Paper No. ___
`Date Filed: March 17, 2017
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_______________________
`
`WOCKHARDT BIO AG,
`Petitioner,
`
`
`
`v.
`
`JANSSEN ONCOLOGY, INC.
`Patent Owner.
`
`_______________________
`
`Case IPR2016-01582
`Patent 8,822,438 B2
`
`_______________________
`
`PATENT OWNER’S RESPONSE
`
`
`
`
`
`
`
`
`
`Date Filed: March 17, 2017
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_______________________
`
`WOCKHARDT BIO AG,
`Petitioner,
`
`
`
`v.
`
`JANSSEN ONCOLOGY, INC.
`Patent Owner.
`
`_______________________
`
`Case IPR2016-01582
`Patent 8,822,438 B2
`
`_______________________
`
`PATENT OWNER’S RESPONSE
`
`
`
`
`
`
`
`
`
`
`IPR2016-01582
`U.S. Patent 8,822,438
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`
`Table of Contents
`
`I.
`
`SUMMARY OF ARGUMENT..................................................................... 1
`
`II. CLAIM CONSTRUCTION .......................................................................... 4
`
`III. Wockhardt Mischaracterizes What the Prior Art Taught a Skilled
`Person in 2006 ................................................................................................ 5
`A. Gerber Did Not Establish that Ketoconazole with Prednisone Was a
`“Safe and Effective” Treatment of Prostate Cancer .......................... 5
`1. A Skilled Person in 2006 Would Not Find the Data in Gerber Had
`
`Established that Ketoconazole and Prednisone Effectively Treats
`
`Prostate Cancer ................................................................................. 6
`
`2. Clinical Studies Before 2006 Showed Ketoconazole with
`
`Prednisone Was Not a Safe and Effective Treatment of Prostate
`
`Cancer ............................................................................................... 9
`
`B. O’Donnell Does Not Establish that Abiraterone Acetate Has an
`Anti-Cancer Effect or Suggest Concomitant Glucocorticoid
`Replacement Therapy ..........................................................................10
`1. Salient Teachings of O’Donnell .....................................................11
`
`2. Abiraterone Acetate and Ketoconazole Were Known to Cause
`
`Different Effects on Steroid Biosynthesis Pathways .....................13
`
`3. Abiraterone Acetate Was Known to Not Cause the Same Side
`
`Effects as Ketoconazole .................................................................16
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`4. There Is No Evidence That Ketoconazole Causes
`
`Mineralocorticoid Excess ...............................................................17
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`5.
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`In 2006, There Was No Evidence that Abiraterone Acetate Would
`
`Cause Mineralocorticoid Excess ....................................................19
`
`6. O’Donnell Establishes No Need for Glucocorticoid Replacement
`
`with Abiraterone Acetate ...............................................................20
`
`7. O’Donnell Cautions Against Glucocorticoid Replacement Therapy
`
`Without a Clinical Justification ......................................................21
`
`8. O’Donnell’s ACTH Stimulation Test Results Did Not Establish a
`
`Need for Glucocorticoid Replacement Therapy with Abiraterone
`
`Acetate ............................................................................................23
`
`C. Sartor Does Not Show that Prednisone Was Known to Be Effective
`in Treating Prostate Cancer in 2006 ..................................................26
`1. Sartor Did Not Establish to a Skilled Person in 2006 that
`
`Prednisone “Treats Prostate Cancer” .............................................28
`
`2. By 2006, It Was Well Known that Glucocorticoids Elicit Only
`
`Transient PSA Responses that Do Not Effectively Treat Prostate
`
`Cancer .............................................................................................30
`
`3. Glucocorticoids Were Given to Manage Unique Side Effects of
`
`Ketoconazole or Cytotoxic Chemotherapy Agents........................32
`
`4. Experts Agree that Prednisone Was Not Known to Have Anti-
`
`Cancer Treatment Effects in Prostate Cancer Patients ..................33
`
`IV. WOCKHARDT’s Obviousness Case is based on hindsight ....................35
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`A. A Skilled Person Would Have Found No Reason to Treat Prostate
`Cancer Patients with Abiraterone Acetate and Prednisone in 2006
` ................................................................................................................35
`1. Docetaxel Chemotherapy Had Become the Standard of Care and
`
`Secondary Hormone Therapy Was Disfavored .............................36
`
`2.
