`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`MYLAN PHARMACEUTICALS INC., ACTAVIS
`LABORATORIES FL, INC., AMNEAL PHARMACEUTICALS LLC,
`AMNEAL PHARMACEUTICALS OF NEW YORK, LLC, DR. REDDY'S
`LABORATORIES, INC., DR. REDDY'S LABORATORIES, LTD.,
`SUN PHARMACEUTICALS INDUSTRIES, LTD.,
`SUN PHARMACEUTICALS INDUSTRIES, INC.,
`TEVA PHARMACEUTICALS USA, INC., WEST-WARD
`PHARMACEUTICAL CORP., and HIKMA PHARMACEUTICALS, LLC,
`Petitioner
`
`v.
`
`JANSSEN ONCOLOGY, INC.,
`
`Patent Owner
`
`Case IPR2016-013321
`Patent 8,822,438 B2
`
`
`
`
`
`
`
`REPLY DECLARATION OF MARC B. GARNICK, M.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF U.S.
`PATENT NO. 8,822,438
`
`
`
`
`1 Case IPR2017-00853 has been joined with this proceedings.
`
`
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`MYLAN PHARMS. INC. EXHIBIT 1104 PAGE 1
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`TABLE OF CONTENTS
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`I. SUMMARY OF OPINIONS ............................................................................... 4
`
`II. LEGAL STANDARDS ....................................................................................... 6
`
`III. PERSON OF ORDINARY SKILL IN THE ART .............................................. 6
`
`IV. THE ’438 PATENT CLAIMS ARE OBVIOUS OVER THE PRIOR
`ART ..................................................................................................................... 7
`
`V. A POSA WOULD HAVE BEEN MOTIVATED TO ADMINISTER
`PREDNISONE WITH ABIRATERONE ACETATE AND HAD A
`REASONABLE EXPECTATION OF SUCCESS. ............................................ 9
`A. A POSA would have been motivated to administer prednisone with
`abiraterone acetate because it is a steroid synthesis inhibitor and had
`a reasonable expectation of success. ............................................................. 9
`(a) Steroid synthesis inhibitors, used to treat advanced prostate cancer,
`are generally administered with a glucocorticoid. ...................................10
`(b) Prednisone was a preferred glucocorticoid. .............................................15
`(c) Dr. Rettig’s opinion regarding any different mechanisms of action
`and hormonal side effect profiles between ketoconazole and
`abiraterone acetate is flawed. ...................................................................16
`(d) Dr. Rettig’s opinion that the prior art did not teach ketoconazole
`was “safe and effective” for the mCRPC does not analyze Gerber
`through the lens of a skilled artisan and fails to address the relevant
`teachings of Gerber ...................................................................................20
`B. O’Donnell and Gerber, in light of the state of the prior art, motivated
`skilled artisans to treat prostate cancer with abiraterone acetate and
`prednisone for glucocorticoid replacement to account for low
`adrenal reserve and provided a reasonable expectation of success. ...........24
`(a) O’Donnell motivated skilled artisans to use, and provided them a
`reasonable expectation of success in using, glucocorticoid
`replacement therapy with abiraterone acetate. .........................................25
`(b) The prior art made clear that treatment with abiraterone acetate
`would likely require glucocorticoid treatment. ........................................29
`(c) Skilled artisans would not shy away from administering
`glucocorticoids based on any fear of side effects or alleged
`potential to fuel cancer .............................................................................35
`
`2
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`TABLE OF CONTENTS
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`C. A POSA would have been motivated to administer prednisone to
`prevent abiraterone acetate-induced mineralocorticoid excess and
`have a reasonable expectation of success in doing so. ...............................43
`(a) Skilled artisans would have been concerned that abiraterone
`acetate may cause mineralocorticoid excess. ...........................................43
`(b) As of the priority date of the ’438 patent, skilled artisans would
`have had concerns that mineralocorticoid excess was possible with
`the use of ketoconazole ............................................................................45
`D. A POSA would have had a reasonable expectation of success in
`using prednisone because it had long been used for its palliative
`effects, in addition to glucocorticoid replacement. .....................................48
`VI. THE CLAIMS OF THE ’438 PATENT REMAIN OBVIOUS DESPITE
`DR. RETTIG’S OPINIONS REGARDING SECONDARY
`CONSIDERATIONS ........................................................................................51
`A. There is no evidence of unexpected results to support the
`nonobviousness of the claims of the ’438 patent, either in the patent
`or elsewhere. ...............................................................................................51
`(a) The claimed invention has not been compared to the closest prior
`art ..............................................................................................................51
`(b) There is no credible evidence that the claimed invention yields
`unexpected results over the use of abiraterone acetate alone ...................55
`(c) Dr. Rettig presented no relevant evidence that the use of
`prednisone avoids clinical resistance to abiraterone and decreases
`steroid
`precursors ..................................................................................................61
`B. Zytiga is not an unexpected commercial success ........................................62
`C. There was no long-felt but unmet need .......................................................63
`D. There was no skepticism or failure of others ..............................................65
`E. There is no nexus between the alleged secondary considerations and
`the scope of the claims of the ’438 patent...................................................67
`
`
`
`3
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`1.
