Trials@uspto.gov
`Tel: 571-272-7822
`
`
`Paper 72
`Entered: January 17, 2018
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`WOCKHARDT BIO AG,
`Petitioner,
`
`v.
`
`
`
`
`
`JANSSEN ONCOLOGY, INC.,
`Patent Owner.
`____________
`
`Case IPR2016-01582
`Patent 8,822,438 B2
`
`____________
`
`
`
`
`Before LORA M. GREEN, RAMA G. ELLURU, and
`KRISTINA M. KALAN, Administrative Patent Judges.
`
`KALAN, Administrative Patent Judge.
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`Tel: 571-272-7822
`
`
`Paper 72
`Entered: January 17, 2018
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`WOCKHARDT BIO AG,
`Petitioner,
`
`v.
`
`
`
`
`
`JANSSEN ONCOLOGY, INC.,
`Patent Owner.
`____________
`
`Case IPR2016-01582
`Patent 8,822,438 B2
`
`____________
`
`
`
`
`Before LORA M. GREEN, RAMA G. ELLURU, and
`KRISTINA M. KALAN, Administrative Patent Judges.
`
`KALAN, Administrative Patent Judge.
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`
`IPR2016-01582
`Patent 8,822,438 B2
`
`
`I. INTRODUCTION
`Wockhardt Bio AG (“Petitioner”) filed a Petition (Paper 4, “Pet.”) to
`institute an inter partes review of claims 1–20 of U.S. Patent No. 8,822,438
`B2 (Ex. 1001, “the ’438 patent”) pursuant to 35 U.S.C. §§ 311–319. Janssen
`Oncology, Inc. (“Patent Owner”) filed a Preliminary Response (Paper 13,
`“Prelim. Resp.”). We instituted an inter partes review of claims 1–20 on
`certain grounds of unpatentability alleged in the Petition (Paper 28, “Dec.”).
`After institution of trial, Patent Owner filed a Patent Owner Response
`(Paper 43, “PO Resp.”). Petitioner filed a Reply (Paper 54, “Reply”). An
`oral hearing was held on May 24, 2017. A transcript of the hearing has been
`entered into the record. Paper 71 (“Tr.”).
`The Board has jurisdiction under 35 U.S.C. § 6. In this Final Written
`Decision, issued pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73, we
`determine that Petitioner has shown by a preponderance of the evidence that
`all claims of the ’438 patent for which trial was instituted, namely, claims 1–
`20, are unpatentable.
`
`II. BACKGROUND
`
`A. Related Matters
`The parties indicate that the ’438 patent is being asserted in a number
`of district court proceedings, some of which have been terminated. Pet. 66;
`Paper 8, 2–4. Patent Owner represents that the following proceedings have
`not been terminated: BTG Int’l Ltd. v. Actavis Labs. FL, Inc., C.A. No. 2:15-
`cv-05909-KM-JBC (D.N.J.), Janssen Biotech, Inc. v. Mylan Pharms. Inc.,
`C.A. No. 1:15-cv-00130-IMK (N.D. W. Va.), BTG Int’l Ltd. v. Amerigen
`Pharms., Inc., C.A. No. 2:16-cv-02449-KM-JBC (D.N.J.), and BTG Int’l Ltd.
`
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`v. Glenmark Pharms. Inc., USA, C.A. No. 2:16-cv-05909 (D.N.J). Paper 32,
`3.
`
`Patent Owner also states that the ’438 patent was the subject of ex
`parte reexamination request No. 90/020,096, but “will not be granted a filing
`date for failure to comply with the requirements of 37 C.F.R. § 1.501(a).” Id.
`at 2.
`B. The ’438 Patent
`The ’438 patent, titled “Methods and Compositions for Treating
`Cancer,” describes methods that comprise “administering a 17α-
`hydroxylase/C17, 20-lyase inhibitor, such as abiraterone acetate (i.e., 3β-
`acetoxy-17-(3-pyridyl)androsta-5,16-diene), in combination with at least one
`additional therapeutic agent such as an anti-cancer agent or a steroid.”
