Case No. IPR2016-01332
`Patent No. 8,822,438
`Filed: April 19, 2017
`
`
`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,
`Petitioners
`
`v.
`
`JANSSEN ONCOLOGY, INC.,
`
`Patent Owner
`
`Case IPR2016-013321
`Patent 8,822,438 B2
`
`
`
`
`
`PETITIONERS’ REPLY TO JANSSEN’S PATENT OWNER RESPONSE
`
`
`
`
`1 Case IPR2017-00853 has been joined with this proceeding.
`
`

`

`TABLE OF CONTENTS
`
`Case No. IPR2016-01332
`Patent No. 8,822,438
`
`
`Page
`
`2.
`
`3.
`
`INTRODUCTION .......................................................................................... 1
`I.
`II. ARGUMENT .................................................................................................. 3
`A.
`Skilled Artisans Would Have Been Motivated To Administer
`Abiraterone Acetate With Prednisone To A Prostate Cancer
`Patient, With A Reasonable Expectation Of Success. ......................... 4
`1.
`Steroid synthesis inhibitors were accepted treatments for
`advanced prostate cancer, and they required concomitant
`glucocorticoid therapy. .............................................................. 4
`Abiraterone acetate was a known next-generation steroid
`synthesis inhibitor. ..................................................................... 5
`Prednisone was a preferred choice in administration of
`glucocorticoid replacement therapy. .......................................... 8
`B. Abiraterone Acetate’s Selective Mechanism of Action Would
`Have Further Motivated Skilled Artisans to Administer It With
`Prednisone ............................................................................................ 8
`1.
`A skilled artisan would have administered glucocorticoid
`replacement therapy with abiraterone acetate to prevent
`adrenal insufficiency and low adrenal reserve. .......................... 9
`A skilled artisan would have administered glucocorticoid
`replacement therapy with abiraterone acetate to prevent
`mineralocorticoid excess. ......................................................... 14
`The Claims Do Not Require Prednisone To Have an Anti-
`Cancer Effect ...................................................................................... 17
`D. Nothing About Prednisone’s Side Effects Would Have
`Dissuaded Skilled Artisans From Administering It To
`Advanced Prostate Cancer Patients With Abiraterone Acetate ......... 19
`1.
`Prednisone’s side effects were minimal and greatly
`outweighed by the dangerous side effects it resolved. ............ 19
`The prior art did not teach that prednisone fueled prostate
`cancer. ...................................................................................... 20
`
`C.
`
`2.
`
`2.
`
`
`
`i
`
`

`

`TABLE OF CONTENTS
`continued
`
`Case No. IPR2016-01332
`Patent No. 8,822,438
`
`
`Page
`
`F.
`
`E.
`
`Janssen’s Suggestion That Ketoconazole Was Not Safe And
`Effective Is Meritless.......................................................................... 20
`No Secondary Considerations Overcome Obviousness ..................... 22
`1.
`There are no unexpected results. .............................................. 22
`2.
`There was no industry skepticism or failure of others. ............ 24
`3.
`The alleged invention did not satisfy a long-felt but
`unmet need. .............................................................................. 25
`Janssen has not established commercial success. .................... 25
`4.
`III. CONCLUSION ............................................................................................. 27
`
`
`
`ii
`
`

`

`Case No. IPR2016-01332
`Patent No. 8,822,438
`
`
`TABLE OF AUTHORITIES
`
`
`CASES
`Ethicon Endo-Surgery, Inc. v. Covidien LP,
`812 F.3d 1023 (Fed. Cir. 2016) .......................................................................... 26
`
`Page
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ............................................................................ 26
`
`Hoffman-La Roche Inc. v. Apotex Inc.,
`748 F.3d 1326 (Fed. Cir. 2014) ............................................................................ 4
`
`In re Copaxone Consol. Cases,
`No. 14-1171-GMS, 2017 WL 401943 (D. Del. Jan. 30, 2017) .......................... 25
`
`In re Grasselli,
`713 F.2d 731 (Fed. Cir. 1983) ............................................................................ 24
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) .............................................................................................. 3
`
`Novartis AG v. Torrent Pharm. Ltd.,
`No. 2016-1352, 2017 WL 1337268 (Fed. Cir. Apr. 12, 2017) ........................... 26
`
`Novo Nordisk A/S v. Caraco Pharm. Labs., Ltd.,
`719 F.3d 1346 (Fed. Cir. 2013) ............................................................................ 7
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) ............................................................................ 4
`
`PharmaStem Therapeutics, Inc. v. ViaCell, Inc.,
`491 F.3d 1342 (Fed. Cir. 2007) .......................................................................... 12
`
`Symbol Techs., Inc. v. Opticon, Inc.,
`935 F.2d 1569 (Fed. Cir. 1991) .......................................................................... 25
`
`
`
`
`
`iii
`
`