`
`I am the same Marc B. Garnick, M.D. who previously submitted a
`
`declarations dated June 30, 2016 and February 8, 2017. I submit this expert
`
`declaration to respond to certain opinions expressed in the expert declaration (Ex.
`
`2038) submitted with Patent Owner’s Response to the Petition.
`
`2.
`
`In addition to my experience, education, and training, and the
`
`materials identified in my earlier declaration (Ex. 1002), I have also considered all
`
`materials identified in Exhibit A, as well as any materials cited herein not
`
`otherwise identified in Exhibit A, as well as any materials cited in Dr. Rettig’s
`
`Declaration (Ex. 2038) not otherwise identified.
`
`3. My curriculum vitae submitted with my original declaration remains
`
`accurate. See Ex. 1002, Ex. A.
`
`4.
`
`The scope of my work and compensation remains the same since I
`
`submitted my original declarations in this proceeding. I was retained as a technical
`
`expert to provide opinions related to the patent at issue. My compensation is not
`
`dependent upon the outcome of the proceedings or my opinions given. I have no
`
`current affiliation with Janssen Oncology, Inc. or the inventors of the patent at
`
`issue.
`
`I.
`
`SUMMARY OF OPINIONS
`
`5.
`
`The administration of abiraterone acetate in combination with
`
`prednisone to treat advanced stage prostate cancer would have been obvious to
`
`4
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`skilled artisans as of the priority date of the ’438 patent. First, skilled artisans
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`would have known that the state of the prior art included administration of
`
`ketoconazole and other steroid synthesis inhibitors, such as aminoglutethimide, in
`
`combination with glucocorticoid replacement. These were well-known and
`
`accepted treatments for advanced prostate cancer. Second, skilled artisans would
`
`have known that abiraterone acetate was a next-generation steroid synthesis
`
`inhibitor, and an obvious choice for administration in advanced stage prostate
`
`cancer—a point that Dr. Rettig does not dispute. Third, skilled artisans would
`
`have expected to need to administer abiraterone acetate with glucocorticoids
`
`because it was known to inhibit the steroid synthesis pathway, like other agents in
`
`its class. In particular, abiraterone acetate was known to be a strong, potent
`
`inhibitor of the CYP17 enzyme, similar to ketoconazole. Fourth, prednisone was a
`
`commonly used glucocorticoid and its characteristics made it an obvious choice for
`
`co-administration with abiraterone acetate.
`
`6.
`
`Dr. Rettig attempts to undercut the obviousness of the claims of the
`
`’438 patent by nitpicking at a number of ancillary issues such as the mechanism of
`
`steroid synthesis inhibition of ketoconazole, and the data supporting expected
`
`disruptions in the synthesis of adrenal steroids when administering abiraterone
`
`acetate. His arguments largely ignore the wealth of art supporting administration
`
`of glucocorticoids, in particular prednisone, with ketoconazole as well as
`
`5
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`aminoglutethimide. As detailed herein, his opinions are unsupported by the state
`
`of the art and the information well within a skilled artisan’s knowledge.