`Ex. 1001, at [54], [57]. As described in the ’438 patent, it is believed that
`testosterone and dihydrotestosterone promote the growth of prostate cancer.
`Id. at 1:49–51. Hormone therapy can be used to suppress the production or
`block the effects of hormones such as testosterone. Id. at 1:43–51.
`The enzyme 17α-hydroxylase/C17, 20-lyase (“CYP17”) is involved in
`testosterone synthesis. Id. at 3:66–4:1. CYP17 inhibitors have been shown
`to be useful in the treatment of cancer, specifically, androgen-dependent
`disorders like prostate cancer. Id. at 5:23–27. Abiraterone acetate, a prodrug
`of abiraterone, is a CYP17 inhibitor. Id. at 2:10–12.
`The ’438 patent describes administration of a therapeutically effective
`amount of a CYP17 inhibitor, such as abiraterone acetate, with a
`therapeutically effective amount of at least one additional therapeutic agent
`including, but not limited to, an anti-cancer agent, such as mitoxantrone,
`paclitaxel, docetaxel, leuprolide, goserelin, triptorelin, seocalcitol,
`
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`bicalutamide, or flutamide, or a steroid, such as hydrocortisone, prednisone,
`or dexamethasone. Id. at 2:9–3:20.
`C. Challenged Claims
`Claim 1 of the ’438 patent is reproduced below:
`1. A method for the treatment of a prostate cancer in a human
`comprising administering to said human a therapeutically
`effective amount of abiraterone acetate or a
`pharmaceutically acceptable salt thereof and a
`therapeutically effective amount of prednisone.
`Ex. 1001, 16:16–20. Dependent claims 2–20 of the ’438 patent describe
`additional limitations of the method, including the amount of abiraterone
`acetate and the amount of prednisone used and the type of prostate cancer
`being treated. Id. at 16:21–17:14.
`D. Prior Art References Relied Upon by Petitioner
`Petitioner relies on the following prior art:
`1. Gerber, G.S. & Chodak, G.W., Prostate specific antigen for
`assessing response to ketoconazole and prednisone in patients with
`hormone refractory metastatic prostate cancer, 144 J. Urol. 1177–
`79 (1990) (“Gerber”) (Ex. 1004);
`2. O’Donnell, A. et al., Hormonal impact of the 17α-hydroxylase/
`C17, 20-lyase inhibitor abiraterone acetate (CB7630) in patients with
`prostate cancer, 90 British Journal of Cancer 2317–25 (2004)
`(“O’Donnell”) (Ex. 1005); and
`3. Sartor, O. et al., Effect of prednisone on prostate-specific antigen in
`patients with hormone-refractory prostate cancer, 52 Urology 252–
`256 (1998) (“Sartor”) (Ex. 1006).
`
`
`
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`E. Instituted Grounds of Unpatentability
`We instituted inter partes review of claims 1–20 of the ’438 patent on
`the following grounds:
`
`Claims Challenged
`Basis
`§ 103(a) 1–20
`
`References
`Gerber, O’Donnell, and
`Sartor
`In support of its challenges, Petitioner relies on the declarations of Paul
`A. Godley, M.D., Ph.D., MPP (Ex. 1002; Ex. 1104; Ex. 1123; Ex. 1129),
`Robert Stoner, Ph.D. (Ex. 1077; Ex. 1103; Ex. 1122; Ex. 1130), and Ian
`McKeague, Ph.D. (Ex. 1106). Patent Owner relies on the declarations of Ian
`Judson, M.D. (Ex. 2028), Matthew Rettig, M.D. (Ex. 2038), Richard Auchus,
`M.D., Ph.D. (Ex. 2040), and Christopher A. Vellturo, Ph.D. (Ex. 2044).
`
`III. ANALYSIS
`
`A. Claim Interpretation
`The Board interprets claim terms in an unexpired patent according to
`the broadest reasonable construction in light of the specification of the patent
`in which they appear. See Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131,
`2144–46 (2016) (upholding the use of the broadest reasonable interpretation
`standard); 37 C.F.R. § 42.100(b). Under that standard, and absent any special
`definitions, we give claim terms their ordinary and customary meaning as
`would be understood by one of ordinary skill in the art at the time of the
`invention. See In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir.
