`
`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 US.
`PATENT NO. 8,822,438
`
`1 Case IPR2017-00853 has been joined with this proceedings.
`
`JANSSEN EXHIBIT 2177
`Wockhardt v. Janssen IPR2016-01582
`
`Wockhardt v. Janssen lPR2016-01582
`
`JANSSEN EXHIBIT 2177
`
`
`
`MYLAN PHARMS. INC. EXHIBIT 1104 PAGE 1
`
`
`
`TABLE OF CONTENTS
`
`I.
`
`SUMMARY OF OPINIONS ............................................................................. ..4
`
`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
`ablraterone acetate because 1t 18 a ster01d synthes1s 1nh1b1tor and had
`a reasonable expectation of success............................................................ ..9
`
`(a)
`
`Steroid synthesis inhibitors, used to treat advanced prostate cancer,
`are generally admlnlstered w1th a glucocort1c01d. ................................. ..10
`
`(b) Prednisone was a preferred glucocorticoid.
`
`(0) Dr. Rettig’s opinion regarding any;J different mechanisms of action
`and hormonal Side effect pro 1165 etween ketoconazole and
`abiraterone acetate 13 flawed.
`
`(d) Dr. Rettig’s o inion that the rior art did not teach ketoconazole
`was “safe an effective’_’ for
`e mCRPC does not analyze Gerber
`through the lens of a skilled artlsan and falls to address the relevant
`teachingsof
`
`B.
`
`O’Donnell and Gerber, in light of the state of the prior art, motivated
`skilled artisans to treat prostate cancer w1th abiraterone acetate and
`prednisone for glucocort1c01d replacement to account for low
`adrenal reserve and provtded a reasonable expectation of success. ......... ..24
`
`(a) O’Donnell motivated skilled artisans to use, and provided them a
`reasonable ex ectattonpf success m usmg, glucocort1c01d
`replacement t erapy w1th abiraterone acetate. ....................................... ..25
`
`(b) The rior art made clear that treatment with abiraterone acetate
`wou (1 11ker require glucocort1c01d treatment.
`
`(c)
`
`Skilled artisans would not shy away from administering
`glucocorticoids based on any fear of side effects or alleged
`potentlal to fiiel cancer ........................................................................... ..35
`
`MYLAN PHARMS. INC. EXHIBIT 1104 PAGE 2
`
`
`
`1.
`
`I am the same Marc B. Gamick, MD. 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.
`
`203 8) 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
`
`MYLAN PHARMS. INC. EXHIBIT 1104 PAGE 4
`
`
`
`TABLE OF CONTENTS
`
`C.
`
`A POSA would have been motivated to administer prednisone to
`revent abiraterone acetatermduced mlnegalocorticmd excess and
`rave a reasonable expectation of success In domg so.
`
`(a) Skilled artisans would have been cpncemed that abiraterone
`acetate may cause mmeralocortlcmd excess. ......................................... ..43
`
`(b) As of the priority date of the ’438 patent, skilled artisans would
`have had concerns that m1neralocort1c01d excess was pos51ble with
`the use of ketoconazole .......................................................................... ..45
`
`D.
`
`A POSA would have had a reasonable expectation ofsuccess in
`usmg predmsone because It had [on been used for its palliative
`effects, 1n addition to glucocorticm 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
`nonobv1ousness of the clalms of the ’438 patent, elther 1n the patent
`or elsewhere. ............................................................................................. . .51
`
`(a) The claimed invention has not been compared to the closest prior
`
`..
`
`..
`
`51
`
`(b) There is no credible evidence that the claimed invention yields
`unexpected results over the use of ablraterone acetate alone ................. ..55
`
`(c) Dr. Rettig presented no relevant evidence that the use of
`prednlsone av01ds clm1calres1stance to ablraterone and decreases
`sterord
`precursors................................................................................................ ..61
`
`B.
`
`C.
`
`D.
`
`E.
