metastatic Castration-
`
`Resistant Prostate Cancer Displaying Bone,” Clinical Cancer
`
`Research, 17:4854-4861 (2011)
`
`JSN 2018
`
`Jubelirer and Hogan, “High Dose Ketoconazole For The Treatment
`
`Of Hormone Refractory Metastatic Prostate Carcinoma: 16 Cases
`
`And Review Of The Literature,” The Journal of Urology, 142:89-
`
`91 (1989)
`
`JSN 2019
`
`Public Citizen Press Room Release – “Antifunal Treatment Should
`
`Be Taken Off the Market, Public Citizen Tells FDAD,” dated
`
`February 24, 2015
`
`JSN 2020
`
`Williams et al., “Objective Responses to Ketoconazole Therapy in
`
`Patients with Relapsed Progressive Prostatic Cancer,” British
`
`
`
`vi
`
`

`
`Exhibit
`
`Description
`
`Journal of Urology, 58:45-51 (1986)
`
`JSN 2021
`
`Boumpas et al., “Glucocorticoid Therapy for Immune-mediated
`
`Diseases: Basic and Clinical Correlates,” Ann. Internal Medicine,
`
`119:1198-1208 (1993)
`
`JSN 2022
`
`Debruyne and Witjes, “Ketoconazole High Dose (H.D.) In The
`
`Management Of Metastatic Prostatic Carcinoma,” The Journal of
`
`Urology, 135(4, pt.2):203A, Abstract 397 (1986)
`
`JSN 2023
`
`Herr and Pfitzenmaier, “Glucocorticoid use in prostate cancer and
`
`other solid tumours: implications for effectiveness of cytotoxic
`
`treatment and metastases,” The Lancet, 7:425-430 (2006)
`
`JSN 2024
`
`Krishnan et al., “A Glucocorticoid-Responsive Mutant Androgen
`
`Receptor Exhibits Unique Ligand Specificity: Therapeutic
`
`Implications for Androgen-Independent Prostate Cancer,”
`
`Endocrinology, 145:1889-1900 (2002)
`
`JSN 2025
`
`Conde and Aronson, “Risk factors for male osteoporosis,” Urologic
`
`Oncology, 21:380-383 (2003)
`
`
`
`vii
`
`
`
`
`
`

`
`
`
`Abbreviation
`
`ADT
`
`Boehringer
`
`BTG
`
`CYP17
`
`DHT
`
`IC50
`
`KSP
`
`mCRPC
`
`PSA
`
`Skilled person
`
`TABLE OF ABBREVIATIONS
`
`Definition
`
`Androgen deprivation therapy
`
`Boehringer Ingelheim
`
`BTG International Ltd.
`
`Cytochrome P450 17α-hydroxylase/ C17, 20-lyase
`
`Dihydrotestosterone
`
`Half maximal inhibition concentration
`
`Kinesin spindle protein
`
`Metastatic castration-resistant prostate cancer
`
`Prostate specific antigen
`
`Person of ordinary skill in the art
`
`
`viii
`
`
`
`
`
`

`
`I.
`
`INTRODUCTION
`
`Patent Owner Janssen Oncology, Inc. (“Janssen”) submits this Patent Owner
`
`Preliminary Response to the Petition by Amerigen Pharmaceuticals Limited
`
`(“Amerigen”) for Inter Partes Review (“IPR”) of U.S. Patent No. 8,822,438 (the
`
`“‘438 patent”). The Board should deny Amerigen’s petition because it does not
`
`establish that Amerigen has a reasonable likelihood of prevailing on obviousness
`
`with respect to any challenged claim.
`
`The ‘438 patent is directed to novel and non-obvious methods for the
`
`treatment of prostate cancer in which “a therapeutically effective amount of
`
`abiraterone acetate” is administered in combination with “a therapeutically
`
`effective amount of prednisone.” (See, e.g., AMG Ex. 1001 at Col. 16, Claim 1).
`
`Abiraterone acetate, first discovered in the early 1990s, is a prodrug for
`
`abiraterone, a specific inhibitor of Cytochrome P450 17α-hydroxylase/ C17, 20-lyase
`
`(“CYP17”) – an enzyme involved in testosterone synthesis in the body.
`
`Abiraterone acetate is described and claimed in United States Patent No. 5,604,213
`
`(the “‘213 patent”), which patent is incorporated by reference in the specification
`
`of the ‘438 patent.
`
`Abiraterone acetate was initially explored as a monotherapy for prostate
`
`cancer in a series of Phase I studies sponsored by Boehringer Ingelheim
`
`(“Boehringer”) designed to establish its safety (but not the efficacy). By 1999,
`
`
`
`