`
`II.
`
`LEGAL STANDARDS
`
`7.
`
`In addition to the legal principles detailed in my previous declaration,
`
`I have been informed that to combine prior art teachings and render patent claims
`
`obvious, the prior art does not need to contain data that alters the standard of
`
`medical care. Instead, a skilled artisan must be motivated to and have a reasonable
`
`expectation of success in learning from the prior art.
`
`III.
`
`PERSON OF ORDINARY SKILL IN THE ART
`
`8.
`
`It continues to be my opinion, as expressed in my opening declaration
`
`(Ex. 1002), that a person of ordinary skill in the art (“POSA”) at the time of filing
`
`of the ’438 patent is someone who is a physician specializing in urology,
`
`endocrinology or oncology, or holds a Ph.D. in pharmacology, biochemistry or a
`
`related discipline (which may include, for example, pharmaceutical sciences).
`
`Additional experience could substitute for the advanced degree.
`
`9.
`
`A person of ordinary skill in the art may also collaborate with one or
`
`more persons of skill in the art for one or more aspects in which the other person
`
`may have expertise, experience, and/or knowledge that was obtained through his or
`
`her education, industrial or academic experiences. A person of ordinary skill in the
`
`art may consult with an endocrinologist, oncologist or medical biochemist and thus
`
`6
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`may rely on opinions of such specialists in evaluating the claims. I have
`
`considered the prior art in light of Patent Owner’s definition of a person of
`
`ordinary skill in the art, and my opinions remain the same.
`
`IV.
`
`THE ’438 PATENT CLAIMS ARE OBVIOUS OVER THE PRIOR
`ART
`
`10. As stated in my original declaration, it remains my opinion that the
`
`claims of the ’438 patent are obvious over the prior art. O’Donnell discloses the
`
`use of abiraterone acetate with glucocorticoid treatment. In particular, the art
`
`taught that abiraterone acetate is a selective CYP17 inhibitor used to treat prostate
`
`cancer. Abiraterone acetate is more effective at suppressing testosterone
`
`production than other similar prior art steroid synthesis inhibitors such as
`
`ketoconazole or aminoglutethimide. Ex. 1003 (O’Donnell 2004) at 2, 6, 7, 8. Like
`
`O’Donnell, the ’213 patent similarly discloses treatment of prostate cancer with
`
`abiraterone acetate. See Ex. 1005 (’213 patent).
`
`11. O’Donnell, moreover, notes that it was “common practice,” before the
`
`priority date, to administer glucocorticoids in the clinical use of the secondary
`
`hormone therapies aminoglutethimide and ketoconazole. Ex. 1003 (O’Donnell
`
`2004) at 7; see also Ex. 1105 (Paulson 1989) at 8-9. O’Donnell then specifically
`
`suggests the use of glucocorticoid therapy with abiraterone acetate. Ex. 1003
`
`(O’Donnell 2004) at 7. O’Donnell thus explicitly teaches the use of glucocorticoid
`
`therapy with abiraterone acetate, as detailed in my original declaration. Moreover,
`
`7
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`O’Donnell was not alone in his thinking that adrenal steroid synthesis inhibitors
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`would require glucocorticoid replacement therapy; this was in the literature and
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`well within the knowledge of skilled artisans such as myself. It was obvious that
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`modulators of adrenal steroid synthesis would require
`
`the concomitant
`
`administration of glucocorticoids.
`
`12. Gerber 1990 discloses the use of a secondary hormone treatment with
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`5 mg of prednisone twice daily. Ex. 1004 (Gerber 1990) at Abstract, 1-3. In
`
`particular, Gerber explains that 5 mg of prednisone administered twice daily is a
`
`safe and effective means of treating side effects associated with treatment with the
`
`ketoconazole, a steroid synthesis inhibitor. Id.
`
`13. A skilled artisan would take these papers and consider them in light of
`
`all of the knowledge gained from practice in treating late-stage prostate cancer
`
`patients with steroid synthesis inhibitors, and in particular with CYP17 inhibitors.
