`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_______________________
`
`AMERIGEN PHARMACEUTICALS LIMITED and
`ARGENTUM PHARMACEUTICALS LLC
`Petitioners,
`
`v.
`
`JANSSEN ONCOLOGY, INC.
`
`Patent Owner.
`
`_______________________
`
`Case IPR2016-002861
`
`Patent 8,822,438 B2
`
`_______________________
`
`PATENT OWNER’S RESPONSE
`
`
`
`
`1 Case IPR2016-01317 has been joined with this proceeding.
`
`JANSSEN EXHIBIT 2151
`Mylan v. Janssen IPR2016-01332
`
`

`

`IPR2016-00286
`US Patent 8,822,438
`
`TABLE OF CONTENTS
`
`Page
`
`I.
`
`INTRODUCTION ......................................................................................... 1
`
`II.
`
`SUMMARY OF ARGUMENT IN RESPONSE ......................................... 2
`
`III. CLAIM CONSTRUCTION .......................................................................... 8
`
`IV. THE PRIOR ART RELIED UPON BY PETITIONERS .......................... 8
`
`A. Gerber (Ex. 1004) ................................................................................ 8
`
`B.
`
`Barrie (Ex. 1005)................................................................................ 10
`
`C. O’Donnell (Ex. 1003) ......................................................................... 10
`
`V.
`
`PETITIONERS’ SCIENTIFICALLY UNSUPPORTABLE LEAP TO
`OBVIOUSNESS ........................................................................................... 12
`
`A.
`
`First Scientifically Erroneous Premise In Petitioners’ Submission:
`Abiraterone Acetate Works the Same Way and Would Have the
`Same Hormonal Side Effects as Ketoconazole ............................... 13
`
`1.
`
`2.
`
`3.
`
`Abiraterone Acetate Has a Different Mechanism of Action
`From Ketoconazole ................................................................... 13
`
`O’Donnell Confirms that Abiraterone Acetate Allows Cortisol
`to be Made in Normal Levels in Patients, Unlike Ketoconazole17
`
`Barrie Confirms that Abiraterone Acetate Acts Differently
`From Ketoconazole ................................................................... 22
`
`B.
`
`Second Scientifically Erroneous Premise In Petitioners’
`Submission: Ketoconazole Caused Mineralocorticoid Excess,
`Which Would Be Expected to Occur with Abiraterone Acetate .. 23
`
`1.
`
`2.
`
`There Is No Prior Art Evidence That Ketoconazole Causes
`Mineralocorticoid Excess .......................................................... 24
`
`There Is No Prior Art Evidence That Abiraterone Acetate
`Would Cause Mineralocorticoid Excess ................................... 26
`
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`IPR2016-00286
`US Patent 8,822,438
`
`
`3.
`
`Even If Mineralocorticoid Excess Was A Problem, It Would
`Not Be Treated With Prednisone .............................................. 28
`
`C.
`
`Third Scientifically Erroneous Premise In Petitioners’
`Submission: Petitioners Ignore Teachings in the Art Regarding
`Toxicity Concerns with Prednisone ................................................. 29
`
`1.
`
`2.
`
`Use of Glucocorticoids Such as Prednisone Was Avoided Due
`to Their Many Negative Side Effects, Particularly Detrimental
`to Patients with mCRPC. .......................................................... 30
`
`The Prior Art Taught that Prednisone Could Fuel the Prostate
`Cancer ....................................................................................... 32
`
`D.
`
`Fourth Scientifically Erroneous Premise In Petitioners’
`Submission: The Combination of Ketoconazole and Prednisone
`Was a “Safe and Effective” Treatment for Prostate Cancer ........ 33
`
`1.
`
`2.
`
`Gerber Did Not Establish That Co-Administration of
`Ketoconazole and Prednisone Is a Safe and Effective Treatment
`for Prostate Cancer .................................................................... 34
`
`The Intervening Prior Art Between 1990 and 2006 Taught That
`Ketoconazole and Prednisone Therapy Was Not A Safe and
`Effective Treatment for Prostate Cancer .................................. 37
`
`VI. PETITIONERS HAVE FAILED TO MEET THEIR BURDEN OF
`DEMONSTRATING OBVIOUSNESS OF THE CLAIMED
`INVENTION ................................................................................................ 38
`
`A. A Correct View of the Prior Art Confirms That There Was No
`Motivation to Combine O’Donnell with Gerber or Barrie with
`Gerber ................................................................................................. 38
`
`1.