`

`Abbreviation
`’438 Patent
`ACTH
`AR
`CRPC
`mCRPC
`CYP17
`DHT
`IDS
`LH
`NDA
`POSA
`PSA
`RCE
`TTPP
`Resp. Br.
`Rettig Decl.
`
`Auchus Decl.
`
`Rettig Dep.
`
`Auchus Dep.
`
`Vellturo Dep.
`
`Vellturo Decl.
`
`Case No. IPR2016-01332
`Patent No. 8,822,438
`
`
`TABLE OF ABBREVIATIONS
`
`Definition
`U.S. Patent No. 8,822,438
`Adrenocorticotropic hormone
`Androgen receptor
`Castration-resistant prostate cancer
`Metastatic castration-resistant prostate cancer
`17α-hydroxylase/C17,20-lyase
`Dihydrotestosterone
`Information Disclosure Statement
`Luteinizing hormone
`New Drug Application
`Person of Ordinary Skill in the Art
`Prostate-specific antigen
`Request for Continued Examination
`Time to PSA progression
`Janssen’s Patent Owner’s Response (Paper No. 35)
`Declaration of Matthew B. Rettig, M.D. in Support of Janssen
`Oncology, Inc.’s Patent Owner Response
`Declaration of Richard Auchus, M.D., Ph.D. in Support of
`Janssen Oncology, Inc.’s Patent Owner Response
`Transcript of the March 31, 2017 Deposition of Matthew B.
`Rettig, M.D.
`Transcript of the April 10, 2017 Deposition of Richard
`Auchus, M.D., Ph.D.
`Transcript of the April 5, 2017 Deposition of Christopher A.
`Vellturo, Ph.D.
`Declaration of Christopher A. Vellturo, Ph.D. in Support of
`Patent Owner Response
`
`iv
`
`

`

`Case No. IPR2016-01332
`Patent No. 8,822,438
`
`
`Declaration of Ian Judson, MD in Support of Janssen
`Oncology, Inc.’s Patent Owner Response
`Transcript of the April 7, 2017 Deposition of Ian Judson, M.D.
`
`Judson Decl.
`
`Judson Dep.
`
`v
`
`

`

`
`
`I.
`
`INTRODUCTION
`
`In 2006, all wisdom pointed to giving abiraterone acetate with prednisone.
`
`Clinical experience—prior drugs in the same class as abiraterone acetate required
`
`administration with a glucocorticoid. Abiraterone acetate’s mechanism of
`
`action—abiraterone acetate’s known inhibition of particular steroid synthesis
`
`pathways risked several conditions resolved by glucocorticoids. Data—abnormal
`
`test results in patients given abiraterone acetate confirmed these risks. Express
`
`teachings—the prior art expressly suggested that skilled artisans give abiraterone
`
`acetate with glucocorticoids. Longstanding practice—doctors had for years
`
`prescribed prednisone to advanced prostate cancer patients for its palliative effects.
`
`No matter which teaching the skilled artisan followed, they all led to the same
`
`solution: administer abiraterone acetate with prednisone to treat prostate cancer.
`
`All claims of the ’438 patent are therefore obvious.
`
`Janssen concedes that abiraterone acetate was known as an effective anti-
`
`prostate cancer agent. Janssen also does not contest that prednisone was widely
`
`used in prostate cancer patients as glucocorticoid replacement therapy and for its
`
`palliative effects. The only question left is whether a skilled artisan would have
`
`used prednisone in combination with abiraterone acetate. The answer is clearly
`
`yes.
`
`1
`
`