`
`In 2006, Glucocorticoids Were Not Given to mCRPC Patients
`
`Absent a Compelling Clinical Justification ...................................38
`
`3.
`
`In 2006, a Skilled Person Would Have Treated Symptoms of
`
`Mineralocorticoid Excess with Other Drugs ..................................43
`
`B. A Skilled Person Would Have Had No Reasonable Expectation of
`Success in Achieving the ’438 Patent Invention ................................45
`1. The Prior Art Provided No Basis for a Skilled Person to Expect
`
`Prednisone Would Treat Prostate Cancer ......................................45
`
`2. The Unpredictability of Drug Combination Therapy in Prostate
`
`Cancer Further Precludes Obviousness..........................................49
`
`V. OBJECTIVE INDICIA OF NONOBVIOUSNESS CONFIRM THE
`PATENTABILITY OF THE CLAIMS .....................................................50
`A. The Claimed Methods Show Unexpected Results ............................50
`1. Clinical Studies Demonstrate Unexpected Anti-Cancer Effects of
`
`Glucocorticoid/ Abiraterone Acetate Combination Treatment ......51
`
`2. Wockhardt’s Criticisms of the Invention’s Unexpected Results Are
`
`Unwarranted ...................................................................................56
`
`B. Skepticism and the Failure of Others ................................................61
`C. The Claimed Invention Met a Long-Felt Need .................................63
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`D. Commercial Success Reinforces the Non-Obviousness of the
`Claimed Invention ................................................................................64
`1. Zytiga®-Based Therapy Enjoys Commercial Success ..................64
`
`2. A Nexus Exists Between the Claimed Invention and Its
`
`Commercial Success ......................................................................66
`
`E. Wockhardt’s Blocking Patent Argument is Flawed .........................68
`
`VI. CONCLUSION ............................................................................................70
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`I.
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`SUMMARY OF ARGUMENT
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`Before the invention of U.S. Patent No. 8,822,438 (“the ’438 patent”),
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`prostate cancer patients with an advanced stage of the disease known as metastatic
`
`castration-resistant prostate cancer (“mCRPC”) faced a dismal prognosis, with few
`
`meaningful treatment options. The claimed invention – a two-time FDA priority
`
`approved method of treating prostate cancer that combines abiraterone acetate and
`
`prednisone – changed that picture dramatically; prostate cancer patients treated
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`with a combination of abiraterone acetate and prednisone enjoy a striking increase
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`in survival.
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`That result was unexpected for several reasons. In 2006, drugs that targeted
`
`androgen synthesis had not been shown to be effective in treating prostate cancer.
`
`Ketoconazole had not shown clinically meaningful efficacy and had never been
`
`approved by the FDA to treat prostate cancer. Abiraterone acetate had shown
`
`some ability to lower testosterone levels, but its efficacy in treating mCRPC was
`
`unknown, and prior attempts to develop it as a monotherapy were terminated after
`
`significant investments and disappointing clinical results. Prednisone, likewise,
`
`had never been shown to be effective in treating prostate cancer and was known to
`
`cause serious side effects of particular concern for patients with mCRPC. And
`
`even if the skilled person had contemplated use of abiraterone acetate, she would
`
`have had no basis for expecting prednisone would enhance its anti-cancer effects.
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`Nonetheless, Petitioner Wockhardt Bio AG (“Wockhardt”) asserts the
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`claimed invention would have been obvious in 2006 to a skilled person based on
`
`its distorted portrayal of three references: Gerber (Ex. 1004), O’Donnell (Ex. 1005)
`
`and Sartor (Ex. 1006). Wockhardt largely embraces the rationale of the two earlier
`
`petitions, asserting a skilled person, from Gerber and O’Donnell, would have
`
`found it obvious to co-administer prednisone with abiraterone acetate based on
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`prior experiences with ketoconazole and the side effects it supposedly causes.
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`Wockhardt, however, tries to bolster those earlier challenges, asserting Sartor (Ex.