`
`Based on my years of experience treating patients with prostate cancer, and in light
`
`of these papers and the state of the art, a skilled artisan would be motivated to treat,
`
`and have a reasonable expectation of success in treating, mCRPC (also referred to
`
`as androgen independent or hormonally refractory prostate cancer) using a
`
`combination of abiraterone acetate with prednisone as claimed in the ’438 patent.
`
`8
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`V.
`
`A POSA WOULD HAVE BEEN MOTIVATED TO ADMINISTER
`PREDNISONE WITH ABIRATERONE ACETATE AND HAD A
`REASONABLE EXPECTATION OF SUCCESS.
`
`A. A POSA would have been motivated to administer prednisone
`with abiraterone acetate because it is a steroid synthesis inhibitor
`and had a reasonable expectation of success.
`
`14. As stated in my first declaration, and as detailed below, as of 2006
`
`skilled artisans would have been motivated to treat, and had a reasonable
`
`expectation of success in treating, advanced prostate cancer with abiraterone
`
`acetate in combination with prednisone. Abiraterone acetate was known to be an
`
`effective treatment for prostate cancer. Moreover, the prior art makes clear that
`
`steroid synthesis
`
`inhibitors,
`
`including CYP17
`
`inhibitors, were commonly
`
`administered with glucocorticoids, and in particular prednisone. Given the wealth
`
`of knowledge available to skilled artisans regarding those inhibitors generally, and
`
`abiraterone acetate specifically, the claimed invention would have been obvious to
`
`skilled artisans.
`
`15. As also detailed below, Dr. Rettig’s quibbles related to the allegedly
`
`different mechanisms of action of ketoconazole and abiraterone acetate do not
`
`change my opinions regarding the obviousness of the claimed invention. His
`
`position is contrary to wisdom that skilled artisans had in 2006, and does not
`
`square with the prior art.
`
`9
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`(a)
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`Steroid synthesis inhibitors, used to treat advanced prostate
`cancer, are generally administered with a glucocorticoid.
`
`16.
`
`In 2006, skilled artisans recognized that steroid synthesis inhibitors
`
`were effective at treating advanced prostate cancer. While an off-label use of the
`
`drug, ketoconazole was a common steroid synthesis inhibitor (also inhibiting the
`
`CYP17 enzyme, like abiraterone acetate) used to treat patients with advanced
`
`prostate cancer. I have, in fact, personally prescribed ketoconazole and
`
`aminoglutethimide to treat patients with advanced prostate cancer on many
`
`occasions. While ketoconazole was one of the more broadly used steroid synthesis
`
`inhibitors, others in that same class include aminoglutethimide.
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`17. First, ketoconazole and aminoglutethimide were well-known in the art
`
`as a treatment for prostate cancer. With respect to ketoconazole it was known to
`
`“blocks the conversion of progestins into androgens . . . both in the testes and in
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`the adrenals.” Ex. 1106 (De Coster 1987) at 6. Ketoconazole was also found to
`
`“consistently reduce[] adrenal steroid production.” Ex. 1107 (Trump 1989) at 5.
`
`In 2002, Harris reported that “ketoconazole . . . has become a standard treatment
`
`option for patients with advanced prostate cancer.” Ex. 1020 (Harris 2002) at
`
`Abstract. Moreover, in 2005, Figg reported that “ketoconazole . . . is a potent
`
`inhibitor of adrenal steroid synthesis” and “is used as a second line hormonal
`
`treatment in patients with androgen independent prostate cancer.” Ex. 1108 (Figg
`
`2005) at 1. As to aminoglutethimide, skilled artisans knew that it may be useful in
`
`10
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`treating advance prostate cancer given it “inhibits the synthesis of adrenal
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`androgen.” Ex..1109 (Chang 1989) at 1. In 2004, Kruit confirmed this, reporting
`
`(while using glucocorticoid replacement therapy) that “combination therapy with
`
`aminoglutethimide and hydrocortisone is an effective treatment modality for
`
`androgen-independent prostate cancer.” Ex. 1110 (Kruit 2004) at 5.