`
`Zytiga is not an unexpected commercial success ...................................... ..62
`
`There was no long—felt but unmet need ..................................................... ..63
`
`There was no skepticism or failure ofothers
`
`There is no nexus between the alleged secondary considerations and
`the scope of the claims of the ’438 patent................................................. ..67
`
`3
`
`MYLAN PHARMS. INC. EXHIBIT 1104 PAGE 3
`
`
`
`aminoglutethimide. As detailed herein, his opinions are unsupported by the state
`
`of the art and the information well within a skilled artisan’s knowledge.
`
`11.
`
`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.
`
`111.
`
`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/orknowledge 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
`
`MYLAN PHARMS. INC. EXHIBIT 1104 PAGE 6
`
`
`
`skilled artisans as of the priority date of the ’438 patent. First, skilled artisans
`
`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 cxpeCted 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
`
`MYLAN PHARMS. INC. EXHIBIT 1104 PAGE 5
`
`
`
`O’Donnell was not alone in his thinking that adrenal steroid synthesis inhibitors
`
`would require glucocorticoid replacement therapy; this was in the literature and
`
`well within the knowledge of skilled artisans such as myself.
`
`It was obvious that
`
`modulators of adrenal
`
`steroid synthesis would require
`
`the
`
`concomitant
`
`administration of glucocorticoids.
`
`12. Gerber 1990 discloses the use of a secondary hormone treatment with
`
`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.
`
`MYLAN PHARMS. INC. EXHIBIT 1104 PAGE 8
`
`
`
`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,
`
`MYLAN PHARMS. INC. EXHIBIT 1104 PAGE 7
`
`
`
`(a)
`
`Steroid synthesis inhibitors, used to treat advancedprostate
`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.
`
`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
`
`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
`
`MYLAN PHARMS. INC. EXHIBIT 1104 PAGE 10
`
`
`
`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.
`
`MYLAN PHARMS. INC. EXHIBIT 1104 PAGE 9
`
`
`
`ketoconazole and aminoglutethimide were to be administered with concomitant
`
`glucocorticoid supplementation to alleviate dangerous and undesirable side effects.
`
`Indeed, Patent Owner’s declarant, Dr. Judson, agreed with this when he stated that
`
`“[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.) 1] 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
`
`12
`
`MYLAN PHARMS. INC. EXHIBIT 1104 PAGE 12
`
`
`
`treating advance prostate cancer given it “inhibits the synthesis of adrenal
`
`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,
`
`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
`
`MYLAN PHARMS. INC. EXHIBIT 1104 PAGE 11
`
`
`
`Ponder, aminoglutethimide was administered along with cortisone acetate.
`
`In
`
`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.
`
`14
`
`MYLAN PHARMS. INC. EXHIBIT 1104 PAGE 14
`
`
`
`throughout the 19903 and early 20008, as detailed in many prior art references. See
`
`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,
`
`37 cc'
`1
`
`5
`
`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 19803. 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
`
`MYLAN PHARMS. INC. EXHIBIT 1104 PAGE 13
`
`
`
`with cancer treatments. For example, prednisone was used in combination with
`
`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 .
`
`(0)
`
`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.) 1197. 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
`
`MYLAN PHARMS. INC. EXHIBIT 1104 PAGE 16
`
`
`
`23.
`
`For example, Paulson provides the following diagram demonstrating
`
`that ketoconazole and aminoglutethimide both function to inhibit production of
`
`testosterone via the steroid synthesis pathway:
`
`LHRH
`
`murmur k
`
`LHRH
`Analogue -,
`
`Adm Wm
`
`mun nu.
`
`
`
`m7“
`
`Ex. 1105 (Paulson 1989) at 7(citing Gamick, M.B.: Urologic cancer. In Scientific
`
`American Medicine. Edited by E. Rubenstein and DD. 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
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`prednisone was a well-known and common choice among glucocorticoids used
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`15
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`
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`practice to administer supplementary hydrocortisone and this may prove necessary
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`with .