`
`1006) showed, by 2006, that prednisone was understood to have treat prostate
`
`cancer, and that experiences with cytotoxic chemotherapy had become part of the
`
`standard of care of prostate cancer patients, a skilled person would have been
`
`motivated to co-administer it with abiraterone acetate.
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`But the evidence refutes every aspect of Wockhardt’s challenge. Gerber did
`
`not establish that ketoconazole (alone or with prednisone) was an effective prostate
`
`cancer treatment, and in 2006 a skilled person would not have equated that agent
`
`with abiraterone acetate. O’Donnell actually refutes Wockhardt’s assertion that
`
`abiraterone acetate would cause side effects necessitating treatment with
`
`prednisone – it reports clinical data showing those side effects were not observed.
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`And numerous experts, including Wockhardt’s, contradicted its proposition that
`
`Sartor had established by 2006 that prednisone was known to be effective in
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`treating prostate cancer. Instead, a skilled person, in 2006, would have known to
`
`not administer prednisone to a prostate cancer patient without a demonstrated
`
`clinical need, due to its serious adverse effects in those patients, and would not
`
`have relied on experiences with cytotoxic chemotherapy agents, which cause
`
`severe side effects not observed with abiraterone acetate.
`
`Wockhardt also presents a grossly distorted picture of the field of prostate
`
`cancer research in 2006. It provides no explanation for why a skilled person would
`
`have focused on Gerber and O’Donnell, papers describing two very different
`
`androgen inhibitors having no track record of clinical success, while ignoring what
`
`it elsewhere describes as the “standard of care” for prostate cancer patients –
`
`cytotoxic chemotherapeutic agents like docetaxel. And, Wockhardt entirely fails
`
`to show why a skilled person would have reasonably expected the particular
`
`combination of abiraterone acetate and prednisone would work to treat prostate
`
`cancer. Wockhardt’s obviousness theory is a textbook case of hindsight.
`
`Finally, Wockhardt has no credible response to evidence showing that co-
`
`administration of prednisone with abiraterone acetate unexpectedly enhanced its
`
`anti-cancer effects and extended the lives of mCPRC patients, meeting a long-felt
`
`need for these patients. Wockhardt’s response to the striking commercial success
`
`of ZYTIGA® combination therapy is to criticize its scale of success and assert the
`
`claims have no nexus to it, ignoring that ZYTIGA®’s label expressly requires co-
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`administration of abiraterone acetate with prednisone and that numerous experts
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`attribute that commercial success directly to the combination of prednisone with
`
`abiraterone acetate. (Ex. 2020 (Serels) 71:6-12).
`
`Petitioners, thus, have entirely failed to meet their burden, and the Board
`
`should affirm the patentability of the contested claims.
`
`II. CLAIM CONSTRUCTION
`
`Each of the claims of the ’438 Patent is directed to a “method for the
`
`treatment of a prostate cancer” and each claim expressly requires administration of
`
`“a therapeutically effective amount of abiraterone acetate” and “a therapeutically
`
`effective amount of prednisone.” (Ex. 1001 at 16:15-20).
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`As it did in IPR2016-00286, the Board construed the terms “treat,”
`
`“treating” and “treatment” to “include the eradication, removal, modification,
`
`management or control of a tumor or primary, regional, or metastatic cancer cells
`
`or tissue and the minimization or delay of the spread of cancer.” See Wockhardt
`
`ID 6. Each claim thus requires each agent to at least have an effect that reduces the
`
`growth or spread of cancer itself.
`
`Neither party has disputed the Board’s interpretation of this claim term, and
`
`Wockhardt has employed it in its Petition. (See Pet. at 22) (asserting prednisone
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`must treat the cancer under the Board’s construction). Consequently, the Board’s
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`construction of “treat,” “treating” and “treatment” should be maintained.1
`
`III. WOCKHARDT MISCHARACTERIZES WHAT THE PRIOR ART
`TAUGHT A SKILLED PERSON IN 2006
`
`Wockhardt relies on three references to support its case for obviousness –
`
`Gerber (Ex. 1004), O’Donnell (Ex. 1005) and Sartor (Ex. 1006). But Wockhardt’s
`
`portrayal of what those references would have taught the skilled person in 2006 is
`
`materially flawed. What this record instead demonstrates is that the claimed
`
`methods, in 2006, would not have been obvious to a skilled person based on
`
`Gerber, O’Donnell and Sartor.