`
`18. While steroid synthesis inhibitors were known to effectively treat
`
`advanced stage prostate cancer, the drugs were also known to have significant side
`
`effects associated with disruption of the endocrine system. CPY17 inhibitors were
`
`known, for example, to cause adrenal insufficiency. See e.g., Ex. 1111 (Goodman
`
`2001) at 28 (Inhibition “pose[s] the common risk of precipitating acute adrenal
`
`insufficiency.”). Adrenal insufficiency occurs when the body does not produce
`
`ample cortisol, and leads to symptoms such as fatigue, weakness, weight loss,
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`hypotension, nausea, and vomiting. Ex. 1025 (Harrison’s 2005) at 36. Skilled
`
`artisans also knew that in certain instances, steroid synthesis inhibitors can also
`
`lead
`
`to “mineralocorticoid excess,” wherein mineralocorticoid
`
`levels are
`
`heightened.
`
` Mineralocorticoid excess was known
`
`to
`
`lead hypertension,
`
`hypokalemia, and fluid retention. Ex. 1025 (Harrison’s 2005) at 32, 33, 37, 39, 40.
`
`19. Given the side effects associated with disruption of certain endocrine
`
`functions, steroid synthesis inhibitors were, and continue to be, administered with
`
`glucocorticoids. As detailed below, the prior art taught, for example, that both
`
`11
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`ketoconazole and aminoglutethimide were to be administered with concomitant
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`glucocorticoid supplementation to alleviate dangerous and undesirable side effects.
`
`Indeed, Patent Owner’s declarant, Dr. Judson, agreed with this when he stated that
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`“[a]t the time, hydrocortisone was the standard steroid administered as a
`
`glucocorticoid replacement with ketoconazole and aminoglutethimide, which were
`
`inhibitors of steroid synthesis that were known to reduce cortisol levels.” Ex. 2028
`
`(Judson Decl.) ¶ 6.
`
`20. First, with respect to ketoconazole, the prior art is replete with
`
`references teaching the use of glucocorticoids. In 1987, De Coster taught that
`
`ketoconazole disrupts both the glucocorticoid and mineralocorticoid pathways,
`
`leading to impaired adrenal function. Ex. 1106 (De Coster 1987) at 1, 6. In light
`
`of
`
`this, De Coster
`
`taught
`
`to “combine high-dose ketoconazole with a
`
`glucocorticoid substitution therapy” when using ketoconazole to treat advanced
`
`stage prostate cancer. Id. at 1-2. Trump 1989 likewise disclosed the use of
`
`ketoconazole along with glucocorticoid replacement therapy for the treatment of
`
`advanced stage prostate cancer while reducing side effects associated with
`
`disruption of the glucocorticoid- and mineralocorticoid pathways. Ex. 1107
`
`(Trump 1989).
`
`21. Teaching treatment of patients with advanced stage prostate cancer
`
`with a combination of steroid synthesis glucocorticoid treatment continued
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`12
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`throughout the 1990s and early 2000s, as detailed in many prior art references. See
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`Ex. 1112 (Small and Vogelzang 1997) at 4 (replacement doses of hydrocortisone
`
`“are required” when treating advance prostate cancer patients with ketoconazole);
`
`see also 1113 (Small 1997) (studying treatment of advanced prostate cancer with
`
`ketoconazole and replacement doses of hydrocortisone); see also Ex. 1020 (Harris
`
`2002) at 1-3 (studying treatment of prostate cancer with ketoconazole and
`
`hydrocortisone); see also Ex. 2063 (Small 2004) (evaluating the use of
`
`ketoconazole
`
`in patients with androgen-independent prostate cancer, and
`
`administering replacement hydrocortisone); see also Ex. 1108 (Figg 2005) at 1
`
`(teaching that “ketoconazole is a potent inhibitor of adrenal steroid synthesis,” “is
`
`used as a second line hormonal treatment in patients with androgen independent
`
`prostate
`
`cancer,”
`
`and
`
`administering
`
`replacement hydrocortisone with
`
`ketoconazole).