`
`2.
`
`3.
`
`O’Donnell Does Not Provide a Motivation to Use Prednisone
`with Abiraterone Acetate to Treat Prostate Cancer .................. 39
`
`Barrie Does Not Provide a Motivation to Use Prednisone with
`Abiraterone Acetate to Treat Prostate Cancer .......................... 41
`
`Gerber Does Not Provide a Motivation to Use Prednisone with
`Abiraterone Acetate to Treat Prostate Cancer .......................... 43
`
`
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`IPR2016-00286
`US Patent 8,822,438
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`
`4.
`
`The Prior Art As a Whole Taught that, for the Clinical Use of
`Abiraterone Acetate, Glucocorticoid Replacement Was Not
`Required .................................................................................... 43
`
`Based on the Prior Art Describing Abiraterone Acetate and
`Ketoconazole, a POSA Had No Reasonable Expectation of Success
`in Arriving at the ’438 Patented Invention ..................................... 45
`
`The Unpredictability of Drug Combination Therapy for the
`Treatment of Prostate Cancer Precludes Obviousness ................. 49
`
`B.
`
`C.
`
`D.
`
`Petitioners’ Obviousness Grounds Rely On Hindsight ................. 51
`
`VII. OBJECTIVE INDICIA OF NONOBVIOUSNESS CONFIRM THE
`PATENTABILITY OF THE CLAIMS ..................................................... 53
`
`A.
`
`Skepticism and the Failure of Others .............................................. 53
`
`B.
`
`The Claimed Invention Shows Unexpected Results ....................... 55
`
`C.
`
`The Claimed Invention Has Met a Long-Felt Need ....................... 59
`
`D.
`
`The Claimed Invention Has Achieved Significant Commercial
`Success ................................................................................................ 60
`
`E. A Nexus Exists Between the Claimed Invention and ZYTIGA®’s
`Commercial Success .......................................................................... 60
`
`VIII. CONCLUSION ............................................................................................ 65
`
`
`
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`IPR2016-00286
`US Patent 8,822,438
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`
`
`
`TABLE OF ABBREVIATIONS
`
`Abbreviation
`
`Definition
`
`ACTH
`
`CYP17
`
`FDA
`
`ID
`
`mCRPC
`
`POSA
`
`PSA
`
`Adenocorticotrophic hormone
`
`17α-hydroxylase/C17,20-lyase
`
`Food and Drug Administration
`
`Institution Decision
`
`Metastatic castration-resistant prostate cancer
`
`Person of skill in the art
`
`Prostate specific antigen
`
`
`
`
`iv
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`IPR2016-00286
`US Patent 8,822,438
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`I.
`
`INTRODUCTION
`
`This proceeding involves a breakthrough discovery in cancer treatment, i.e.,
`
`that prednisone can be used in combination with abiraterone acetate to effectively
`
`treat prostate cancer. The inventors had the insight that, by giving therapeutic
`
`doses of both drugs, the life of a patient with prostate cancer could be significantly
`
`prolonged because prednisone administered in combination with abiraterone
`
`acetate could produce a far greater anti-cancer effect than would have occurred
`
`with abiraterone acetate alone. That discovery gave rise to the claimed methods
`
`which are protected by U.S. Patent No. 8,822,438 (“the ’438 Patent”).
`
`Prior to these patented methods, the prognosis for prostate cancer patients
`
`with an advanced stage of the disease known as metastatic castration-resistant
`
`prostate cancer (“mCRPC”) was dismal and the limited treatment options available
`
`were largely ineffective. The claimed methods have resulted in dramatic
`
`improvements in patient survival that could not have been predicted. Because of
`
`the enormous potential benefit to patients, the Food and Drug Administration
`
`(“FDA”) gave the commercial embodiment, ZYTIGA®, priority review status for
`
`each of its approved indications, all of which specify that abiraterone acetate be
`
`used in combination with prednisone.