`2007). Any special definitions for claim terms must be set forth with
`reasonable clarity, deliberateness, and precision. See In re Paulsen, 30 F.3d
`1475, 1480 (Fed. Cir. 1994). Only those terms which are in controversy need
`to be construed, and only to the extent necessary to resolve the controversy.
`
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`See Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co. Ltd., 868 F.3d
`1013, 1017 (Fed. Cir. 2017) (“we need only construe terms ‘that are in
`controversy, and only to the extent necessary to resolve the controversy’”)
`(quoting Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed.
`Cir. 1999)).
`With respect to claim interpretation, “[u]sually [the specification] is
`dispositive; it is the single best guide to the meaning of a disputed term.” In
`re Abbott Diabetes Care Inc., 696 F.3d 1142, 1149 (Fed. Cir. 2012) (citations
`omitted). “To act as its own lexicographer, a patentee must ‘clearly set forth
`a definition of the disputed claim term’ other than its plain and ordinary
`meaning.” Thorner v. Sony Computer Entm’t Am. LLC, 669 F.3d 1362, 1365
`(Fed. Cir. 2012) (quoting CCS Fitness, Inc. v. Brunswick Corp., 288 F.3d
`1359, 1366 (Fed. Cir. 2002)).
`Petitioner proposes that we construe the claim terms “treat,” “treating,”
`“treatment,” and “therapeutically effective amount of prednisone.” Pet. 20–
`21. Petitioner notes that these claim terms have already been construed in
`IPR2016-00286,1 Paper 14, and states that it analyzes the claims under those
`constructions for the purpose of this proceeding. Id. In our Decision on
`Institution, we applied our claim constructions of “treat,” “treating,”
`“treatment,” and “therapeutically effective amount of prednisone,” as set
`forth in IPR2016-00286, to the present case. Dec. 5–7; IPR2016-00286,
`Paper 14, 5–7. Thus, we construed those terms as follows:
`
`
`
`
`1 IPR2016-00286 is an earlier-filed case involving the ’438 patent, the same
`grounds, and the same Patent Owner.
`
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`
`Claim term(s)
`“treat,” “treating,” and
`“treatment”
`
`Construction
`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
`Ex. 1001, 3:46–50
`an amount of prednisone effective for
`“therapeutically effective
`treating prostate cancer
`amount of prednisone”
`Patent Owner states: “Neither party has disputed the Board’s
`interpretation of this claim term [‘treat,’ ‘treating’ and ‘treatment’] and
`[Petitioner] has employed it in its Petition.” PO Resp. 4. Patent Owner
`further states that “the Board’s construction of ‘treat,’ ‘treating’ and
`‘treatment’ should be maintained.” Id. at 5.
`Patent Owner also submitted a claim construction of the terms
`“treatment” and “treating” by the district court in a companion litigation.
`Ex. 2010. The district court, after a lengthy analysis, construed the disputed
`terms as follows: “Treatment/treating means 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.” Id. at 30. The district court read out of the definition the term
`“includes.” Id. Although we are not bound by the district court’s reasoning
`and claim constructions in related proceedings, we do not disregard the
`determinations of a court interpreting the same claim term in a related patent
`in a concurrent proceeding. Power Integrations, Inc. v. Lee, 797 F.3d 1318,
`1326–27 (Fed. Cir. 2015) (“The fact that the board is not generally bound by
`a previous judicial interpretation of a disputed claim term does not mean,
`however, that it has no obligation to acknowledge that interpretation or to
`
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`assess whether it is consistent with the broadest reasonable construction of
`the term.”). Thus, although we acknowledge and have considered the district
`court’s interpretation, we retain our broadest reasonable construction of the
`terms “treat,” “treatment,” and “treating.”
`We see no reason to modify our claim construction positions in light of
`the record developed at trial, and we maintain our claim constructions from
`the Decision on Institution for the purposes of this Decision. No other claim
`terms have been presented to us for construction following institution of trial,
`and we determine that no other claim terms require express construction.