`
`however, Boehringer had abandoned the abiraterone acetate development program.
`
`Phase II and III clinical trials that would have been needed to prove that
`
`abiraterone acetate was clinically effective for treating prostate cancer were not
`
`performed. For the next five years no other pharmaceutical company or other
`
`institution was willing to risk sponsoring any further clinical trials using
`
`abiraterone acetate.
`
`Prednisone is a synthetic glucocorticoid, a type of steroid that regulates the
`
`use of carbohydrates and proteins in the body, and is typically used clinically for
`
`its anti-inflammatory effects. (JSN Ex. 2003[Remington (2000)] at 1363-64); see
`
`also AMG Ex. 1001 at Col. 10, lines 15-21). Prednisone was known at the time of
`
`the original Boehringer trials, but patients in the trials “were not allowed to take
`
`concomitant steroids.” (AMG Ex. 1003 [O’Donnell (2004)] at 2319). At the time,
`
`glucocorticoids, such as prednisone, were known to have various undesirable side
`
`effects, and were thought to potentially stimulate the growth of prostate cancer
`
`cells.
`
`The inventors of the ‘438 patent discovered that the therapeutic anti-cancer
`
`effects of abiraterone acetate treatment may be enhanced and prolonged by
`
`administering abiraterone acetate and prednisone, each in a therapeutically
`
`effective amount, to prostate cancer patients. The inventors had the insight that
`
`prostate cancer patients could obtain far better therapeutic benefits if treated using
`
`
`
`2
`
`

`
`both drugs in therapeutically effective amounts than if treated with either
`
`abiraterone acetate or prednisone alone.
`
`It is undisputed that the prior art does not report that prednisone had ever
`
`been administered together with abiraterone acetate prior to the invention of the
`
`‘438 patent.
`
`As Amerigen also concedes, none of the prior art it relies upon teaches or
`
`suggests that prednisone could have any anti-cancer effect, much less that it would,
`
`in combination with abiraterone acetate, provide an unexpectedly effective
`
`treatment for prostate cancer. The inventors of the ‘438 patent followed a path that
`
`was contrary to the prior art to discover the beneficial therapeutic effect of the
`
`combination treatment using abiraterone acetate and prednisone in patients with
`
`prostate cancer, opening the doors for the late stage clinical development and
`
`commercialization of Janssen’s prostate cancer drug ZYTIGA®.
`
`Amerigen’s analysis of the prior art completely ignores this inventive aspect
`
`of the ‘438 patent by failing to address that the ‘438 patent claims expressly
`
`require a “therapeutically effective amount of prednisone.” (Pet. at 5 (describing
`
`the claims as directed to “administering therapeutically effective amounts of
`
`abiraterone acetate ... in combination with prednisone”)). Amerigen’s failure to
`
`address this claim element, i.e., “therapeutically effective amount of prednisone,”
`
`in its obviousness analysis is fatal to its petition.
`
`
`
`3
`
`

`
`The admissions of Amerigen and its obviousness expert, Dr. Scott Serels
`
`(“Dr. Serels”), demonstrate that Amerigen has not established the requisite
`
`reasonable likelihood of success of prevailing in demonstrating obviousness as to
`
`any claim of the ‘438 patent. Indeed, Amerigen and Dr. Serels repeatedly admit
`
`that the enhanced anti-cancer effect of a treatment method in which a
`
`therapeutically effective amount of prednisone is administered in combination with
`
`abiraterone acetate – the claimed invention – is unexpected and contrary to the
`
`teachings of the prior art. (See, e.g., Pet. at 14, 23, 27, AMG Ex. 1002 at ¶ 74).
`
`Given these admissions, Amerigen cannot prevail in demonstrating obviousness of
`
`any claim, and its petition should, accordingly, be denied.
`
`Nonetheless, even if the Board were to overlook the requirement for a
`
`“therapeutically effective amount of prednisone” in the ‘438 patent claims,
`
`Amerigen’s obviousness arguments, which are based upon three prior art
`
`references, O’Donnell (2004) (which was a principal focus during the ‘438
`
`prosecution), Gerber (1990) (which was also considered by the Examiner) and the
`
`‘213 patent (which is incorporated by reference in the ‘438 specification), would
`
`still lack merit. Indeed, these are exactly the kind of arguments Congress sought to
`
`discourage in authorizing the Office to deny institution based on petitions that
`
`simply raise “the same or substantially the same prior art or arguments” as those
`
`
`
`4
`
`