`

`
`
`All prior drugs in abiraterone acetate’s class were administered with
`
`glucocorticoid replacement therapy. Skilled artisans in 2006 knew that abiraterone
`
`acetate was a next-generation steroid synthesis inhibitor. Prior steroid synthesis
`
`inhibitors used to treat prostate cancer—ketoconazole and aminoglutethimide—
`
`worked by inhibiting testosterone production, but were less potent than abiraterone
`
`acetate. Abiraterone acetate, by virtue of being in the same drug class, worked the
`
`same way. However, skilled artisans knew that, because their inhibition of
`
`testosterone production also undesirably suppressed natural glucocorticoid
`
`production, ketoconazole
`
`and
`
`aminoglutethimide
`
`required
`
`concomitant
`
`glucocorticoid replacement therapy. Prior art testing of abiraterone acetate
`
`revealed that it too may have these undesirable side effects. The same studies
`
`expressly suggested concomitant glucocorticoid therapy as the solution. Skilled
`
`artisans would therefore have been motivated to prescribe a glucocorticoid like
`
`prednisone in combination with abiraterone acetate, just like they did with
`
`ketoconazole and aminoglutethimide.
`
`Janssen asserts that abiraterone acetate cannot be compared to prior steroid
`
`synthesis inhibitors because its mechanism of action is more selective. But
`
`abiraterone acetate’s more selective mechanism of action was understood to inhibit
`
`glucocorticoid synthesis like prior steroid synthesis inhibitors, and thus require
`
`glucocorticoid replacement therapy. Moreover, abiraterone acetate’s selectivity
`
`2
`
`

`

`
`
`would have only further motivated skilled artisans to administer it with
`
`glucocorticoids. The prior art warned that abiraterone acetate’s impact on the
`
`steroid synthesis pathways risked adrenal insufficiency, low adrenal reserve, and
`
`mineralocorticoid excess, all of which could be fatal. Glucocorticoids, such as
`
`prednisone, were the only therapy that could address all three problems. A skilled
`
`artisan thus would have acted conservatively and administered prednisone with
`
`abiraterone acetate. And even if prednisone were not required to prevent fatal side
`
`effects, for years it had been prescribed to prostate cancer patients to relieve cancer
`
`symptoms. The ’438 patent’s claims, which issued solely based on the examiner’s
`
`suspect finding of commercial success, are therefore obvious.
`
`Throughout its responsive brief Janssen attempts to misconstrue the Board’s
`
`claim construction to require that prednisone have a separate anti-tumor effect.
`
`The Board already rejected that interpretation in claim construction, and again
`
`upon Janssen’s motion for rehearing in the Amerigen IPR. If Janssen wanted to
`
`narrow the claims, it should have moved to amend. It did not. Therefore, the
`
`Board’s construction applies, and all claims are obvious.
`
`II. ARGUMENT
`“One of the ways in which a patent’s subject matter can be proved obvious
`
`is by noting that there existed at the time of invention a known problem for which
`
`there was an obvious solution encompassed by the patent’s claims.” KSR Int’l Co.
`
`3
`
`

`

`
`
`v. Teleflex Inc., 550 U.S. 398, 419-20 (2007). In pharmaceutical cases,
`
`“[c]onclusive proof of efficacy is not necessary to show obviousness. All that is
`
`required is a reasonable expectation of success.” Hoffman-La Roche Inc. v. Apotex
`
`Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014) (citations omitted); see also Pfizer, Inc.
`
`v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007) (citations omitted) (“[O]nly a
`
`reasonable expectation of success, not a guarantee, is needed.”).
`
`A.
`
`SKILLED ARTISANS WOULD HAVE BEEN MOTIVATED TO
`ADMINISTER ABIRATERONE ACETATE WITH PREDNISONE TO A
`PROSTATE CANCER PATIENT, WITH A REASONABLE EXPECTATION
`OF SUCCESS.
`
`No expert in this case has disputed that it would have been obvious in 2006
`
`to treat advanced prostate cancer with abiraterone acetate. The only question that
`
`Janssen’s experts appear to dispute is whether skilled artisans would have found it
`
`obvious to simultaneously administer prednisone with abiraterone acetate when
`
`treating advanced prostate cancer. The prior art and expert testimony answer that
`
`question with a resounding yes.
`
`1.
`
`Steroid synthesis inhibitors were accepted treatments for
`advanced prostate cancer, and they required concomitant
`glucocorticoid therapy.
`
`From
`
`the
`
`late 1970s
`
`through
`
`the priority date, ketoconazole and
`
`aminoglutethimide were commonly administered to treat advanced prostate cancer.
`
`Ex. 1104 ¶¶16-18. Both of these agents were considered steroid synthesis
`
`inhibitors—they worked by inhibiting steroid synthesis pathways, causing
`
`4
`
`