`
`A. Gerber Did Not Establish that Ketoconazole with Prednisone Was
`a “Safe and Effective” Treatment of Prostate Cancer
`
`In instituting these proceedings, the Panel relied on Wockhardt’s assertion
`
`that Gerber teaches that ketoconazole in combination with prednisone provides a
`
`“safe and effective” treatment of prostate cancer. ID at 10. (See also Pet. 25).
`
`Contrary to Wockhardt’s assertion, ketoconazole with prednisone was not
`
`
`1
`The prior art would not have suggested co-administering prednisone even if
`
`the claims did not require it to have an anti-cancer effect in view of, inter alia, the
`
`absence of side effects of abiraterone acetate and its adverse effects in prostate
`
`cancer patients. See § IV.A.2-3.
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`considered to be a “safe and effective” method for treating prostate cancer in 2006
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`(or even today).
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`1.
`
`A Skilled Person in 2006 Would Not Find the Data in
`Gerber Had Established that Ketoconazole and Prednisone
`Effectively Treats Prostate Cancer
`
`Gerber describes a retrospective chart review of serum prostate specific
`
`antigen (“PSA”) levels for 15 patients with hormone refractory (i.e., castration
`
`resistant) metastatic prostate cancer who received ketoconazole and prednisone.
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`(Ex. 1004 at 1179; Ex. 2038 (Rettig) ¶80).
`
`A retrospective chart review is not a controlled clinical trial designed to
`
`establish the safety or efficacy of a drug or treatment. Instead, it is an analysis of
`
`pre-existing patient records to discern trends or patterns within selected groups of
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`patients. (Ex. 2038 ¶177). Because these reviews commonly employ criteria that
`
`excludes relevant contrary evidence, their conclusions are often given little weight.
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`As Wockhardt’s expert, Dr. Godley agreed, these types of reviews fall on the
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`“lower” end of the hierarchy of meaningful clinical evidence. (Ex. 2161 (Godley)
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`87:7-88:19).
`
`Consequently, experts in this and the related Amerigen and Mylan IPR
`
`proceedings agreed that a skilled person would not have considered the data in
`
`Gerber to have established, by 2006, that ketoconazole with prednisone was a “safe
`
`and effective” treatment of prostate cancer. (Ex. 2038 ¶84, 173, 175; see also 178-
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`188); Ex. 2020 (Serels) 176:24-177:7; (PSA data in Gerber “[n]ot [enough to
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`make] a definite conclusion” that patients experienced a clinical response), 157:15-
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`158:4, 158:17-159:10).
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`One reason for this is that Gerber portrays any decline in PSA, regardless of
`
`degree or duration, as being a “[p]atient response” to treatment. (Ex. 1004 at 1178;
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`Ex. 2038 ¶87, 182, 184; Ex. 2161 (Godley) 33:12-19). But by 2006, those types of
`
`PSA declines were not considered clinically significant patient responses. Instead,
`
`based on a 1999 report of the PSA Working Group, skilled persons understood that
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`PSA reductions greater than 50% that were sustained for at least four weeks were
`
`required. (Ex. 2057 (Bubley) at 3464 (“investigators should report, at minimum, a
`
`PSA of at least 50%, which must be confirmed by a second PSA value 4 or more
`
`weeks later”); see also Ex. 2038 ¶185, 64-67; Ex. 2057 (Bubley) at Abstract,
`
`3461-62, 3464; Ex. 2047 (Stamey) at Abstract, 544). Measured against those
`
`accepted standards, the results reported in Gerber fall far short – only two out of
`
`the fifteen patient records met those criteria. (Ex. 1004 at 1178; Ex. 2038 ¶86).
`
`Gerber itself discounts these PSA responses. It observes that while PSA
`
`declines occurred in 80% of patients administered a combination of ketoconazole
`
`and prednisone, those PSA declines were short-lived in 75% of those patients.
`
`From that, it concludes the responses were “unlikely [to have] significant impact
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`on survival” and “probably do not reflect significant disease regression.”2 (Ex.
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`1004 at 1178; Ex. 2038 ¶187).