`
`previously considered by the Office. See 35 U.S.C. § 325(d); see also infra
`
`Section VIII.D.
`
`Amerigen argues that a person of ordinary skill in the art (the “skilled
`
`person”) would have combined O’Donnell (2004) or the ‘213 patent with Gerber
`
`(1990) with a reasonable expectation of success in arriving at the claimed
`
`invention because: (1) O’Donnell (2004) or the ‘213 patent allegedly taught
`
`administration of a therapeutically effective amount of abiraterone acetate to treat a
`
`patient with prostate cancer; and (2) Gerber (1990) allegedly taught that
`
`ketoconazole (an anti-fungal agent with a different mechanism of action that was
`
`never approved by the FDA to treat prostate cancer) could safely and effectively be
`
`administered with prednisone. (See generally Pet. at 36-40). According to
`
`Amerigen, the skilled person would have understood from the prior art that it relies
`
`on in its petition that ketoconazole administration caused a side effect known as
`
`“mineralocorticoid excess”, which results in hypertension, hypokalemia, and fluid
`
`retention. Amerigen further contends that the skilled person would have believed
`
`that the same side effect would occur following abiraterone acetate administration,
`
`and would have been motivated to add prednisone to abiraterone acetate to prevent
`
`this side effect. This argument has two critical – and fatal – flaws.
`
`First, the data from the Boehringer Phase I clinical trials described in
`
`O’Donnell (2004) showed that abiraterone acetate was safe and well-tolerated as a
`
`
`
`5
`
`

`
`monotherapy, and its administration did not result in a significant change in serum
`
`cortisol levels of patients. Because serum cortisol levels remained normal, the
`
`skilled person would have understood from O’Donnell (2004) that abiraterone
`
`acetate treatment would not cause any side effects associated with cortisol
`
`suppression (including the alleged “mineralocorticoid excess”), meaning that
`
`administration of prednisone would have been contraindicated. Indeed, O’Donnell
`
`(2004) mentions that further studies would be needed to see if a glucocorticoid
`
`would need to be used at all. The skilled person would thus not have concluded
`
`from O’Donnell (2004) that the administration of prednisone should be combined
`
`with administration of abiraterone acetate, much less expected that a greatly
`
`enhanced anti-cancer effect could result from such a combination.
`
`Second, both Amerigen and Dr. Serels admit that “administration of
`
`glucocorticoids, including prednisone, is known to have many significant adverse
`
`effects” (AMG Ex. 1002 at ¶ 85), a fact that militates against the administration of
`
`prednisone in any treatment regimen, and especially one in combination with
`
`abiraterone acetate. Due to prednisone’s known side effects, a person of ordinary
`
`skill would not only have concluded that prednisone use was unnecessary, but also
`
`that the administration of prednisone with abiraterone acetate was undesirable.
`
`Because Amerigen has not established either a motivation to combine nor a
`
`reasonable expectation of success in arriving at the claimed invention, it cannot
`
`
`
`6
`
`

`
`prevail on obviousness as to any claim of the ‘438 patent. Additional reasons for
`
`denial of inter partes review include Amerigen’s failure to meet the requirements
`
`of 35 U.S.C. §§ 311(b), redundancy, and that the petition should be rejected under
`
`35 U.S.C. § 325(d).
`
`II. BACKGROUND
`
`A.
`
`Prostate Cancer Treatment Prior to the Discovery of the ‘438
`Patent Invention
`
`Prostate cancer results from the uncontrolled growth of abnormal cells in the
`
`prostate gland. Once a prostate cancer tumor develops, androgens such as
`
`testosterone promote prostate cancer growth. At its early stages, localized prostate
`
`cancer is often curable with local therapy including, for example, surgical removal
`
`of the prostate gland and radiotherapy. However, when local therapy fails to cure
`
`prostate cancer, as it does in up to a third of men, the disease progresses into
`
`incurable metastatic cancer (i.e., disease in which the cancer has spread from one
`
`part of the body to other parts).
`
`In 2006, early stage metastatic prostate cancer was treated with androgen
`
`deprivation therapy (“ADT”) by surgical or medical castration. This remains the
`
`case today. ADT reduces testosterone to “castrate” levels. Because the aim of
`
`ADT is to reduce circulating levels of androgens, it is considered a first-line
`
`“hormonal therapy.”
`
`In almost all patients with metastatic prostate cancer, however, the response
`
`
`
`7
`
`