`B. Principles of Law
`A claim is unpatentable under 35 U.S.C. § 1032 if the differences
`between the subject matter sought to be patented and the prior art are such
`that the subject matter as a whole would have been obvious at the time the
`invention was made to a person having ordinary skill in the art to which said
`subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
`(2007). The question of obviousness is resolved on the basis of underlying
`factual determinations including: (1) the scope and content of the prior art;
`(2) any differences between the claimed subject matter and the prior art;
`(3) the level of ordinary skill in the art; and (4) objective evidence of
`nonobviousness. Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966). A
`decision on the ground of obviousness must include “articulated reasoning
`with some rational underpinning to support the legal conclusion of
`
`
`2 The Leahy-Smith America Invents Act, Pub. L. No. 112-29, 125 Stat. 284
`(2011) (“AIA”), amended 35 U.S.C. § 103. Because the ’438 patent has an
`effective filing date before the effective date of the applicable AIA
`amendments, throughout this Decision we refer to the pre-AIA versions of
`35 U.S.C. § 103.
`
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`obviousness.” In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006). The
`obviousness analysis “should be made explicit” and it “can be important to
`identify a reason that would have prompted a person of ordinary skill in the
`relevant field to combine the elements in the way the claimed new invention
`does.” KSR, 550 U.S. at 418. We analyze the asserted grounds of
`unpatentability in accordance with the above-stated principles.
`C. Level of Skill in the Art
`We adopt Petitioner’s contention that a person of ordinary skill in the
`
`art
`
`would be a treating clinician specializing in oncology, typically
`holding an M.D. degree, with at least five years of experience
`specializing in medical oncology. Alternatively, a POSA would
`have an M.D., with at least five years of experience specializing
`in urology and at least two years of clinical experience. A POSA
`would have also typically worked as part of a multi-disciplinary
`team and drawn upon not only his or her own skills, but also
`taken advantage of certain specialized skills of others in the team,
`to solve a given problem.
`
`Pet. 3–4 (citations omitted). Patent Owner does not appear to dispute
`Petitioner’s definition in its Patent Owner Response. See generally PO Resp.
`The level of ordinary skill in the art in this case is further demonstrated by
`the prior art asserted in the Petition. See Okajima v. Bourdeau, 261
`F.3d 1350, 1355 (Fed. Cir. 2001).
`D. Overview of the Prior Art
`1. O’Donnell
`O’Donnell, which is titled “Hormonal impact of the 17α-
`hydroxylase/C17,20-lyase inhibitor abiraterone acetate (CB7630) in patients
`with prostate cancer,” discloses that treatment of prostate cancer with
`
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`abiraterone acetate, at a dose of 500–800 mg, can successfully suppress
`testosterone levels. Ex. 1005, Abstract. O’Donnell also discloses that
`ketoconazole, another CYP17 inhibitor, has been evaluated as a possible
`agent with which to achieve decreased production of adrenal steroids, but that
`abiraterone acetate was developed as a more selective inhibitor. Id. at 2318.
`O’Donnell further discloses that adrenocortical suppression may require
`administration of replacement glucocorticoid. Id. at Abstract, 2323.
`O’Donnell states that “[s]ome impact on adrenal reserve was predictable
`from the steroid synthesis pathway.” Id. at 2323. Regarding administration
`of ketoconazole, O’Donnell states that “it is common practice to administer
`supplementary hydrocortisone” and that this may prove necessary with
`abiraterone acetate. Id. On the basis of the clinical evidence, O’Donnell
`reports that the need for concomitant therapy of abiraterone acetate with a
`glucocorticoid needs to be further investigated. Id.