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`.
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`. abiraterone acetate”); Ex. 1023 (Attard 2005) at 2-3.
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`28.
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`Dr. Rettig’s criticism that “O’Donnell does not
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`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.) 11 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,
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`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.) 1111103-107.
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`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
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`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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`
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`cortisol. Ex. 1003 (O’Donnell) at 2; see also supra W 16-23. Whenever a drug
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`has such an effect on cortisol
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`levels, skilled artisans would seek to employ
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`replacement therapy.
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`27. Moreover, as detailed in my first declaration and herein, treating a
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`cancer patient with a drug that alters adrenal steroid production (as with
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`ketoconazole, abiraterone acetate, and aminoglutethimide) would cause a skilled
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`artisan to be very concerned about the many dramatic and dangerous side effects
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`that can, and are likely to, occur as a result of the inhibition of adrenal steroid
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`synthesis. See, e.g., Ex. 1025 (Harrison’s 2005) at 36, 37; Ex. 1098 (Arlt 2003) at
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`1, 4-5 (noting that adrenal
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`insufficiency clinical symptoms can be weakness,
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`fatigue, weight loss, nausea, vomiting, hypotension and hyperpigmentation); see
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`also Ex. 1098 (Arlt 2003) at 1 (stating that “[a]drenal insufficiency .
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`.
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`.
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`is life
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`threatening when overlooked”); Ex. 1025 (Harrison’s 2005) at 32, 33, 37, 39, 40
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`(noting that common symptoms of mineralocorticoid excess symptoms include
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`hypertension, hypokalemia, and hypematremia). A skilled artisan would thus be
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`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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`
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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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`((1) 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 ofa skilled artisan andfails 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.) 1111 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 (Gamick Decl.)1fi]
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`33, 43-46, 58-59, 78-80; supra 1111 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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`
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`111] 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 1111 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
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`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
`
`production,
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`irrespective of any variation in enzymes inhibited.
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`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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`19
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`
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`(Rettig Decl.) 1] 188.
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`Indeed, simply because this use of ketoconazole was not the
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`subject of FDA approval does not mean the art surrounding it, including Gerber,
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`fails to inform skilled artisans that ketoconazole was an accepted, safe, and
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`effective treatment for advanced stage prostate cancer.
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`35.
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`Instead, skilled artisans reading Gerber as of 2006 would take his data
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`in context with additional prior art finding ketoconazole beneficial in treating late-
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`stage cancer patients. As above, (supra 111] 16-23 ), numerous prior art references
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`demonstrate that ketoconazole was a useful agent for treating advanced stage
`
`prostate cancer. In particular, skilled artisans would look to radiographic response
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`data. Gerber notes that others prior to him had found that “5 of 36 patients had a
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`greater than 50% decrease in tumor mass or a regression of disease on bone scan
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`when treated with the
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`combination of ketoconazole
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`and physiological
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`glucocorticoid replacement therapy.” Ex. 1004 (Gerber 1990) at 3 citing Ex. 1107
`
`(Trump 1989).. The radiographic response date in Trump 1989 had,
`
`indeed,
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`already established the utility of ketoconazole with glucocorticoid replacement
`
`therapy in treating advanced stage prostate cancer. Thus, Dr. Rettig’s complaints
`
`about the use of prostate specific androgen (“PSA”) level data in Gerber do not
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`accurately reflect a skilled artisan’s reading of the data. As of 1990, when Gerber
`
`was published, other publications had already recognized that ketoconazole was a
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`usefiil agent in the treatment of prostate cancer. Supra 111] 16-23.
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`22
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`
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`inhibitor of CYP17 it was an obvious choice. Ex. 1002 (Garnick Decl.)1H[ 46, 55-
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`56, 58—59; supra 1111 26-31. As also detailed herein, in my original declaration, and
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`by Dr. Bantle (Ex. 1097 111] 44-55, 68-88), skilled artisans would have been
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`concerned about adrenal
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`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