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`This skepticism was shared by others at the time Gerber was published. For
`
`example, one author reported in a contemporaneous publication that “[i]t is likely
`
`that the effects of ketoconazole and prednisone in decreasing PSA levels have little
`
`or nothing to do with clinical improvement.” (Ex. 2049 (Blackard) at
`
`1621(emphasis added); Ex. 2038 ¶189-91; see also 82).
`
`Wockhardt nonetheless asserts that a skilled person would have read Gerber
`
`as establishing that “some patients with progressive prostate cancer despite
`
`previous hormone therapy, will derive significant benefit from the combination of
`
`ketoconazole and glucocorticoid replacement therapy.” (Pet. at 14 (citing Ex. 1004
`
`at 1179)). But that is not a conclusion a skilled person would have reached in
`
`2006. By then, the skilled person would have recognized that any suggestion in
`
`Gerber that patients had a meaningful clinical benefit rested on a scientifically
`
`discredited premise – that any PSA decrease of any duration was a response. (Ex.
`
`
`2
`Gerber reports two patients had longer term 50% PSA declines, but does not
`
`provide any radiographic evidence or survival data to confirm these patients
`
`experienced a clinical benefit. (Ex. 2038 ¶187; see also Ex. 2046 (Therasse); ¶62-
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`68 (describing accepted endpoints for evaluating response).
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`2038 ¶189-91; Ex. 2049 (Blackard) at 1621; Ex. 2053 (Lara) at 140, Ex. 2054
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`(Kuzel) at 1965; Ex. 2055 (Scher) at 2928; Ex. 2056 (Sternberg) at 331).
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`A skilled person thus would not have interpreted Gerber as establishing that
`
`ketoconazole with prednisone was effective in treating prostate cancer in 2006, as
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`Wockhardt contends. (Ex. 2038 ¶193-94).
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`2.
`
`Clinical Studies Before 2006 Showed Ketoconazole with
`Prednisone Was Not a Safe and Effective Treatment of
`Prostate Cancer
`
`Wockhardt ignores extensive clinical evidence existing by 2006 that showed
`
`that ketoconazole and prednisone was not a safe and effective treatment of prostate
`
`cancer. (Ex. 2038 ¶192-194; Ex. 2020 (Serels) at 176:4-8; Ex. 2124 (Ratain) at
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`50:13-51:1). That evidence included clinical trials that showed:
`
`(i)
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`ketoconazole plus replacement glucocorticoid provided only modest
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`activity and no difference in survival from patients receiving only
`
`antiandrogen withdrawal, and showed “unacceptable toxicity” from
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`ketoconazole (Ex. 2063 (Small) at 1026, 1030-31);
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`(ii) use of ketoconazole plus glucocorticoid replacement vs. ketoconazole
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`plus doxorubin did not justify phase 3 evaluation and was fraught with
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`morbidity (Ex. 2064 (Millikan) at Abstract, 113-115); and
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`(iii) “no study has yet demonstrated a survival benefit with the use of
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`[secondary hormonal therapies such as ketoconazole], which can be
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`expensive as well as toxic.” (Ex. 1015 (Oh) at 91).
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`A skilled person would have found this clinical data to establish, before
`
`August of 2006, that ketoconazole with prednisone was not a safe and effective
`
`treatment for prostate cancer. (Ex. 2038 ¶193, 175-76; Ex. 2020 (Serels) 61:15-
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`18).
`
`Wockhardt’s expert, Dr. Godley, agreed that ketoconazole has never been
`
`shown to provide a survival benefit and has never been approved for the treatment
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`of prostate cancer. (Ex. 1002 (Godley) 48:17-22, 135:22-136:19; Ex. 2038 ¶192).
`
`He also acknowledged that ketoconazole causes intolerable side effects, the most
`
`serious being liver damage. (Id. at 46:18-47:6; Ex. 2038 ¶93).
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`Thus, by 2006, a skilled person would not have considered ketoconazole
`
`with prednisone to be a safe and effective treatment of prostate cancer, but would
`
`have believed the opposite.