`2. Gerber
`Gerber, which is titled “Prostate Specific Antigen for Assessing
`Response to Ketoconazole and Prednisone in Patients with Hormone
`Refractory Metastatic Prostate Cancer,” discloses use of ketoconazole, a
`known CYP17 enzyme inhibitor and inhibitor of gonadal and adrenocortical
`steroid synthesis, with prednisone to treat patients with progressive prostate
`cancer. Ex. 1004, 1177. Gerber provides that patients exhibiting
`progressively increasing prostate specific antigen (“PSA”) levels, when
`treated with ketoconazole and prednisone, experienced a decrease in PSA
`levels. Id. at 1178–79. Based on its study, Gerber concludes that “there
`appears to be a small subgroup of patients with progressive prostate cancer
`despite hormonal therapy who will derive significant benefit from the
`
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`combination of ketoconazole and glucocorticoid replacement therapy.” Id.
`at 1179.
`3. Sartor
`Sartor, which is titled “Effect of Prednisone on Prostate-Specific
`Antigen in Patients with Hormone-Refractory Prostate Cancer,” discloses a
`trial in which patients with hormone-refractory progressive prostate cancer,
`who were not receiving concomitant anticancer therapies, were treated with
`10 mg of prednisone orally two times a day. Ex. 1006, Abstract. Sartor
`discloses that administration of prednisone alone, as shown by its results, led
`to an average decline of 33% in PSA responses after initiating prednisone; a
`majority of patients had PSA progression-free survival for a matter of months
`following treatment. Id. at 254, Table III. Sartor concludes that prednisone
`“can decrease PSA by more than 50% in approximately one third of patients”
`and hypothesizes “a dose-responsive relationship between glucocorticoid
`dose and PSA decline.” Id. at Abstract.
`E. Obviousness Analysis
`1. Petitioner’s Arguments
`Petitioner argues that Gerber teaches co-administering the CYP17
`inhibitor ketoconazole with prednisone to treat prostate cancer. Pet. 28–29
`(citing Ex. 1004, 1177–79). Petitioner further argues that abiraterone acetate
`“was known to be a potent and more specific inhibitor of CYP17 than
`ketoconazole and it effectively reduced testosterone levels” (citing Ex. 1002
`¶ 72) and that O’Donnell discloses administering abiraterone acetate to
`castrate and non-castrate males (citing Ex. 1005, 2320–21, 2324). Id. at 29–
`30. Petitioner argues that “prednisone was known to treat prostate cancer, as
`well as to offset the side effects from administering a CYP17 inhibitor, such
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`as abiraterone acetate and ketoconazole” (citing Ex. 1002 ¶¶ 75–84), and that
`Sartor “teaches administering 20 mg/day prednisone as a monotherapy in
`patients with mCRPC” (citing Ex. 1006, 252–54). Id. at 31. Petitioner
`presents a claim chart for claim 1, citing the prior art disclosures that
`Petitioner alleges teach each element of claim 1. Id. at 25–28. Petitioner
`further argues that one of ordinary skill in the art would have had a
`reasonable expectation of success in practicing the method of claim 1,
`because Gerber “teaches methods of treating prostate cancer safely and
`effectively using the CYP17 inhibitor ketoconazole,” O’Donnell “teaches
`administering the more selective CYP17 inhibitor abiraterone acetate
`effectively suppresses testosterone levels—a focus of prostate cancer
`treatment—in castrate and non-castrate males with prostate cancer,” and
`Sartor “discloses that mCRPC patients had a signification reduction in PSA
`levels, i.e., ≥ 50%, when administered prednisone as a monotherapy.” Id.
`at 34–35.
`Petitioner argues that one of ordinary skill in the art “would have had a
`reason to modify Gerber’s method of administering ketoconazole to use
`abiraterone acetate, as taught in O’Donnell” because “abiraterone acetate is a
`potent and more selective inhibitor of CYP17 than ketoconazole and that
`abiraterone acetate effectively suppressed testosterone levels in both castrate
`and non-castrate males.” Pet. 24 (citing Ex. 1002 ¶ 67). Additionally,
`Petitioner argues, one of ordinary skill in the art “would have had a reason to
`maintain coadministration of prednisone, as taught in Gerber, because
`prednisone was known to treat prostate cancer on its own, as demonstrated by
`Sartor.” Id. (citing Ex. 1002 ¶ 68). Petitioner summarizes that one of
`ordinary skill in the art, reading Gerber, O’Donnell, and Sartor, “would have
`
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`had a reason to co-administer a therapeutically effective amount of
`prednisone with abiraterone acetate because (1) prednisone was known to
`treat prostate cancer and (2) prednisone would reduce the side effects of
`mineralocorticoid excess that could result from abiraterone acetate
`treatment.” Id. at 33–34 (citing Ex. 1002 ¶¶ 83–84).