`
`In challenging the claims, Petitioners point to no prior art that even hints at
`
`the possibility that the administration of prednisone in combination with
`
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`112358292 v3
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`IPR2016-00286
`US Patent 8,822,438
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`abiraterone acetate could provide any surprising or unexpected benefit in treating
`
`the cancer. Petitioners thus side-step the benefit of the claimed invention to argue
`
`that prednisone would have been co-administered with abiraterone acetate therapy
`
`for “safety and tolerability” reasons. But the very prior art references relied upon
`
`by Petitioners show just the opposite: the prior art shows that abiraterone acetate
`
`was very well-tolerated, meaning no further drug therapy was needed for “safety
`
`and tolerability” reasons.
`
`In instituting the present proceeding, the Panel was misled by Petitioners’
`
`mischaracterization of the prior art and of the underlying science. The present
`
`record shows that Petitioners’ contentions regarding the motivation to combine and
`
`reasonable expectation of success—each relying on Petitioners’ flawed view of the
`
`science and the state of the art—do not withstand scrutiny and must be rejected.
`
`II.
`
`SUMMARY OF ARGUMENT IN RESPONSE
`
`Petitioners allege all claims of the ’438 Patent are invalid as obvious over
`
`O’Donnell in view of Gerber (Ground 1), and that claims 1-4 and 6-11 are invalid
`
`as obvious over Barrie in view of Gerber (Ground 2). For each Ground, Petitioners
`
`argue that “administration of ketoconazole resulted in adverse side effects
`
`including high blood pressure, hypokalemia and swelling associated with
`
`adrenocorticotropic hormone (‘ACTH’) drive and mineralocorticoid excess,” and
`
`that those side effects would be treated with prednisone. (Pet. at 27).
`
`
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`Mineralocorticoid excess syndrome is a clinical condition resulting from the over-
`
`production of mineralocorticoids to dangerous levels. (Ex. 2038 (Rettig) ¶48; Ex.
`
`2066 at 81; Ex. 2087 at 717). Erroneously arguing that a person of ordinary skill
`
`in the art (“POSA”) would have viewed ketoconazole and abiraterone acetate as
`
`essentially interchangeable, Petitioners contend that “one of skill in the art would
`
`have expected that the co-administration of prednisone with abiraterone would
`
`improve the safety and tolerability of administering abiraterone by reducing the
`
`potential for side effects associated with the administration of a CYP17 inhibitor
`
`[e.g., ketoconazole].” (Pet. at 27).
`
`The present record, however, demonstrates that none of the prior art cited by
`
`Petitioners or their expert, Dr. Serels, provides any support for Petitioners’ “safety
`
`and tolerability” arguments. There were no “safety and tolerability” issues
`
`warranting a need for administering prednisone with abiraterone acetate. Indeed,
`
`the only reference that discloses any information regarding the clinical data for
`
`abiraterone acetate, O’Donnell, states that the compound was “very well tolerated”
`
`and that “no serious adverse events attributable to treatment were recorded.” (Ex.
`
`1003 at 2323). Petitioners’ motivation to combine abiraterone acetate with
`
`prednisone is therefore defeated by the very prior art references it has put forward.
`
`Indeed, Petitioners present the scientifically flawed theory that a POSA
`
`administering abiraterone acetate would have been motivated to co-administer
`
`
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`IPR2016-00286
`US Patent 8,822,438
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`prednisone because prednisone had been co-administered with a different drug –
`
`ketoconazole. Under Petitioners’ theory, methods of administering ketoconazole
`
`disclosed in the prior art would have been translated to abiraterone acetate because
`
`both compounds allegedly acted by the same mechanism. But they do not act the
`
`same. Indeed, contrary to the facts advanced by Petitioners and preliminarily
`
`accepted in the Institution Decision (“ID”), the present record, including testimony
`
`from Petitioners’ own expert, Dr. Serels, now shows:
`
` Ketoconazole and abiraterone acetate do not have the same
`
`mechanism of action and do not have the same effect on cortisol
`
`synthesis;
`
` While ketoconazole suppresses cortisol to cause side effects requiring
`
`glucocorticoid replacement therapy, abiraterone acetate does not;
`
` The record presented by Petitioners ignores the numerous compelling
`
`reasons to avoid giving prednisone to patients with prostate cancer;
`
`and
`
` The combination of ketoconazole and prednisone was never
`
`established as a “safe and effective” treatment for prostate cancer.