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`B. O’Donnell Does Not Establish that Abiraterone Acetate Has an
`Anti-Cancer Effect or Suggest Concomitant Glucocorticoid
`Replacement Therapy
`
`Wockhardt, as Amerigen and Mylan did, asserts that O’Donnell would have
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`led a skilled person to modify the ketoconazole plus prednisone regimen described
`
`in Gerber by co-administering abiraterone acetate instead of ketoconazole, but
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`maintaining co-administration of prednisone. (Pet. 24, 30-31). That, it contends,
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`was because a skilled person in 2006 would have believed that “inhibiting CYP17
`
`can lead to adrenal suppression and mineralocorticoid excess due to increased
`
`ACTH” (Pet. at 32) and that “like ketoconazole, administering abiraterone acetate
`
`would require co-administering a glucocorticoid, such as prednisone, to prevent
`
`mineralocorticoid excess.” (Pet. at 11-12).
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`But, by 2006, ketoconazole was known to not cause “mineralocorticoid
`
`excess,” and the O’Donnell paper reports that abiraterone acetate does not cause
`
`clinical symptoms of adrenal suppression requiring glucocorticoid replacement.
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`(Ex. 2151 (Amerigen PO Response) at 17-28; Ex. 2154 (Mylan PO Response) at
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`18-27). Thus, the undisputed facts contradict Wockhardt’s supposed impetus for a
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`skilled person to co-administer prednisone with abiraterone acetate.
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`1.
`
`Salient Teachings of O’Donnell
`
`O’Donnell was published in 2004, and describes three Phase I safety studies
`
`of abiraterone acetate monotherapy in patients with stable disease. (Ex. 1005 at
`
`2318; Ex. 2038 ¶90, 91; Ex. 2040 (Auchus) ¶¶19-20). As it states, “[t]his is the
`
`first report of the effects of a specific 17α-hydroxylase/C17,20-lyase inhibitor in
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`humans.” (Ex. 1005 at 2318 (emphasis added); Ex. 2038 ¶101).
`
`The O’Donnell studies were not designed to assess the clinical effectiveness
`
`of abiraterone acetate in treating prostate cancer, but the safety of abiraterone
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`acetate and to determine its dosing that would result in maximum testosterone
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`suppression in castrate and non-castrate men with prostate cancer. (Ex. 1005 at
`
`2318; Ex. 2038 ¶92; Ex. 2016 (Garnick) at 150:11-14). Importantly, prostate
`
`cancer treatment was not an endpoint, and O’Donnell did not measure PSA or
`
`assess survival benefits. (Ex. 2038 ¶92; Ex. 2016 (Garnick) at 145:3-9; 150:11-14;
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`Ex. 2124 (Ratain) at 72:9-21; Ex. 2020 (Serels) at 178:11-18). O’Donnell also
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`reports that patients in the studies were not allowed to take concomitant steroids.
`
`(Ex. 1005 at 2319; Ex. 2038 ¶91).
`
`O’Donnell reports that “abiraterone acetate was very well tolerated and no
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`serious adverse events attributable to treatment were recorded.” (Ex. 1005 at 2322;
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`Ex. 2038 ¶113; Ex. 2040 (Auchus) ¶¶21, 26; Ex. 2161 (Godley) 104:15-105:2). It
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`also reports no hematologic or biochemical effects and no alteration in resting
`
`heart rate or blood pressure. (Ex. 1005 at 2322; Ex. 2038 ¶113, 124-25; Ex. 2040
`
`(Auchus) ¶21; Ex. 2161 (Godley) 105:20-22). O’Donnell also found abiraterone
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`acetate to have “no effect on 17α-OH-progesterone production [the precursor to
`
`cortisol]” and “no significant effect on cortisol levels in these patients” (Ex. 1005
`
`at 2322-23; Ex. 2038 ¶114-119; Ex. 2040 (Auchus) ¶¶22-25; Ex. 2161 (Godley)
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`107:2-25). O’Donnell concludes by proposing that the next study of abiraterone
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`acetate take place in castrate patients (i.e., concomitant GnRH dosing), notably
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`omitting any suggestion to co-administer glucocorticoids for any purpose. (Ex.
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`1005 at 2324; Ex. 2038 ¶¶130; see also 124-127, 129).
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`2.