`Claims 2–20 each depend directly or indirectly from claim 1.
`Petitioner contends these dependent claims also are unpatentable under 35
`U.S.C. § 103 based on Gerber, O’Donnell, and Sartor. Pet. 36–46.
`2. Patent Owner’s Non-Obviousness Arguments
`Patent Owner presents a series of arguments directed to the art relied
`upon in Petitioner’s ground, and arguments related to objective indicia of
`non-obviousness. PO Resp. 5–69. We address each in turn.
`a. Patent Owner’s First Argument – Gerber
`Patent Owner argues that, contrary to Petitioner’s assertions regarding
`the prior art’s teachings about the use of ketoconazole and prednisone,
`Gerber does not establish that ketoconazole and prednisone was an effective
`treatment for prostate cancer. PO Resp. 5–6. First, Patent Owner argues that
`Gerber did not demonstrate to one of ordinary skill in the art that co-
`administration of ketoconazole and prednisone effectively treats prostate
`cancer. Id. at 6. Patent Owner criticizes Gerber for not being a controlled
`clinical trial and criticizes Gerber’s methodology as falling short when
`measured against accepted standards. Id. at 7 (citing Ex. 1004, 1178;
`Ex. 2038 ¶ 86). Second, Patent Owner argues that clinical studies before
`2006 taught that ketoconazole and prednisone therapy was not a safe and
`effective treatment for prostate cancer. Id. at 9. By 2006, Patent Owner
`argues, clinical trials showed that ketoconazole plus replacement
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`glucocorticoid provided only modest activity and no difference in survival
`from patients receiving only antiandrogen withdrawal, and did not justify
`phase 3 evaluation. Id.
`Petitioner argues that, notwithstanding Patent Owner’s attacks on
`Gerber as not being a controlled clinical trial, Gerber is prior art for all that it
`teaches, namely, the combination of ketoconazole and prednisone as treating
`prostate cancer. Reply 3 (citing Ex. 1104 ¶ 8). Petitioner replies that
`Gerber’s methodology is sufficient to demonstrate that ketoconazole used
`with prednisone to treat prostate cancer has “modest activity,” and that the
`claims require nothing more. Id. at 4.
`We disagree that Petitioner’s arguments and evidence regarding the
`administration of ketoconazole with prednisone are lacking. Gerber, despite
`the fact that it was not a controlled clinical trial, nevertheless is a peer-
`reviewed article published in a reputable journal, indicating that treatment
`with ketoconazole and prednisone demonstrated some degree of success in a
`group of patients. Ex. 1004. O’Donnell (2004), which is later in time than
`Gerber (1990), corroborates that in the clinical use of ketoconazole, it is
`“common practice” to administer supplementary hydrocortisone. Ex. 1005,
`2323. Patent Owner’s arguments do not undercut the teachings of Gerber, or
`Gerber’s demonstration that the combination of ketoconazole and prednisone
`worked for some patients, in which it was reasonably well tolerated,
`considering the circumstances. Ex. 1002 ¶¶ 61, 71; Ex. 1004, 1079; see
`Duramed Pharms., Inc. v. Watson Labs., Inc., 413 F. App’x 289, 294 (Fed.
`Cir. 2011) (a reference is “prior art for all that it discloses, and there is no
`requirement that a teaching in the prior art be scientifically tested, or even
`guarantee success”). Gerber reasonably stands for the proposition that
`
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`administration of ketoconazole and prednisone is tolerated and effective in a
`subset of patients, and at the time it was published, indicated some measure
`of efficacy for certain mCRPC patients.