`

`
`
`production of testosterone (which fuels prostate cancer growth) to drop. Id. In the
`
`process, however, ketoconazole and aminoglutethimide also inhibit production of
`
`numerous other steroids used to regulate the human body, such as cortisol. Id.; Ex.
`
`1097 ¶¶30-31.
`
`When cortisol and other compounds involved in steroid synthesis are
`
`inhibited, conditions known as mineralocorticoid excess and adrenal insufficiency
`
`can result, leading to clinical symptoms including hypertension, hypokalemia, fluid
`
`retention, fatigue, nausea and vomiting, weight loss, and hypotension. Ex. 1097
`
`¶¶32-33, 37-39, 41; Ex. 1104 ¶¶16-23. Skilled artisans knew that steroid synthesis
`
`inhibitors would likely cause some of these side effects, but they also knew to treat
`
`these side effects with glucocorticoids. Ex. 1097 ¶¶40, 42; Ex. 1104 ¶¶16-23. At
`
`the priority date, and indeed for decades prior, skilled artisans treated advanced
`
`prostate cancer patients by administering steroid synthesis
`
`inhibitors
`
`in
`
`combination with glucocorticoids. Ex. 1104 ¶¶16-23.
`
`2.
`
`Abiraterone acetate was a known next-generation steroid
`synthesis inhibitor.
`
`By 2006, abiraterone acetate emerged as a next-generation steroid synthesis
`
`inhibitor, effective in treating prostate cancer. Ex. 1002 ¶46; Ex. 1104 ¶¶14-31;
`
`Ex. 1003 at 2. In particular, abiraterone acetate was designed to be a selective and
`
`potent inhibitor of CYP17, an enzyme involved in certain reactions in the steroid
`
`synthesis pathway. Ex. 1097 ¶¶25-29; Ex. 1003 at 2 (“In clinical trials both
`
`5
`
`

`

`
`
`[ketoconazole and aminoglutethimide] have shown some activity . . . supporting
`
`the concept of a more selective inhibitor of the [CYP17] enzyme.”). It is likely for
`
`these reasons that Janssen’s experts do not assert that using abiraterone acetate was
`
`non-obvious.2
`
`Because abiraterone acetate is in the same class of treatment agents as
`
`ketoconazole and aminoglutethimide, a skilled artisan would have been concerned
`
`that abiraterone acetate would induce similar side effects as other steroid synthesis
`
`inhibitors. Ex. 1104 ¶¶14-31; Ex. 1097 ¶¶44-49. Indeed, describing abiraterone
`
`acetate as inspired by ketoconazole and aminoglutethimide, O’Donnell noted that
`
`“[s]ome impact on adrenal reserve was predictable from the steroid synthesis
`
`pathway [mechanism of action].” Ex. 1003 at 7; Ex. 1104 ¶¶40-48; Ex. 1097 ¶¶48-
`
`49. Because these side effects can be fatal, a skilled artisan would therefore have
`
`2 Near the end of their response brief, Janssen alleges that Mylan’s obviousness
`
`arguments rely on “hindsight bias” because other prostate cancer drugs were being
`
`developed in 2006. Resp. Br. at 41-43. But Janssen never disputes that
`
`abiraterone acetate was known to be effective for treating prostate cancer, in part
`
`based on past success with ketoconazole and aminoglutethimide. And none of
`
`Janssen’s experts opine that administration of abiraterone acetate to treat advanced
`
`prostate cancer would have been nonobvious. See id. at 41-43 (citing paragraphs
`
`56-61 of Dr. Rettig’s declaration, which are background paragraphs).
`
`6
`
`