`
`Abiraterone Acetate and Ketoconazole Were Known to
`Cause Different Effects on Steroid Biosynthesis Pathways
`
`A skilled person would have known that because ketoconazole and
`
`abiraterone acetate have materially different effects on the steroid biosynthesis
`
`pathways, they would exhibit different clinical profiles and side effects. (Ex. 2038
`
`¶100-106, 111).
`
`In 2006, ketoconazole was known to be a non-selective steroid synthesis
`
`inhibitor with far-reaching and profoundly inhibitory effects on the synthesis of all
`
`steroids. As O’Donnell points out, “[k]etoconazole is relatively unselective,
`
`inhibiting both cholesterol side chain cleavage and 11β-hydroxylase.” (Ex. 1005
`
`at 2318 (emphasis added); Ex. 2038 ¶102; see also Ex. 1040 (Sonino) at 812
`
`(“[c]holesterol-side-chain blockade by ketoconazole has been demonstrated ...
`
`cholesterol side chain cleavage has a higher sensitivity to ketoconazole than C17,20-
`
`lyase”)). Figure 2 below summarizes the effects ketoconazole has on these
`
`pathways.
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`13
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`A skilled person would have understood that “cholesterol side chain
`
`cleavage” refers to the first step in steroid synthesis, whose inhibition would
`
`suppress production of all other steroids, including not only testosterone, but also
`
`mineralocorticoids and glucocorticoids. (Ex. 2038 ¶¶109-110; Ex. 2040 (Auchus)
`
`¶¶36-38; Ex. 2065 at 1065). That person also would have appreciated that because
`
`ketoconazole inhibits the action of 11-β-hydroxylase, it also directly inhibits
`
`production of corticosterone and cortisol. (Ex 1005 (O’Donnell) at 2318; Fig. 2
`
`(above); Ex. 2038 ¶102-104); Ex. 2040 (Auchus) ¶37; Ex. 1040 (Sonino) at 815
`
`(“ketoconazole is a potent inhibitor of cortisol production, through 11β-
`
`hydroxylase and cholesterol side chain cleavage”). Consequently, the skilled
`
`person would have believed “replacement doses of [glucocorticoids such as]
`
`hydrocortisone may be required” with ketoconazole. (Ex. 1011 (Harris) at 544; see
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`14
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`also Ex. 2038 at ¶¶105; Ex. 1004 (Gerber) at 1177 (“[ketoconazole] is a potent
`
`inhibitor of gonadal and adrenocortical steroid synthesis”)).
`
`By contrast, by 2006, abiraterone acetate was known to be a selective
`
`CYP17 inhibitor, meaning it targets only CYP17. (Ex. 1005 (O’Donnell) at 2317
`
`(abiraterone acetate is “a specific 17α-hydroxylase/C17,20-lyase inhibitor in
`
`humans”) (emphasis added)). Abiraterone acetate does not inhibit cholesterol side
`
`chain cleavage or 11β-hydroxylase, which means it does not inhibit the production
`
`of corticosterone and does not have the same inhibitory effect on cortisol
`
`production as ketoconazole. (Ex. 2038 ¶106-108; Fig. 1 (below)); Ex. 1030
`
`(Barrie) at 25:45-49; Ex. 2040 (Auchus) ¶¶36, 39-45; Ex. 1002 (Godley) ¶39; Pet.
`
`30).
`
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`15
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`3.
`
`Abiraterone Acetate Was Known to Not Cause the Same
`Side Effects as Ketoconazole
`
`Wockhardt admits that, by 2006, material differences between ketoconazole
`
`and abiraterone acetate were well known, observing that, “ketoconazole was an
`
`unselective CYP17 inhibitor, weakly and non-selectively inhibiting several P450
`
`enzymes,” while “abiraterone acetate was known to be a potent and more specific
`
`CYP17 inhibitor than ketoconazole.” (Pet. at 11).
`
`Importantly, however, Wockhardt overlooks the clinical significance of
`
`these distinctions, including, in particular, that “studies with abiraterone acetate
`
`suggested that it did not inhibit corticosterone production” while ketoconazole
`
`does. (Pet. at 29-30). That distinction is important because it was known before
`
`2006 that corticosterone can offset the clinical consequences of reductions in
`
`cortisol production. (Ex. 2038 ¶¶31; see also 25, 38, 133; Ex. 2040 (Auchus) ¶¶43,
`
`46-47; Ex. 1033 (Ganong) at 282 (describing the “glucocorticoids cortisol and
`
`corticosterone”)).