`b. Patent Owner’s Second Argument – O’Donnell
`Patent Owner argues that O’Donnell does not establish that abiraterone
`acetate has an anti-cancer effect, or suggest concomitant glucocorticoid
`replacement therapy. PO Resp. 10. Petitioner replies that O’Donnell teaches
`abiraterone acetate as a potent, more specific CYP17 inhibitor than
`ketoconazole, and provides a motivation for maintaining prednisone.
`Reply 5.
`First, Patent Owner argues that O’Donnell was designed to assess the
`safety of abiraterone acetate, rather than its clinical effectiveness, and that
`O’Donnell found that “abiraterone acetate was very well tolerated and no
`serious adverse effects attributable to treatment were recorded” over the 12-
`day testing period. PO Resp. 10–12 (citing Ex. 1005, 2322). Petitioner
`replies that O’Donnell assessed abiraterone acetate for “testosterone
`suppression in castrate and non-castrate men with prostate cancer,” which is a
`goal of prostate cancer treatment, and gives a person of ordinary skill in the
`art “more than adequate grounds to rely on O’Donnell’s teachings.” Reply 6
`(citing Ex. 1002 ¶ 26). We find that O’Donnell’s stated purpose of
`investigating the ability of abiraterone acetate to suppress testosterone in
`prostate cancer patients would have led one of ordinary skill in the art to rely
`on O’Donnell’s teachings. Ex. 1005, 2317, Abstract. We recognize that the
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`study conducted in O’Donnell was limited in time and scope, but agree with
`Petitioner that this does not detract from O’Donnell’s teachings.
`Second, Patent Owner argues that abiraterone acetate and ketoconazole
`were known to cause different effects on steroid biosynthesis pathways. PO
`Resp. 13. Patent Owner emphasizes that ketoconazole “was known to be a
`non-selective steroid synthesis inhibitor” whereas abiraterone acetate “was
`known to be a selective CYP17 inhibitor” that targets only CYP17. Id. at 13–
`15 (citing Ex. 2038 ¶¶ 102, 106–08, Fig. 1; Ex. 1005, 2317–18). Petitioner
`replies that the differences in the steroid biosynthesis pathway between
`abiraterone acetate and ketoconazole are “inconsequential and irrelevant,”
`focusing instead on the knowledge that “both ketoconazole and abiraterone
`were CYP17 inhibitors used for the treatment of prostate cancer, and that
`abiraterone was known in the art to be a potent, more selective inhibitor of
`CYP17 than ketoconazole.” Reply 6 (citing Ex. 1002 ¶¶ 37–39, 62–65).
`Based on the information presented during trial, we understand that
`ketoconazole and abiraterone acetate do not have identical mechanisms. See,
`e.g., Ex. 1005, 2318, Figure 1. As noted by both Petitioner and Patent
`Owner, however, abiraterone acetate and ketoconazole are both CYP17
`inhibitors. Pet. 11–13; PO Resp. 13–15. Although Patent Owner urges us to
`focus on the differences in the mechanisms of operation of ketoconazole and
`abiraterone acetate (PO Resp. 13–15), we look not only at the differences, but
`also at the similarities.
`The evidence demonstrates that one of ordinary skill would have been
`aware of the differences and the similarities in the mechanisms, and
`nevertheless would have compared and analogized between the two.
`Ex. 1005, 2318, Figure 1; Ex. 1002 ¶ 67. O’Donnell refers to ketoconazole
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`in its discussion of abiraterone acetate, indicating that teachings regarding
`ketoconazole administration were a starting point for exploration of
`abiraterone acetate administration. Ex. 1005, 2318. O’Donnell, after
`evaluating ketoconazole as an agent, turns to an evaluation of abiraterone
`acetate as a more selective CYP17 inhibitor, i.e., as an improvement on
`ketoconazole. Ex. 1005, 2318. After presenting the results from its studies,
`O’Donnell discusses that, in the clinical use of ketoconazole, “it is common
`practice to administer supplementary hydrocortisone” and that, therefore,
`“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. This statement represents the proposition that one of
`ordinary skill in the art would use the example of ketoconazole’s clinical use
`to take the next investigative steps with abiraterone acetate. We have not
`been presented with evidence that dissuades us from taking this statement at
`face value. Thus, we are persuaded that one of ordinary skill in the art would
`understand that both ketoconazole and abiraterone are CYP17 inhibitors,
`albeit with different mechanisms. With this knowledge, and given the
`teachings of the prior art on administration of ketoconazole and
`administration of abiraterone acetate, we find that one of ordinary skill in the
`art would look to the administration of ketoconazole for guidance on how to
`administer abiraterone acetate.