`
`to ADT is short-lived and the prostate cancer progresses into a state known as
`
`“metastatic castration-resistant prostate cancer” (“mCRPC”). In 2006, this
`
`condition was also described as “hormone-resistant prostate cancer,” “hormone-
`
`refractory prostate cancer,” or “androgen-independent prostate cancer.” In 2006,
`
`once a patient’s prostate cancer progressed to a castration-resistant state, the
`
`patient’s prognosis was dismal.
`
`In 2006, the mechanism for subsequent progression to mCRPC was not fully
`
`understood and it was believed that there were many different contributing factors.
`
`(JSN Ex. 2004 [Rumohr (2006)] at 529). There was a general skepticism that the
`
`reduction of testosterone levels to “sub-castrate” levels would benefit patients who
`
`were “castration resistant.” (See, e.g., JSN Ex. 2005 at ¶ 8; JSN Ex. 2006 at 2).1
`
`In 2006, a mCRPC diagnosis typically led to death within about 12 months.
`
`Traditionally, the focus of treatment at the early stage of mCRPC was symptomatic
`
`relief (otherwise referred to as palliative care). However, following two
`
`“landmark” Phase III clinical trials showing a survival benefit of docetaxel
`
`chemotherapy in mCRPC patients, future clinical trials became focused on
`
`building on the survival improvement seen with docetaxel-based therapy. (JSN
`
`
`1 Janssen Exhibits JSN 2005 and JSN 2006 were cited in the Opposition of
`
`European patent 2061561, the European equivalent of the ‘438 patent.
`
`
`
`8
`
`

`
`Ex. 2007 [Burgess & Roth (2006)] at Abstract, 227, 231, 233; see also AMG Ex.
`
`1022). In addition to the subsequent surge in clinical trials evaluating docetaxel-
`
`based regimens, new classes of cytotoxic agents were under development including
`
`kinesin spindle protein (KSP) inhibitors (e.g. SB-715992) and epothilones (e.g.
`
`EPO906, BMS-247550), as well as myriad promising new cytotoxic agents in
`
`known classes (e.g. satraplatin, amonafide). (JSN Ex. 2008 [Strother (2005)] at
`
`954-55; JSN Ex. 2009 [Hadaschik (2007)] at 185).
`
`Although the focus of future therapies was on cytotoxic chemotherapy, a
`
`wide range of alternative treatment strategies for mCRPC continued to be
`
`explored, including, for example, immunotherapy approaches such as vaccines,
`
`activated autologous dendritic cells, and monoclonal antibodies; gene therapy
`
`approaches; and targeted biological agents. Among the biological agents were
`
`numerous sub-classes of agents such as growth factor inhibitors, signal
`
`transduction inhibitors, apoptosis regulators, cell-cycle regulators, proteasome
`
`inhibitors, neo-angiogenesis inhibitors, anti-metastatic agents, differentiation
`
`agents, and epigenetic therapeutics. (JSN Ex. 2010 [Papatsoris (2005)] at 278).
`
`Each of these sub-classes of therapeutic strategies had many potential candidates
`
`under development, many of which were in Phase I, Phase II, and Phase III clinical
`
`trials at the time of the invention. (Id. at 279-80). In fact, as of 2006, “[o]ver 200
`
`compounds ha[d] entered clinical development for use in advanced prostate
`
`
`
`9
`
`