`

`
`
`approached administration of abiraterone acetate conservatively. Ex. 1104 ¶¶25-
`
`31, 40-58; Ex. 1097 ¶¶33, 41, 82.
`
`To explain, a skilled artisan would have understood that when an agent
`
`inhibits any portion of the steroid synthesis pathways, it would likely cause
`
`downstream inhibition. Because the adrenal pathways delicately balance crucial
`
`bodily functions like stress response, metabolism, and blood pressure, skilled
`
`artisans would have expected that any disruption to those pathways would lead to
`
`problems requiring treatment. Ex. 1097 ¶¶21-33, 37-39, 41; Ex. 1104 ¶¶16-31, 40-
`
`58. Glucocorticoids were widely prescribed to correct imbalances in the adrenal
`
`pathways, including those induced by steroid synthesis inhibitors. Ex. 1097 ¶¶40,
`
`42, 55, 62-66; Ex. 1104 ¶¶20-22, 40-70. Thus, in light of steroid synthesis
`
`inhibitors’ known effects on the adrenal pathways, a skilled artisan would have
`
`been motivated to administer glucocorticoids with abiraterone acetate to counteract
`
`expected endocrine disruptions, and would have held a reasonable expectation of
`
`success. Ex. 1097 ¶¶21-66; Ex. 1104 ¶¶20-22, 40-79; see Novo Nordisk A/S v.
`
`Caraco Pharm. Labs., Ltd., 719 F.3d 1346, 1351-52 (Fed. Cir. 2013) (finding
`
`obviousness where one drug was substituted for another with a similar mechanism
`
`of action).
`
`7
`
`

`

`
`
`3.
`
`Prednisone was a preferred choice in administration of
`glucocorticoid replacement therapy.
`
`Skilled artisans would have been motivated to use prednisone, in particular,
`
`as concomitant glucocorticoid therapy. Ex. 1104 ¶¶24, 80-87. Janssen does not
`
`contest the choice of prednisone as an obvious glucocorticoid to use. That is likely
`
`because prednisone was a well-known choice for glucocorticoid therapy, and thus
`
`obvious. Prednisone had been used for years for its known palliative effects for
`
`advanced cancer patients, giving artisans confidence it was a safe and effective
`
`choice. Id. Prednisone was also a common choice among skilled artisans for use
`
`with other cancer treatments, such as mitoxantrone. Id. ¶24. Finally, Gerber
`
`specifically discloses the use of prednisone with ketoconazole. Ex. 1004; Ex. 1104
`
`¶24. Prednisone would therefore have been the preferred, obvious glucocorticoid
`
`to administer.
`
`B. ABIRATERONE ACETATE’S SELECTIVE MECHANISM OF ACTION
`WOULD HAVE FURTHER MOTIVATED SKILLED ARTISANS TO
`ADMINISTER IT WITH PREDNISONE
`
`Skilled artisans’ knowledge that abiraterone acetate was a next-generation
`
`steroid synthesis inhibitor—a drug class requiring glucocorticoid therapy—would
`
`have directed the skilled artisan to administer it with glucocorticoids. Janssen
`
`attempts to distance abiraterone acetate from other steroid synthesis inhibitors by
`
`noting abiraterone acetate’s selective mechanism of action. Resp. Br. at 13-17.
`
`But abiraterone acetate’s mechanism of action only underscores the obviousness of
`
`8
`
`

`

`
`
`combining it with prednisone. As detailed below, abiraterone acetate was known
`
`to be a potent, selective inhibitor of the CYP17 enzyme, and the art taught skilled
`
`artisans that glucocorticoid replacement would be necessary to counter side effects
`
`of abiraterone acetate’s CYP17 inhibition.
`
`1.
`
`A skilled artisan would have administered glucocorticoid
`replacement therapy with abiraterone acetate to prevent
`adrenal insufficiency and low adrenal reserve.
`
`The CYP17 enzyme is a critical link in the adrenal pathways that produce
`
`testosterone and cortisol. Ex. 1097 ¶¶23. As of 2006, abiraterone acetate was
`
`known as a substantially more potent inhibitor of the CYP17 enzyme than other
`
`steroid synthesis inhibitors like ketoconazole. Ex. 1005 at 3:26-30, 23:23, 24:61-
`
`62 (data that abiraterone acetate is about ten times more potent than ketoconazole);
`
`Ex. 1085 at 4, Table 1; Ex. 1003 at 2; Ex. 1023 at 4; Ex. 1104 ¶26; Ex. 1097 ¶¶25-
`
`29, 86, 90-92. While abiraterone acetate’s inhibition of CYP17 results in
`
`decreased testosterone production—which is responsible for its therapeutic effects
`
`in prostate cancer patients—a skilled artisan would also have expected it to reduce
`
`cortisol production.3 Ex. 1097 ¶¶25-29, 44-45, 50-51; Ex. 1104 ¶¶25-31; Ex. 1135
`
`3 As Dr. Bantle explains and Dr. Auchus recognized, Janssen’s diagrams at page 14
`
`of the Patent Owner Response purportedly depicting abiraterone acetate’s and
`
`ketoconazole’s effects on the adrenal steroid synthesis pathways are inaccurate and
`
`misleading. Ex. 1097 ¶¶24-31; Ex. 1143 at 39:39-41:20.
`
`9
`
`