`
`Petitioners’ simplistic view of the prior art is undermined by the actual
`
`science. The adrenal steroid synthesis pathway is highly complex. (Ex. 2038
`
`(Rettig) ¶25-39; Ex. 2086 at 705-710; Ex. 2058 at 545-46). It involves numerous
`
`
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`US Patent 8,822,438
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`enzymes that act on numerous steroids and steroid precursors. (Id.) Abiraterone
`
`acetate and ketoconazole are completely different compounds that affect the
`
`adrenal steroid synthesis pathway in completely different ways. (Ex. 2038 (Rettig)
`
`¶85-87, 93-103).
`
`Abiraterone acetate is a selective inhibitor of just one of the numerous
`
`enzymes involved in adrenal steroid synthesis, 17α-hydroxylase/C17,20-lyase
`
`(“CYP17”). (Ex. 1003 (O’Donnell) at 2318). Abiraterone acetate reduces
`
`production of testosterone and other androgens (i.e., male sex steroids) without
`
`completely eliminating all steroid production because it targets only the CYP17
`
`enzyme. (Ex. 2038 (Rettig) ¶94, 97, 103). In contrast, ketoconazole is unselective
`
`and was known to suppress production of all adrenal and gonadal steroids because
`
`it targets many enzymes, not just CYP17. (Ex. 1003 (O’Donnell) at 2318). This
`
`difference, which Petitioners’ expert, Dr. Serels, admitted he failed to recognize
`
`when formulating his opinions, is critical because it means that clinical experience
`
`with ketoconazole would not have been translated to abiraterone acetate. (Ex.
`
`2038 (Rettig) ¶103-105; see also Ex. 2037 (Serels Tr.) at 84:2-18). Petitioners and
`
`their expert failed to account for this key distinction when formulating the
`
`scientifically incorrect contention that experience with one drug interchangeably
`
`translates to the other. The present record, including the very prior art references
`
`that Petitioners rely upon, shows that this is not the case.
`
`
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`
`Petitioners also failed to account for the well-known toxicities associated
`
`with glucocorticoids and the reasons why a POSA would not have administered
`
`prednisone to prostate cancer patients absent some urgent and compelling clinical
`
`need. The record now shows that the mere “prediction” of a “safety or tolerability”
`
`issue would not have motivated one of ordinary skill in the art to administer
`
`prednisone in light of these toxicities. (Ex. 2038 (Rettig) ¶115; Ex. 2040 (Auchus)
`
`at 13-15, 32-33, 43, 45).
`
`Not only was the Panel misled about any motivation to use prednisone, it
`
`was also misled about the expectation of success that a POSA would have had
`
`regarding its use with abiraterone acetate. Prompted by Petitioners, the Panel
`
`preliminarily but mistakenly found that “the relative success of administration of
`
`ketoconazole together with prednisone to treat prostate cancer” would have led a
`
`POSA to expect that prednisone in combination with abiraterone acetate would be
`
`safe and effective in treating prostate cancer. (ID at 9).
`
`But as Petitioners’ expert admitted, the Gerber reference, which discussed
`
`ketoconazole and prednisone and was relied upon to support this finding, lacked
`
`the information that a POSA would have needed to draw any conclusions
`
`regarding the efficacy of that combination to treat prostate cancer. (Ex. 2037
`
`(Serels Tr.) at 176:24-177:7). One of the co-authors of Gerber, Dr. Gerald
`
`Chodak, has now submitted a declaration confirming that the study reported in
`
`
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`US Patent 8,822,438
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`Gerber was not designed to evaluate clinical efficacy and did not examine safety.