`
`cancer.” (JSN Ex. 2011 [Armstrong (2006)] at 138).
`
`To the extent they were considered, disparate classes of secondary hormonal
`
`agents were also investigated with little success, including androgen receptor
`
`ligands, estrogenic compounds, gonadotropin-releasing hormone antagonists, and
`
`CYP17 inhibitors with greater potency than abiraterone acetate. (See e.g., JSN Ex.
`
`2012 [Duc (2003)] at Abstract (“These non-steroidal compounds (including YM
`
`55208, a reference competitor) proved to be more active in vivo than abiraterone
`
`acetate in this model”).)
`
`B.
`
`The Initial Failed Efforts to Develop Abiraterone Acetate
`
`The clinical trials reported in O’Donnell (2004) (the primary prior art relied
`
`upon by Amerigen) were funded and sponsored by Boehringer, which licensed
`
`abiraterone acetate from BTG International Ltd. (“BTG”) in 1996 with the goal of
`
`developing an alternative first-line hormonal therapy. (JSN Ex. 2013). In 1999,
`
`following completion of the O’Donnell clinical trials, Boehringer lost interest,
`
`shuttering the entire development program without performing the Phase II and
`
`Phase III clinical trials that would have been needed to prove abiraterone acetate
`
`was clinically effective for treating prostate cancer. (JSN Ex. 2005 at ¶ 7).
`
`Subsequent attempts to find an alternative partner for developing abiraterone
`
`acetate proved extremely difficult. (Id.). Even attempts to publish the O’Donnell
`
`(2004) manuscript were met with skepticism in the field and the manuscript was
`
`
`
`10
`
`

`
`rejected by various medical journals, including Clinical Cancer Research, which
`
`received reviewer comments stating that there existed “little persuasive data” that
`
`residual androgens are important in stimulating prostate cancer growth. (Id. at ¶ 8;
`
`JSN Ex. 2006). In fact, no clinical data concerning abiraterone acetate was ever
`
`reported until O’Donnell was published in 2004.
`
`C. The Discovery of the ‘438 Patent Invention
`
`1.
`
`The Inventors’ Unexpected Discovery That Treatment with
`Abiraterone Acetate and Prednisone Has Therapeutic
`Effects
`
`In 2004, Cougar2 exclusively licensed patents and know-how relating to
`
`abiraterone acetate from BTG and conducted a series of Phase I, II, and III clinical
`
`trials using abiraterone acetate therapy aimed at demonstrating clinical efficacy.
`
`(JSN Ex. 2014 [Attard (2008)]; JSN Ex. 2015 [Attard 2009]).
`
`At this time, the inventors of the ‘438 patent postulated that, in patients with
`
`mCRPC who experienced a benefit from abiraterone acetate treatment alone, the
`
`effects would eventually decline and their cancer would begin to grow again
`
`because of an increase in testosterone-precursor adrenal steroids that could
`
`potentially activate the androgen receptor, thereby fueling prostate cancer growth.
`
`The inventors hypothesized that the additional administration of a therapeutically
`
`
`2 Johnson & Johnson acquired Cougar in July 2009.
`
`
`
`11
`
`

`
`effective amount of glucocorticoid, such as prednisone or dexamethasone, to
`
`abiraterone acetate therapy might reduce the body’s production of these
`
`testosterone-precursor adrenal steroids and have anti-cancer activity. To test this
`
`hypothesis, the inventors devised an extension study to be included in the first
`
`Cougar-sponsored abiraterone acetate clinical trial (COU-AA-001); patients whose
`
`cancer progressed on abiraterone acetate alone would then be offered abiraterone
`
`acetate in combination with a glucocorticoid (dexamethasone) while changes in
`
`PSA3 levels in this patient group would be monitored. (See generally JSN Ex.
`
`2014 [Attard (2008)] at 4565, 4568-69, Appendix A1; JSN Ex. 2015 [Attard 2009]
`
`at 3743, 3745-47).
`
`The COU-AA-001 clinical trial began in December 2005. The figure below,
`
`adopted from Attard (2008) (Appendix A1, Figure 2), illustrates the results of the
`
`extension study. These data show that a number of patients who had progressed on
`
`abiraterone acetate alone (i.e., who had experienced a rise in PSA levels) showed
`
`clinical improvement (i.e., a subsequent drop of PSA) when a glucocorticoid
`
`treatment was added in combination with abiraterone acetate therapy. In addition,
`
`
`3 PSA (or “prostate specific antigen”) is a prostate-specific protein produced by
`
`both normal prostate epithelial cells and prostate cancer cells. Rising PSA levels
`
`can indicate recurrent prostate cancer.
`
`
`
`12
`
`