`

`
`
`at 34:21-37:18, 49:12-50:4 (Dr. Rettig admitting he used the wrong data to
`
`advance his counterarguments).
`
`Skilled artisans would have been concerned about this reduction in cortisol
`
`and expected such a reduction to require glucocorticoid replacement therapy.
`
`Cortisol is the primary natural glucocorticoid produced in humans. Ex. 1097 ¶¶22.
`
`Insufficient cortisol levels cause a condition known as adrenal insufficiency, which
`
`is characterized by weakness, fatigue, weight loss, nausea, vomiting, hypotension,
`
`and hyperpigmentation. Id. ¶¶32-33. Adrenal insufficiency, which is the same
`
`condition
`
`induced by ketoconazole and aminoglutethimide
`
`that
`
`requires
`
`administration of glucocorticoids, can be fatal if left untreated. Id.
`
`While skilled artisans would have had concerns about adrenal insufficiency
`
`with abiraterone acetate in light of the art describing other agents such as
`
`ketoconazole and aminoglutethimide, the prior art also contained independent data
`
`finding that abiraterone acetate may induce adrenal insufficiency. Id. ¶¶48, 50-55;
`
`Ex. 1104 ¶¶40-48. In a dose-finding study, O’Donnell administered patients
`
`abiraterone acetate for twelve days. Ex. 1097 ¶50. On day 1 and 11, patients were
`
`given a Synacthen
`
`test, considered
`
`the standard diagnostic for adrenal
`
`insufficiency, based on the investigators’ concern that abiraterone acetate—like
`
`ketoconazole and aminoglutethimide—may cause adrenal insufficiency. Ex. 1097
`
`¶¶34-35, 48, 50; Ex. 1104 ¶¶40-48; Ex. 1143 at 62:15-20. Even though all patients
`
`10
`
`

`

`
`
`tested normal at day 1, O’Donnell reports that every single patient developed
`
`abnormal Synacthen test results by day 11. Ex. 1003 at 5; Ex. 1097 ¶¶48, 50.
`
`Particularly given prior experience with ketoconazole and aminoglutethimide,
`
`these results strongly suggested to skilled artisans that abiraterone acetate risked
`
`inducing adrenal insufficiency. Ex. 1104 ¶¶40-48; Ex. 1097 ¶¶47-53.
`
`Janssen asserts that O’Donnell would have taught away from the use of
`
`prednisone with abiraterone acetate because O’Donnell found no significant effect
`
`on cortisol levels or clinical symptoms after 11 days. Resp. Br. at 16-17, 20-26;
`
`Ex. 1143 at 68:23-69:11. But a skilled artisan would have understood that normal
`
`cortisol levels and few clinical symptoms were likely after only 11 days of
`
`treatment, and that the Synacthen test was ideal for identifying early adrenal
`
`insufficiency. Ex. 1097 ¶¶67-84; Ex. 1104 ¶¶45-46. A skilled artisan would have
`
`also understood that patients with cortisol levels on the low end of the normal
`
`spectrum can still have adrenal insufficiency. Ex. 1097 ¶¶70-71.
`
`Moreover, a skilled artisan would also have been concerned that abiraterone
`
`acetate would cause low adrenal reserve. Low adrenal reserve, which is closely
`
`related to adrenal insufficiency, is an inability to significantly increase cortisol
`
`production as needed in response to physiologic stress. Id. ¶38. The prior art
`
`taught that patients showing normal cortisol levels and few clinical symptoms,
`
`coupled with abnormal Synacthen results, likely at least suffered from low adrenal
`
`11
`
`