`
`(Ex. 2042 (Chodak) ¶16-18; Ex. 2048 (Altman) at Table 2). The fact that Gerber
`
`published in 1990 and that when the ’438 Patent invention was made, 16 years
`
`later, ketoconazole still had not been approved for use in prostate cancer treatment
`
`(and indeed never has been) provides real-world evidence that underscores
`
`Petitioners’ misguided reliance on ketoconazole. (Ex. 2042 (Chodak) ¶34; Ex.
`
`2038 (Rettig) ¶171; Ex. 2063 (Small (2004) at 1031; Ex. 2064 (Millikan) at 115).
`
`Petitioners’ safety and tolerability theory is simply inapplicable to
`
`abiraterone acetate. Petitioners cannot rely on Gerber’s use of prednisone with
`
`ketoconazole as evidence of a “reasonable expectation of success” and neither of
`
`the other references even remotely suggests any safety or tolerability problem with
`
`abiraterone acetate. There can be no “expectation of success” of solving a problem
`
`that the prior art does not teach in the first place.
`
`Petitioners do not contend that there was any expectation of improved
`
`efficacy by combining prednisone with abiraterone acetate as now claimed. In
`
`fact, Petitioners themselves admit the contrary – that there was no expectation of
`
`success in the prior art of combining prednisone with abiraterone acetate therapy to
`
`improve efficacy, as in the claimed invention in which the combination of
`
`prednisone and abiraterone acetate enhances the patient’s response in fighting the
`
`prostate cancer. (Pet. at 14; see infra Section VI.A.4).
`
`
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`7
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`IPR2016-00286
`US Patent 8,822,438
`
`
`At bottom, Petitioners have failed to meet their burden of establishing that
`
`the challenged claims are unpatentable. The claimed methods are not obvious and
`
`the Panel should affirm the validity of the challenged claims.
`
`III. CLAIM CONSTRUCTION
`
`Each of the claims of the ’438 Patent is directed to a “method for the
`
`treatment of a prostate cancer” and each claim expressly requires administration of
`
`“a therapeutically effective amount of abiraterone acetate” and “a therapeutically
`
`effective amount of prednisone.” (Ex. 1001 at 16:15-20).
`
`The ID properly construes the claim element “a therapeutically effective
`
`amount of prednisone” to be “an amount of prednisone effective for treating
`
`prostate cancer.” (ID at 6-7). The ID further properly construes the 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.” (ID at 5).
`
`IV. THE PRIOR ART RELIED UPON BY PETITIONERS
`
`A. Gerber (Ex. 1004)
`
`Gerber published in 1990. Gerber describes a retrospective chart review of
`
`serum prostate specific antigen (“PSA”) levels for 15 patients with hormone
`
`refractory (i.e., castration resistant) metastatic prostate cancer who received
`
`ketoconazole and prednisone in combination. Ketoconazole was originally
`
`
`
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`IPR2016-00286
`US Patent 8,822,438
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`developed as an antifungal agent but was found to be a potent inhibitor of all
`
`adrenocortical and gonadal steroid synthesis. (Ex. 1004 at 1179).
`
`In Gerber, prednisone was used with ketoconazole as “glucocorticoid
`
`replacement therapy,” which was given with ketoconazole to counteract a known
`
`clinical side effect resulting from the inhibition of all testicular and adrenal
`
`steroids, including cortisol. ((Id. at 1179; Ex. 2042 (Chodak) ¶29; Ex. 2038
`
`(Rettig) ¶175).
`
`Gerber reports that any decline in PSA, regardless of degree, was considered
`
`a “response.” (Ex. 1004 at 1178). Gerber was written at a time when PSA testing
`
`was new, and 16 years later, by the time of the invention, PSA results were
`
`analyzed differently. (Ex. 2042 (Chodak) ¶¶35-40; Ex. 2057 (Bubley) at 3461,
`
`3462). While Gerber reported that 80% of patients experienced some decline in
`
`PSA, in 75% of these patients, the PSA declines were short-lived, which led the
`
`authors to conclude that they were “unlikely [to have] significant impact on
`
`survival” and “probably do not reflect significant disease regression.”2 (Ex. 1004
`
`
`2 Gerber reports that two patients had longer term declines in PSA of greater than
`
`50%, but does not provide any radiographic evidence or survival data which would
`
`be necessary to confirm that these patients experienced a clinical benefit. (Ex.