`
`patients who previously had progressed when treated with a glucocorticoid alone,
`
`before they received abiraterone acetate, were initially treated with abiraterone
`
`acetate; when these patients progressed on abiraterone acetate treatment alone, they
`
`were administered the combination of abiraterone acetate and a glucocorticoid, and
`
`these patients also showed a clinical improvement.
`
`
`
`The results of the extension study confirmed a beneficial therapeutic effect
`
`in the combination administration of abiraterone acetate and a glucocorticoid.
`
`These results were incorporated into the COU-AA-004 clinical trial protocol,
`
`which is the first clinical trial specifically designed to evaluate combination
`
`therapy involving abiraterone acetate and prednisone in patients with mCRPC.
`
`(JSN Ex. 2016 [Danila (2010)]).
`
`The unexpected clinical benefits of the ‘438 patent invention were further
`
`demonstrated in additional Phase I-II clinical trial results, as measured by the time
`
`to PSA progression in chemotherapy-naïve patients. Table 1 below shows that
`
`
`
`13
`
`

`
`patients who received abiraterone acetate as a monotherapy had a median time to
`
`PSA progression of 7.5 months. (JSN Ex. 2015 [Attard (2009)] at 3745). Patients
`
`who initially received abiraterone acetate monotherapy but subsequently
`
`progressed and then received the combination of the glucocorticoid dexamethasone
`
`and abiraterone acetate, had a median time to PSA progression4 of 12.4 months or
`
`12 months (two patient groups were defined according to prior treatment before the
`
`study with dexamethasone). (Id. at 3743, 3745-3746). Thus, there was an
`
`increased (improved) time to PSA progression of about 5 months when
`
`glucocorticoids were added to the treatment regimen upon progression following
`
`abiraterone acetate monotherapy. Surprisingly, however, Table 1 also shows that
`
`when abiraterone acetate was administered in addition to prednisone from the start,
`
`there was a median time to PSA progression of 16.3 months, i.e., these patients on
`
`average responded for more than twice as long as patients on abiraterone acetate
`
`monotherapy. (JSN Ex. 2017 [Ryan (2011)] at 4856-4857).
`
`
`4 Time to PSA progression was measured from the start of abiraterone acetate
`
`monotherapy to the end of the combination therapy.
`
`
`
`14
`
`

`
`
`
`Table 1
`
`Clinical
`
`Patient group
`
`Treatment
`
`Time to PSA
`
`Source
`
`Trial
`
`
`
`Progression
`
`COU-AA-
`
`Chemo-naïve
`
`Abiraterone
`
`7.5 months
`
`JSN Ex. 2015
`
`001
`
`acetate
`
`(225 days)
`
`Attard et al.
`
`monotherapy
`
`(2009), at 3745.
`
`COU-AA-
`
`Chemo-naïve
`
`Abiraterone
`
`12 months
`
`JSN Ex. 2015,
`
`001
`
`
`
`acetate +
`
`(361 days)
`
`Attard et al.
`
`Dexamethasone
`
`dexamethasone
`
`(2009), at 3743,
`
`naïve
`
`at progression
`
`3745-3746.
`
`COU-AA-
`
`Chemo-naïve
`
`Abiraterone
`
`12.4 months
`
`JSN Ex. 2015,
`
`001
`
`
`
`acetate +
`
`(372 days)
`
`Attard et al.
`
`Previously
`
`dexamethasone
`
`(2009), at 3743,
`
`failed
`
`at progression
`
`3745.
`
`dexamethasone
`
`monotherapy
`
`COU-AA-
`
`Chemo-naïve
`
`Abiraterone
`
`16.3 months
`
`JSN Ex. 2017,
`
`002,
`
`Amendment
`
`5
`
`acetate +
`
`Ryan et al.
`
`prednisone from
`
`(2011), at 4856-
`
`the start
`
`4857.
`
`
`Subsequently, in Phase III clinical trials, the combination of abiraterone
`
`acetate and prednisone further demonstrated an unexpected survival benefit in
`
`patients with advanced prostate cancer. This was the first non-cytotoxic secondary
`
`
`
`15
`
`

`
`hormonal therapy to do so. (AMG Ex. 1009 [Ryan (2013)]; AMG Ex. 1034 [de
`
`Bono (2011)]).
`
`2.
`
`The ‘438 Patent
`
`The ‘438 patent, entitled “Methods and Compositions for Treating Cancer,”
`
`issued on September 2, 2014 and names as inventors Mr. Alan H. Auerbach and
`
`Dr. Arie S. Belldegrun. (AMG Ex.1001 [‘438 Patent]).5
`
`The ‘438 patent contains 20 claims. Independent Claim 1 recites:
`
`A method for the treatment of a prostate cancer in a human
`
`comprising administering to said human a therape