`

`
`
`reserve. Id. ¶¶38, 52-54, 71. Like adrenal insufficiency, low adrenal reserve can
`
`be fatal. Id. ¶39.
`
`O’Donnell expressed these exact same concerns. Discussing the abnormal
`
`Synacthen results, O’Donnell recognized that “[s]ome impact on adrenal reserve
`
`was predictable from the steroid synthesis pathway.” Ex. 1003 at 7; Ex. 1104 ¶45;
`
`Ex. 1097 ¶¶48-49.
`
` O’Donnell continued: “In the clinical use of both
`
`aminoglutethimide and ketoconazole, it is common practice to administer
`
`supplementary hydrocortisone4 and this may prove necessary with [CYP17]
`
`inhibitors such as abiraterone acetate.” Ex. 1003 at 7 (footnote added); Ex. 1097
`
`¶55. O’Donnell also expressly directed further investigation of administration of
`
`glucocorticoids with abiraterone acetate: “In the light of this clinical evidence,
`
`further studies with abiraterone acetate will be required to ascertain if concomitant
`
`therapy with glucocorticoid is required on a continuous basis, at times of
`
`physiological stress, if patients become symptomatic or indeed at all.” Ex. 1003 at
`
`7; Ex. 1097 ¶55. Indeed, Dr. Judson, the lead investigator in the O’Donnell trial,
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`reaffirmed this conclusion in his declaration submitted in these proceedings. Ex.
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`2028 at ¶6. At most, all that O’Donnell left was the use of routine methods to
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`conduct the investigation it suggested. But that is not invention. PharmaStem
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`Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1363-64 (Fed. Cir. 2007)
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`4 A glucocorticoid, like prednisone.
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`12
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`

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`
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`(“Scientific confirmation of what was already believed to be true may be a
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`valuable contribution, but it does not give rise to a patentable invention . . . . Good
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`science and useful contributions do not necessarily result in patentability.”).
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`Also, in reviewing O’Donnell, Attard 2005 noted the abnormal Synacthen
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`test results and explained that, going forward, “[p]atients will be closely monitored
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`for the development of glucocorticoid insufficiency.” Ex. 1023 at 5; Ex. 1104
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`¶¶39-58; Ex. 1097 ¶48. Therefore, rather than dismiss the abnormal Synacthen
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`results as Janssen proposes, a skilled artisan—like O’Donnell and Attard—would
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`have been motivated to administer glucocorticoid therapy with abiraterone acetate
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`to prevent potentially deadly adrenal insufficiency and low adrenal reserve.5 Ex.
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`1104 ¶¶39-58; Ex. 1097 ¶¶43-55; Ex. 1135 at 69:17-70:3, 75:9-77:20.
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`5 Contrary to Janssen’s assertions, nothing in the ’213 patent would have altered a
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`skilled artisan’s motivation to administer abiraterone acetate with prednisone, or
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`their reasonable expectation of success. The ’213 patent teaches that abiraterone
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`acetate powerfully inhibits the CYP17 enzyme. Ex. 1005 at 3:26-30, 23:23, 24:61-
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`62; Ex. 1097 ¶¶85-86. Skilled artisans would therefore have understood that
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`cortisol production would be depleted, and would have anticipated the need to
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`replace it with glucocorticoid therapy. Ex. 1097 ¶¶87-88. Moreover, Janssen’s
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`argument that corticosterone production could compensate for reduced cortisol is a
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`red herring. Corticosterone is only a minor glucocorticoid in humans, so a skilled
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`13
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`
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`Janssen asserts that a skilled artisan would not have interpreted O’Donnell
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`like Attard 2005, and points to later studies allegedly approved and performed
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`without glucocorticoid replacement. Resp. Br. 26. But those studies involved
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`concomitant therapy designed to avoid side effects like mineralocorticoid excess.
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`Ex. 1104 ¶¶91. They also underscored that abiraterone acetate risks significant
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`side effects—in one trial, a patient died of hypokalemia (a predictable effect of
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`mineralocorticoid excess). Id. ¶¶56-58. Janssen immediately put all additional
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`patients on prednisone glucocorticoid replacement therapy, 5 mg dosed twice
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`daily. Id.
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`2.
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`A skilled artisan would have administered glucocorticoid
`replacement therapy with abiraterone acetate to prevent
`mineralocorticoid excess.
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`A skilled artisan in 2006 would also have been concerned that abiraterone
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`acetate could induce mineralocorticoid excess. Ex. 1097 ¶¶56-62; Ex. 1104 ¶¶71-
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`79. Because abiraterone acetate is a selective steroid synthesis inhibitor, it blocks
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`only two of the three major steroid synthesis pathways (the pathways that produce
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`testosterone and cortisol, but not the pathway that produces mineralocorticoids).
`
`
`artisan would not expect that it could fully replace lost cortisol. Id. ¶¶87-88. And
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`if it could, as corticosterone is produced along the mineralocorticoid pathway, the
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`skilled artisan would have been concerned about mineralocorticoid excess, as
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`detailed in the following section. Id. ¶88.
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`14
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`