`
`2042 (Chodak) ¶27; Ex. 2038 (Rettig) ¶82, 167).
`
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`IPR2016-00286
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`at 1178).
`
`B.
`
`Barrie (Ex. 1005)
`
`U.S. Patent 5,604,213 – Barrie – issued in 1997 and describes a novel class
`
`of compounds that are “powerful hydroxylase/lyase inhibitors.” (Ex. 1005 at 1:38-
`
`39). The abiraterone acetate compound is just one of numerous others disclosed.
`
`Barrie states that the compounds may be useful for treating prostate cancer and
`
`breast cancer. (Id. at Abstract; 10:47-56.).
`
`Barrie describes in vivo testing involving male mice with abiraterone acetate,
`
`one other compound of the invention, and the non-specific compound
`
`ketoconazole. (Id. at 25:14-20). Blood samples were tested for testosterone. (Id.
`
`at 25:26-28). In addition, adrenals, prostate, seminal vesicles, testes and kidneys of
`
`the mice were removed, weighed, and compared. (Id. at 25:28-31). In describing
`
`the test results, Barrie specifically states that whereas “[k]etoconazole caused an
`
`increase in adrenal weight at the two highest doses,” abiraterone acetate “had no
`
`significant effect, suggesting that abiraterone acetate did not inhibit corticosterone
`
`biosynthesis” (Id. at 25:45-48). Corticosterone is the major glucocorticoid in mice,
`
`and plays a similar role to cortisol in humans. (Ex. 2040 (Auchus) ¶45-46; Ex.
`
`2038 (Rettig) ¶101).
`
`C. O’Donnell (Ex. 1003)
`
`
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`IPR2016-00286
`US Patent 8,822,438
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`
`O’Donnell published in 2004 and is the only prior art evidence providing
`
`any clinical data for abiraterone acetate. O’Donnell describes a series of three
`
`Phase 1 safety studies in which abiraterone acetate was tested in humans. (Ex.
`
`1003 at 2318). O’Donnell says “[t]his is the first report of the effects of a specific
`
`17α-hydroxylase/C17,20-lyase inhibitor in humans.” (Id.) (emphasis added). The
`
`studies were conducted to determine the dose of abiraterone acetate that would
`
`result in maximum testosterone suppression in castrate and non-castrate men with
`
`prostate cancer and to evaluate the safety of abiraterone acetate. (Id.). O’Donnell
`
`discloses that patients in the studies were not allowed to take concomitant steroids.
`
`(Id. at 2319).
`
`The O’Donnell authors reported that “abiraterone acetate was very well
`
`tolerated and no serious adverse events attributable to treatment were recorded.”
`
`(Id. at 2322). There were no haematologic or biochemical effects, and no
`
`alteration in resting heart rate or blood pressure observed. (Id.). The authors
`
`reported that abiraterone acetate had “no effect on 17α-OH-progesterone
`
`production [the precursor to cortisol]” and “no significant effect on cortisol levels
`
`in these patients” (Id. at 2322-23).
`
`
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`V.
`
`PETITIONERS’ SCIENTIFICALLY UNSUPPORTABLE LEAP TO
`OBVIOUSNESS
`
`Petitioners base their “safety and tolerability” obviousness theory upon a
`
`scientifically flawed analogy, that abiraterone acetate’s mechanism of action is
`
`“like” that of ketoconazole (see Pet. at 25), and that based on ketoconazole’s side
`
`effects, a POSA would be motivated to co-administer prednisone with abiraterone
`
`acetate to address “safety and tolerability” issues (see Pet. at 27, 55, 56). But not
`
`only does abiraterone acetate act by a different mechanism of action than
`
`ketoconazole, the clinical data reported for abiraterone acetate confirms that it is a
`
`very different compound as compared to ketoconazole and that whatever
`
`motivation there would have been to co-administer prednisone with ketoconazole
`
`simply did not exist with abiraterone acetate.