`
`22. Moreover,
`
`another
`
`adrenal
`
`steroid
`
`synthesis
`
`inhibitor—
`
`aminoglutethimide—is also administered for the treatment of advanced prostate
`
`cancer along with replacement glucocorticoids. Like ketoconazole, the art has
`
`taught the use of aminoglutethimide with glucocorticoid replacement therapy since
`
`the 1980s. For example, as early as 1984, Ponder taught that aminoglutethimide
`
`“is an inhibitor of several enzymes involved in adrenal steroid synthesis” and could
`
`be used in treatment of advanced prostate cancer. Ex. 1114 (Ponder 1984) at 1. In
`
`13
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`Ponder, aminoglutethimide was administered along with cortisone acetate. In
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`1989, Chang and Labrie,
`
`in separate publications,
`
`taught
`
`the use of
`
`aminoglutethimide for the treatment of prostate cancer as well. Ex. 1109 (Chang
`
`1989) at 1; see also Ex. 1115 (Labrie 1989) at 2-5 (635-38). In both, concomitant
`
`glucocorticoid supplementation was administered. Ex. 1109 (Chang 1989) at 1;
`
`see also Ex. 1115 (Labrie 1989) at 2-5. Also like ketoconazole, such teachings
`
`remained in the prior art for years. For example, in 2004 Kruit reported a study in
`
`which patients with advanced prostate cancer were treated with aminoglutethimide
`
`and hydrocortisone. Ex. 1110 (Kruit 2004). Kruit found that “combination
`
`therapy with aminoglutethimide and hydrocortisone is an effective treatment
`
`modality for androgen-independent prostate cancer.” Id. at 5.
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`14
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`23. For example, Paulson provides the following diagram demonstrating
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`that ketoconazole and aminoglutethimide both function to inhibit production of
`
`testosterone via the steroid synthesis pathway:
`
`
`
`Ex. 1105 (Paulson 1989) at 7(citing Garnick, M.B.: Urologic cancer. In Scientific
`
`American Medicine. Edited by E. Rubenstein and D.D. Federman, New York,
`
`Scientific American Medicine, 1987.).
`
`(b) Prednisone was a preferred glucocorticoid.
`24. A skilled artisan would be further motivated to administer prednisone,
`
`in particular. It is notable that Dr. Rettig never asserts that a POSA would have
`
`chosen another glucocorticoid over prednisone. This is likely because he knows
`
`prednisone was a well-known and common choice among glucocorticoids used
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`15
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`with cancer treatments. For example, prednisone was used in combination with
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`mitoxantrone. Ex. 1101 (Osoba 1999); see also Ex. 1006 (Tannock 1996); see also
`
`Ex. 1116 (Berry 2002). Moreover, prednisone was known to have palliative
`
`effects for patients with advanced forms of prostate cancer, making it a likely
`
`choice. Ex. 1031 (Tannock 1989). Finally, Gerber employed the use of
`
`prednisone with ketoconazole, another CYP17 inhibitor, suggesting it would
`
`appropriate for use with abiraterone acetate. Ex. 1004 (Gerber 1990). The record
`
`therefore demonstrates—and Dr. Rettig does not argue otherwise—that prednisone
`
`was the obvious choice of glucocorticoid for administration with abiraterone
`
`acetate.
`
`(c) Dr. Rettig’s opinion regarding any different mechanisms of
`action and hormonal side effect profiles between ketoconazole
`and abiraterone acetate is flawed.
`
`25. Dr. Rettig’s opinions regarding variations between the mechanisms of
`
`action of ketoconazole and abiraterone acetate miss the point, and do not alter my
`
`opinions regarding the obviousness of the claims of the ’438 patent. Dr. Rettig
`
`states that the opinions in my first declaration are “scientifically incorrect and have
`
`no support in the prior art.” Ex. 2038 (Rettig Decl.) ¶97. Dr. Rettig is wrong.