`

`
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`Ex. 1097 ¶¶22-29, 56; Ex. 1104 ¶¶72-73. With two of the three pathways
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`inhibited, a skilled artisan would have worried that nearly all steroid synthesis
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`would be channeled down the third (mineralocorticoid) pathway. Ex. 1097 ¶57;
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`Ex. 1104 ¶¶72-73. This worry would have been particularly salient because the
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`prior art taught that the body stimulates steroid synthesis when cortisol levels are
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`low. Ex. 1097 ¶57; Ex. 1104 ¶¶72-73. As abiraterone acetate inhibits cortisol
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`synthesis, a skilled artisan would have expected this additional stimulation to fuel
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`even more mineralocorticoid production. Ex. 1097 ¶57; Ex. 1104 ¶¶72-73.
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`Because mineralocorticoid excess can be fatal, a skilled artisan would have
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`approached such a side effect with extreme caution. Ex. 1097 ¶61; Ex. 1104 ¶¶72-
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`79.
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`O’Donnell’s test results were consistent with mineralocorticoid excess. Ex.
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`1097 ¶¶59-60. Synacthen tests measure the body’s ability to stimulate additional
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`cortisol production. Id. ¶¶34, 59. A skilled artisan would have known that if
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`Synacthen results were abnormal, the patient’s steroid production was already at
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`maximum stimulation. Id. ¶59. With abiraterone acetate inhibiting two of the
`
`three steroid synthesis pathways, a skilled artisan would have expected that the
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`O’Donnell patients’ overstimulated steroid synthesis pathways could result in
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`excess mineralocorticoid production. Id. ¶¶56-58. Similarly, Attard 2005
`
`suggested that “[p]atients will be closely monitored for the development
`
`15
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`

`

`
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`of . . . hypertension,” a standard symptom of mineralocorticoid excess, and a
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`common side effect in patients with CYP17 deficiencies. Ex. 1023 at 5.
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`Predicting this, Attard 2005 provided the following graphic teaching the “excess
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`synthesis” of mineralocorticoids.
`
`
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`Id. at 3. Skilled artisans would thus have anticipated the possibility of
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`mineralocorticoid excess based on abiraterone acetate’s method of inhibition,
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`motivating skilled artisans to administer, and providing a reasonable expectation of
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`success with, glucocorticoid replacement therapy.6 Ex. 1097 ¶¶56-66; Ex. 1135 at
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`79:16-81:12.
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`6 Based on analogies to genetic deficiencies, Dr. Auchus claims that abiraterone
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`acetate would not cause endocrine dysfunction. Ex. 2040 ¶¶49-66. As Dr. Bantle
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`16
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`

`

`
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`Janssen asserts that there was no evidence in 2006 that ketoconazole could
`
`cause mineralocorticoid excess. Resp. Br. at 18-19. But multiple references noted
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`that mineralocorticoid accumulation could occur with ketoconazole, and it was a
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`known phenomenon in clinical practice. Ex. 1104 ¶¶76-79. Regardless, to the
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`extent skilled artisans would have considered abiraterone acetate’s more selective
`
`mechanism of action at all, they would have understood that it risked
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`mineralocorticoid excess.
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` Ex. 1097 ¶¶56-62; Ex. 1104 ¶¶72-79.
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` As
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`glucocorticoids were known to remedy mineralocorticoid excess, skilled artisans
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`would therefore have been motivated to administer prednisone with abiraterone
`
`acetate to prevent mineralocorticoid excess. Ex. 1097 ¶62; Ex. 1104 ¶¶72-79.
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`C. THE CLAIMS DO NOT REQUIRE PREDNISONE TO HAVE AN ANTI-
`CANCER EFFECT
`