`
`As explained in detail below, the record now before the Panel, including
`
`admissions from Petitioners’ own expert, Dr. Serels, and the additional
`
`Declarations of Drs. Matthew Rettig, Gerald Chodak, Richard Auchus, and Dr.
`
`Christopher Vellturo submitted herewith, demonstrates that Petitioners’ arguments
`
`and Dr. Serels’ declaration opinions are premised on scientifically inaccurate
`
`principles that misrepresent the teachings of the prior art and are founded entirely
`
`on hindsight.
`
`
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`US Patent 8,822,438
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`
`A.
`
`First Scientifically Erroneous Premise In Petitioners’ Submission:
`Abiraterone Acetate Works the Same Way and Would Have the
`Same Hormonal Side Effects as Ketoconazole
`
`1.
`
`Abiraterone Acetate Has a Different Mechanism of Action
`From Ketoconazole
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`The central premise of Petitioners’ flawed arguments is that abiraterone
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`acetate and ketoconazole act in the same manner and would have been assumed to
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`have the same hormonal side effects. In view of Petitioners’ arguments, the Panel
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`found that “[k]etoconazole and abiraterone acetate are both characterized as
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`CYP17 inhibitors,” and also concluded that the side effects of administering
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`ketoconazole would apply equally to abiraterone acetate. (ID. at 8-9).
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`Petitioners’ arguments, however, are founded on an erroneous scientific
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`assumption, i.e., that abiraterone acetate and ketoconazole were known to reduce
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`androgens by the same mechanism of action. Further evidence now in the record,
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`including Dr. Serels’ own testimony, shows that this assumption is simply
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`scientifically untrue. (Ex. 2037 (Serels Tr.) at 59:20-24). Indeed, the very prior art
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`that Petitioners rely upon—O’Donnell—teaches that ketoconazole and abiraterone
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`acetate have very different mechanisms of action and do not act in the same way.
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`To the contrary, while ketoconazole has far-reaching and profound effects on the
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`synthesis of all steroids, abiraterone acetate does not. These differences mean that
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`a POSA would not have translated the clinical experience with ketoconazole to
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`abiraterone acetate, as Petitioner suggests. (Ex. 2038 (Rettig) ¶103, 122-123; Ex.
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`2090 (Tucker) at 2413-14; Ex. 2018 at 90; Ex. 1020 (Harris) at 544). This
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`difference is taught in the O’Donnell reference itself. (Ex. 1003 at 2318).
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`Specifically, O’Donnell teaches that abiraterone acetate “was developed as a
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`mechanism-based steroidal inhibitor following observations that nonsteroidal 3-
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`pyridyl esters had improved selectivity for inhibition.” (Ex. 1003 at 2318)
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`(emphasis added). O’Donnell also teaches that “[t]his is the first report of the
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`effects of a specific 17α-hydroxylase/C17,20-lyase inhibitor in humans.” (Id. at
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`2317) (emphasis added). As the record now shows, a POSA would understand
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`from these teachings that abiraterone acetate targets only CYP17 and does not
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`inhibit other enzymes in the steroid synthesis pathway. (Ex. 2038 (Rettig) ¶94).
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`Because of its specific mechanism of action, a POSA would understand that
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`abiraterone acetate still allows for the production of other adrenal steroids that the
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`body needs, such as glucocorticoids and mineralocorticoids, even while inhibiting
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`androgen production. (Id. at ¶103).
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`In contrast to abiraterone acetate’s highly selective mechanism of action,
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`O’Donnell teaches that “[k]etoconazole is relatively unselective, inhibiting both
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`cholesterol side chain cleavage and 11β-hydroxylase.” (Ex. 1003 at 2318)
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`(emphasis added). The “cholesterol side chain cleavage” step described in
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`O’Donnell is the very first step in steroid synthesis, during which cholesterol is
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`converted to pregnenolone, the building block for all steroid hormones. (Ex. 2038
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`(Rettig) ¶95, 96; Ex. 2040 (Auchus) ¶44). A POSA would understand that the
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`inhibition of this first step resulted in the suppression of the production of all other
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`steroids. (Ex. 2038 (Rettig) ¶96; Ex. 2040 (Auchus) ¶45). Thus, from O’Donnell
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`itself, a POSA would understand that ketoconazole is a blunt instrument that
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`inhibits androgen production by inhibiting all adrenal steroid synthetic pathways.