`
`26. First, while it is true that ketoconazole is a non-selective inhibitor, and
`
`abiraterone acetate is a strong, selective inhibitor of CYP17, the fact remains that
`
`both, as well as aminoglutethimide, inhibit adrenal steroid synthesis, including
`
`16
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`cortisol. Ex. 1003 (O’Donnell) at 2; see also supra ¶¶ 16-23. Whenever a drug
`
`has such an effect on cortisol levels, skilled artisans would seek to employ
`
`replacement therapy.
`
`27. Moreover, as detailed in my first declaration and herein, treating a
`
`cancer patient with a drug that alters adrenal steroid production (as with
`
`ketoconazole, abiraterone acetate, and aminoglutethimide) would cause a skilled
`
`artisan to be very concerned about the many dramatic and dangerous side effects
`
`that can, and are likely to, occur as a result of the inhibition of adrenal steroid
`
`synthesis. See, e.g., Ex. 1025 (Harrison’s 2005) at 36, 37; Ex. 1098 (Arlt 2003) at
`
`1, 4-5 (noting that adrenal insufficiency clinical symptoms can be weakness,
`
`fatigue, weight loss, nausea, vomiting, hypotension and hyperpigmentation); see
`
`also Ex. 1098 (Arlt 2003) at 1 (stating that “[a]drenal insufficiency . . . is life
`
`threatening when overlooked.”); Ex. 1025 (Harrison’s 2005) at 32, 33, 37, 39, 40
`
`(noting that common symptoms of mineralocorticoid excess symptoms include
`
`hypertension, hypokalemia, and hypernatremia). A skilled artisan would thus be
`
`motivated to administer, and have a reasonable expectation of successfully
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`administering, glucocorticoid replacement therapy in combination with a drug for
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`the treatment of advanced prostate cancer that inhibits cortisol production, which a
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`POSA would expect abiraterone acetate to do. See Ex. 1003 (O’Donnell 2004) at 7
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`(“In the clinical use of both aminoglutethimide and ketoconazole it is common
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`17
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`practice to administer supplementary hydrocortisone and this may prove necessary
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`with . . . abiraterone acetate”); Ex. 1023 (Attard 2005) at 2-3.
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`28. Dr. Rettig’s criticism that “O’Donnell does not indicate that
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`ketoconazole inhibits the CYP17 enzyme or that ketoconazole is a ‘CYP17
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`inhibitor’” is likewise flawed. Ex. 2038 (Rettig Decl.) ¶ 99. The prior art is
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`replete with commentary noting that ketoconazole does, in fact, inhibit the CYP17
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`enzyme, even as it inhibits other enzymes. Ex. 1003 (O’Donnell 2004) at 2, 7; Ex.
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`1078 (Barrie) at 1, 3; Ex. 1085 (Potter 1995) at 1. Indeed, Dr. Rettig’s own figures
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`show that ketoconazole has an inhibitory effect on the CYP17 enzyme. Ex. 2038
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`(Rettig Decl.) at 41. Given this, it appears that Dr. Rettig’s only substantive
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`concern is that in addition to inhibiting the CYP17 enzyme, ketoconazole also
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`inhibits others enzymes in the same pathway, a fact I have not contested.
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`29. Dr. Rettig, relying on Dr. Auchus, also argues that the ’213 patent’s
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`disclosures related to mechanism of action suggest that treatment with abiraterone
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`acetate treatment would not require glucocorticoid treatment. Ex. 2038 (Rettig
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`Decl.) ¶¶ 103-107. I disagree with Dr. Rettig. This is based on Dr. Bantle’s
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`opinions that (1) the prior art makes clear that “cortisol is substantially inhibited by
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`abiraterone acetate,” and (2) that a skilled artisan “would not expect increased
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`corticosterone production to fully compensate for lower cortisol production
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`resulting from abiraterone acetate’s CYP17 inhibition.”. Ex. 1097 (Bantle Decl.)
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`18
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`¶¶ 44-55, 85-88. As detailed in my original declaration, it is my opinion that the
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`disclosures of the ’213 patent supports the obviousness of the claims of the ’438
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`patent.