`
`Understanding this, a skilled person before 2006 would not have expected
`
`abiraterone acetate to cause the same types of side effects in humans as the non-
`
`selective inhibitor, ketoconazole. For example, because abiraterone acetate does
`
`not inhibit the pathway resulting in production of corticosterone, and has only a
`
`modest inhibitory effect on one enzyme in the pathway resulting in cortisol, a
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`16
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`skilled person would not have expected abiraterone acetate to cause clinically
`
`meaningful reductions in glucocorticoid production, and thus would not cause the
`
`same impact on adrenal functions as ketoconazole. (Ex. 2038 ¶133). Thus, it
`
`would not have been surprising to a skilled person that a modest decrease in
`
`cortisol synthesis in patients given abiraterone acetate, if it occurred, would not
`
`translate into clinical symptoms. (Id.).
`
`That, in fact, is exactly what O’Donnell reports, explaining that “no
`
`significant effect on cortisol levels” were observed in patients treated with
`
`abiraterone acetate (Ex. 1005 at 2222-23), that abiraterone acetate was “well
`
`tolerated,” and no hypertension was seen in patients given it. (Id. at 2322).
`
`Consequently, in 2006, a skilled person would not have equated the clinical
`
`experiences of ketoconazole, particularly its side effects, with those of abiraterone
`
`acetate, and would have found no justification to co-administer prednisone with
`
`abiraterone acetate on the basis of those experiences with ketoconazole. (Ex.
`
`2038 ¶132, 133).
`
`4.
`
`There Is No Evidence That Ketoconazole Causes
`Mineralocorticoid Excess
`
`A skilled person in 2006 would not have believed that ketoconazole causes
`
`mineralocorticoid excess. Instead, by 2006, it was well known that ketoconazole
`
`inhibits the production of all steroids and leads to a reduction in the amounts of
`
`17
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`mineralocorticoids that are produced. (Ex. 2038 ¶104; Ex. 2040 (Auchus) ¶¶37-
`
`38; Ex. 2016 (Garnick) at 33:15-34:11, 36:7-16; Ex. 2019 (Serels) ¶10). As
`
`Sonino succinctly explains:
`
`Since ketoconazole interferes with C17,20 lyase and is a more potent
`
`inhibitor of cholesterol side-chain cleavage activity, it can be expected
`
`that patients treated with the agent will be free of side effects such as
`
`mineralocorticoid excess.”
`
`(Ex. 1040 at 815) (emphasis added).
`
`Other prior art confirms that ketoconazole reduces mineralocorticoid
`
`production in patients. (Ex. 2040 (Auchus) ¶59; Ex. 2067 (Palmer) at 585). In
`
`fact, ketoconazole was used to manage symptoms of mineralocorticoid excess.
`
`(Ex. 2040 (Auchus) ¶38; Ex. 2066 (Mantero) at Abstract, 82; Ex. 1009
`
`(Harrison’s) at 2138). And, notably, Wockhardt admits in its petition that
`
`“ketoconazole was known to have off target effects such as reducing the
`
`production of the mineralocorticoid corticosterone, due to its inhibiting
`
`cytochrome P450 proteins other than CYP17.” (Pet. at 30) (emphasis added).
`
`Thus, undisputed evidence refutes another premise of Wockhardt’s supposed
`
`motivation for the skilled person to co-administer glucocorticoids with “CYP17
`
`inhibitors” such as abiraterone acetate – its incorrect belief that ketoconazole
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`18
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`requires co-administration of glucocorticoids because it causes mineralocorticoid
`
`excess.3
`
`5.
`
`In 2006, There Was No Evidence that Abiraterone Acetate
`Would Cause Mineralocorticoid Excess
`
`Wockhardt also mischaracterizes what O’Donnell would have conveyed to
`
`the skilled person in 2006 concerning mineralocorticoid excess. (Pet. at 16; see
`
`also Pet. at 33).
`
`O’Donnell nowhere mentions mineralocorticoid excess or its associated
`
`symptoms, such as hypertension, hypokalemia, or fluid retention, occurring in
`
`patients give
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