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`(Ex. 2038 (Rettig) ¶97). In contrast, abiraterone acetate would have been
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`understood to target a different enzyme downstream from the enzyme targeted by
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`ketoconazole. (Id.).
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`Other prior art cited by Petitioners teach the same thing: “[k]etoconazole
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`…suppresses testicular and adrenal steroidogenesis by inhibition of the conversion
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`of cholesterol to pregnenolone [i.e., the first steroid synthesis step]...ketoconazole
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`is a potent inhibitor of all adrenal steroid synthetic pathways.” (Ex. 1020 (Harris)
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`at 544 (emphasis added); see also Ex. 1004 (Gerber) at 1177 (“[ketoconazole] is a
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`potent inhibitor of gonadal and adrenocortical steroid synthesis”)). The prior art
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`explains that it was for this reason —because clinical evidence showed that
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`ketoconazole suppressed production of all steroids —that “replacement doses of
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`hydrocortisone [a glucocorticoid] may be required.” (Ex. 1020 (Harris) at 544; Ex.
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`2018 (Jubelirer) at Table 3; Ex.2090 (Tucker)). But, as explained above,
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`abiraterone acetate was understood not to suppress production of all adrenal
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`steroids. First, it was known in the art that abiraterone acetate did not inhibit the
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`first step in the steroid synthesis pathway, unlike ketoconazole. Second, it was
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`known in the art that abiraterone acetate was not a “potent inhibitor” of
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`glucocorticoids, unlike ketoconazole, because, as reported in O’Donnell, patients
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`maintained normal serum cortisol levels (see infra Section V.A.2). As such, the
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`reasons for providing glucocorticoid replacement with ketoconazole would have
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`been understood to not apply to abiraterone acetate.
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`Remarkably, Petitioners’ expert, Dr. Serels, admitted in his deposition that,
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`when formulating his opinions, he failed to consider that ketoconazole suppresses
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`all adrenal steroids and that abiraterone acetate does not. (Ex. 2037 (Serels Tr.) at
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`59:23-60:1; 60:20-25; 124:23-25; 125:1-7). Specifically, Dr. Serels admitted that
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`he did not know that, unlike abiraterone acetate (which only inhibits CYP17),
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`ketoconazole inhibits the enzyme in the first step of steroid synthesis (See id. at
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`80:9-12 (Q: Were you aware that ketoconazole inhibits cholesterol side-chain
`
`cleavage when you prepared your declaration? A: No.). But when Dr. Serels
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`actually considered that fact and was asked in his deposition to circle the steroids
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`that would be inhibited by administration of ketoconazole, he admitted that
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`ketoconazole “could effect [sic] any one of these [adrenal steroids]…So, I mean,
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`I’d have to circle the entire page.” (Id. at 124:23-125:7 (circling entire Figure 1
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`from Ex. 1003)).
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`Dr. Serels also admitted that he did not even “discuss that ketoconazole
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`inhibits 11-beta-hydroxylase” in his declaration because he “did not consider it to
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`be important….” (Id. at 82:15-83). But it is – it is another enzyme inhibited by
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`ketoconazole but not by abiraterone acetate that is necessary for the production of
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`cortisol. (Ex. 2038 (Rettig) ¶97). Indeed, it is critically important because it
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`establishes that abiraterone acetate has a different mechanism of action as
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`compared to ketoconazole and that Petitioners’ arguments to the contrary
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`misrepresented the teachings of the prior art. Given these differences, a POSA
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`would not have found it appropriate to simply apply the clinical experience with
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`ketoconazole, including its side effects, and methods of managing those side
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`effects, to abiraterone acetate. (Ex. 2038 (Rettig) ¶103-104).
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`2. O’Donnell Confirms that Abiraterone Acetate Allows
`Cortisol to be Made in Normal Levels in Patients, Unlike
`Ketoconazole
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`The fact that ketoconazole and abiraterone acetate act by different
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`mechanisms of action manifests itself clinically. Again, this was known i