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`30. Moreover, as detailed above, the published prior art as well as the
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`knowledge skilled artisans would have gained through training and experience
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`taught that advanced prostate cancer drugs that inhibit adrenal steroid synthesis are
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`in the same class of drugs. Supra ¶¶ 16-23. A skilled artisan would thus consider
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`them similar in terms of clinical effect and expected side effects, and despite some
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`variations among the enzymes inhibited in the steroid synthesis pathway, skilled
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`artisans would think about them as a group of drugs and be able to draw certain
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`conclusions about them on the whole. Relevant here, skilled artisans would
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`anticipate administering any steroid synthesis
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`inhibitor with replacement
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`glucocorticoid therapy for treatment of patients with advanced prostate cancer.
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`31.
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`In sum, Dr. Rettig’s opinions regarding the variations in steroid
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`synthesis inhibition between ketoconazole and abiraterone acetate fall flat and do
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`not render the claims of the ’438 patent non-obvious. As detailed in my first
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`declaration and herein, abiraterone acetate was known to reduce cortisol
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`production, irrespective of any variation in enzymes inhibited. Ex. 1003
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`(O’Donnell 2004) at 2; Ex. 1023 (Attard 2005) at 2-3. Because abiraterone
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`acetate, like other prior art molecules used in the treatment of advanced stage
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`prostate cancer, was known to reduce cortisol production, skilled artisans would
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`seek to use replacement therapy to prevent very dangerous, and expected, side
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`effects.
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`(d) Dr. Rettig’s opinion that the prior art did not teach
`ketoconazole was “safe and effective” for the mCRPC does not
`analyze Gerber through the lens of a skilled artisan and fails to
`address the relevant teachings of Gerber.
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`32.
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`In addition to quibbling with the variations in mechanisms of action of
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`ketoconazole and abiraterone acetate, Dr. Rettig also argues that ketoconazole was
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`not known to be a safe and effective treatment for mCRPC patients. Ex. 2038
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`(Rettig Decl.) ¶¶ 167-188. His opinion on that relies largely on a misguided view
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`of Gerber and the relevant question in this proceeding. Dr. Rettig also fails to take
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`into account the wealth of prior art describing the successful use of ketoconazole,
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`as well as the general knowledge of practicing oncologists as of the priority date.
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`33.
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`In the context relevant here—deciding whether the use of abiraterone
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`acetate in combination with prednisone was obvious as claimed in the ’438
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`patent—a skilled artisan would find Dr. Rettig’s concerns about the findings in
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`Gerber of no relevance. As detailed herein and in my original declaration, skilled
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`artisans would have looked at the wealth of prior art on treatment of advanced
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`stage prostate cancer with steroid synthesis inhibitors. Ex. 1002 (Garnick Decl.) ¶¶
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`33, 43-46, 58-59, 78-80; supra ¶¶ 16-23. Reviewing this art, a skilled artisan
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`would have then determined that because abiraterone acetate was a specific, strong
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`20
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`inhibitor of CYP17 it was an obvious choice. Ex. 1002 (Garnick Decl.) ¶¶ 46, 55-
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`56, 58-59; supra ¶¶ 26-31. As also detailed herein, in my original declaration, and
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`by Dr. Bantle (Ex. 1097 ¶¶ 44-55, 68-88), skilled artisans would have been
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`concerned about adrenal insufficiency. Gerber reports the successful use of
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`prednisone with a steroid synthesis inhibitor to address side effects associated with
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`adrenal insufficiency, which would have guided a skilled artisan, in light of the
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`prior art and the knowledge of a skilled artisan, to use prednisone. Ex. 1004
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`(Gerber 1990).
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`34. Dr. Rettig’s opinions on whether Gerber shows ketoconazole is safe
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`and effective are also in conflict with the state of the art. Dr. Rettig appears to
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`argue that because ketoconazole was never FDA approved for mCRPC treatment,
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`and Gerber was a small study measuring prostate specific antigen (“PSA”) levels,
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`that ketoconazole was not known as “safe and effective.” Ex. 2038 (Rettig Decl.)
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`¶¶ 167-188. Given this, Dr. Rettig’s disag