`Third, Patent Owner argues that abiraterone acetate was known to not
`cause the same side effects as ketoconazole. PO Resp. 16. Patent Owner
`elaborates that “a skilled person would not have expected abiraterone acetate
`to cause clinically meaningful reductions in glucocorticoid production, and
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`thus would not cause the same impact on adrenal functions as ketoconazole.”
`Id. at 16–17 (citing Ex. 2038 ¶ 133). Petitioner replies that Patent Owner
`carefully admits that a person of ordinary skill in the art would have expected
`abiraterone acetate to inhibit cortisol production. Reply 7 (citing PO
`Resp. 16–17). Nevertheless, Petitioner argues, one of ordinary skill “would
`have sought to keep prednisone when administering abiraterone, expecting a
`decrease in cortisol due to inhibition of CYP17 by abiraterone.” Reply 7
`(citing Ex. 1104 ¶ 20).
`Both parties present evidence that, based on their respective
`mechanisms of action, administration of ketoconazole would inhibit
`production of cortisol, and administration of abiraterone acetate inhibits at
`least one of the pathways of cortisol production. Pet. 11–13; Ex. 2038 ¶ 100,
`Figs. 4–5; Tr. 14:21–16:5; Ex. 1005, 2318. Patent Owner states that
`abiraterone acetate “does not have the same inhibitory effect on cortisol
`production as ketoconazole” but appears to agree that abiraterone acetate
`inhibits cortisol to some degree. PO Resp. 15, 16–17. Petitioner additionally
`asserts that Dr. Rettig’s figures omit a second pathway by which abiraterone
`acetate inhibits cortisol production. Reply 6–7 (citing Ex. 2038 ¶ 100,
`Figs. 4–5); Ex. 1104 ¶ 16. Based on the evidence presented, we agree with
`Petitioner and find that the action of abiraterone acetate would lead to
`decreased production of cortisol sufficient to alert one of ordinary skill in the
`art to the existence of such a decrease.
`Fourth, Patent Owner argues that there is no evidence that
`ketoconazole causes mineralocorticoid excess. PO Resp. 17. Rather, Patent
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`Owner argues, ketoconazole reduces mineralocorticoid production in
`patients. Id. at 18 (citing Ex. 2038 ¶ 104; Ex. 2040 ¶¶ 37–38, 59).
`Fifth, Patent Owner argues that there was no evidence, in 2006, that
`abiraterone acetate would cause mineralocorticoid excess. Id. at 19. More
`particularly, Patent Owner argues that O’Donnell does not mention
`mineralocorticoid excess, nor does other prior art. Id. at 18–19 (citing
`Ex. 2038 ¶¶ 161–64).
`Petitioner replies that one of ordinary skill in the art “would have
`predicted that abiraterone drive[s] the production of excess
`mineralocorticoids.” Reply 8 (citing Ex. 1002 ¶¶ 35, 79–81; Ex. 1104 ¶¶ 33–
`36). Petitioner further replies that Patent Owner’s witness admitted that
`corticosterone levels would increase and compensate for the lack of cortisol,
`and that glucocorticoid supplementation is part of the “cornerstone of
`therapy” in patients “with congenital 17α-hydroxylase/17,20-lyase
`deficiency.” Reply 8–9 (citing Ex. 2040 ¶ 47; Ex. 1089, 79:2–80:22, 91:10–
`93:10).
`Petitioner appears to agree with Patent Owner that ketoconazole does
`not cause mineralocorticoid excess. Tr. 16:12–15 (“Now you have a second
`problem with abiraterone that you don’t have with ketoconazole that is
`solved again with glucocorticoid supplementation like prednisone. And that
`problem is mineralocorticoid excess.”). However, reg
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