`
`BIEFORE "l.‘Hl£ PA"I"I*IT\l'l‘ 'l'R'lAI, ANT) APPI."-Al, BOARD
`
`Ametigen Pltarrnaceuticals Limited and Argentum Pltarmaeeuticals LLC
`
`Petitioners
`
`v.
`
`Janssen Oncology, Inc.
`
`Patent Owner
`
`U.S. Patent No. 8,322,438 to Auerbach et :1!
`Issue Date: September 2, 2014
`Title: I\/Icthnds and Compositions for Treating Cancer
`
`4
`
`Inter Panes Review No. 2016-00286‘
`
`DECLARATION OF DR. SCOTT R. SERELS, MD.
`
`I declare that all slatetttents made lterein on my own lmowletlge are true and that
`all statements made on it1l’or1n.ation and bclicfare believed 10 be true, and
`
`further, that these statements were made. with the knowledge that willful false
`statements and the like so made are punishable by line or imprisonment, or
`both, under Section 1001 ofT1'tlc I8 of the United States Code.
`'
`‘K
`.-
`,
`,
`I
`/ .
`/‘
`./
`
`é//’
`
`///6//7
`
`Scott R. Serels, M.D.
`
`Date I
`
`‘ Case IPR2(ll6—0l3 I 7 has been joined with thix proceeding.
`
`JANSSEN EXHIBIT 2122
`
`Mylan v. Janssen IPR2016-01332
`
`JANSSEN EXHIBIT 2122
`Mylan v. Janssen IPR2016-01332
`
`
`
`Table of Contents
`
`I. Introduction ................................................................................................................................ .. 3
`
`II. Mechanism of Action of Ketoconazole and Abiraterone Acetate .......................... ..4
`
`III. Overstaternent of Gerber According to Dr. Chodak .................................................. ..7
`
`IV. Secondary Considerations Do Not Indicate that the Claims of the ‘438 Patent
`Are Non—Obvious ......................................................................................................................... .. 12
`
`Page 2
`
`
`
`
`
`I, Scott R. Serels, M.D., do hereby declare:
`
`I. Introduction
`
`1.
`
`My qualifications are generally described in Section A, paragraphs 4-
`
`7, of my declaration submitted on December 5, 2015, (AMG 1002).
`
`2.
`
`I
`
`am making this declaration at
`
`the
`
`request of Amerigen
`
`Pharmaceuticals, Ltd., in the matter of the Inter Partes Review (IPR) of U.S. Patent
`
`No. 8,822,438 (the “’438 Patent”), as set forth in the above caption.
`
`3.
`
`I am being compensated for my work in this matter at the rate of
`
`$500.00 per hour. My compensation in no way depends on the outcome of this
`
`proceeding. The opinions I set forth herein are my own, and are based on the
`
`education, experience, training and skill that I have accumulated in the course of my
`
`career as a practicing urologist and researcher, as well as the materials I have
`
`reviewed in connection with this case.
`
`4.
`
`For this declaration, I was asked to review and discuss the declarations
`
`of Patent Owner’s experts, Dr. Chodak (JSN 2042), Dr. Auchus (JSN 2040) and Dr.
`
`Vellturo (JSN 2044).
`
`I have reviewed their declarations and the transcripts of their
`
`depositions in this matter.
`
`I have also reviewed the declarations of Dr. Dorin (AMG
`
`1093) and Dr. Ratain (AMG 1091).
`
`5.
`
`Initially, I note that the Petition states that a person of ordinary skill in
`
`w,w,.»,yw,r.-m,,,.p,,.r,,,,.....*..,
`
`
`
`the art (“POSA”) would be a physician specializing in urology or oncology, or
`
`holding a Ph.D.
`
`in pharmacology, biochemistry or a related discipline with
`
`additional experience substituting for the advanced degree.
`
`I understand that the
`
`Patent Owner has disagreed with this definition because “it includes ‘a Ph.D. in
`
`pharmacology, biochemistry or a related discipline’ and a physician ‘specializing in
`
`urology or oncology’ who does not treat or study prostate cancer.” My opinion
`
`would not change whether we use the Patent Owner’s definition of a POSA or the
`
`definition according to the Petition.
`
`6.
`
`I have reviewed the declaration of Dr. Auchus (JSN 2040) and
`
`understand that he asserts that a POSA, a urologist or oncologist with experience
`
`treating patients with prostate cancer, would work in a team or setting that includes
`
`access to one or more or individuals who have expertise in endocrinology,
`
`biochemistry, pharmacology, and/or molecular biology or a related field of science.
`
`I agree that a POSA would not be an endocrinologist but would have access to an
`
`endocrinologist, to the extent needed.
`
`11. Mechanism of Action of Ketoconazole and Abiraterone Acetate
`7.
`I have read the declaration of Dr. Auchus and understand that he
`
`disagrees with part of a conclusion in my declaration (AMG 1002,
`
`ll 34) that
`
`ketoconazole “was known to reduce cortisol
`
`levels and potentially result
`
`in
`
`mineralocorticoid excess.” (JSN 2040 (Auchus Declaration) ll 36.) While he agrees
`
`*1: 133 (170
`
`(D 4;
`
`
`
`with my explanation that ketoconazole was known to reduce cortisol
`
`levels, he
`
`disagrees that ketoconazole potentially results in mineralocorticoid excess. As I
`
`explained in my declaration at paragraph 33, ketoconazole is a non—specific inhibitor
`
`of 17-0 hydroxylase, an enzyme critical to steroid synthesis.
`
`In my declaration I
`
`contrasted the non-specificity of ketoconazole with that of abiraterone acetate, which
`
`is a selective CYPI 7 inhibitor (paragraphs 26, 45). Although both compounds were
`
`known to reduce cortisol levels and therefore would have been expected to share
`
`common adverse effects because of those reduced levels, e.g., increased ACTH
`
`drive, the lack of specificity of ketoconazole will result in additional effects that are
`
`not seen with abiraterone acetate. Nonetheless, the common inhibitory effect on
`
`cortisol production and resulting increase in ACTH as a consequence of
`
`administering either abiraterone acetate or ketoconazole would have plainly and
`
`sufficiently suggested to a POSA the use of a glucocorticoid, such as prednisone,
`
`with both compounds as glucocorticoid replacement therapy.
`
`8.
`
`At the time I prepared my declaration,
`
`I did not fully consider the
`
`various mechanisms by which ketoconazole was known to inhibit adrenal steroid
`
`synthesis beyond that of inhibiting CYP 17 enzyme activity.
`
`In forming my
`
`opinions, I relied primarily on the disclosures in the prior art regarding the inhibition
`
`by ketoconazoleof CYP l7 enzymatic activity, including the specific disclosures in
`
`O’Donnell (AMG 1003 at 2318) and Barrie (AMG 1005 at col. 24, lines 61-62),
`
`Page 5
`
`
`
`
`
`because inhibition of CYP 17 enzymatic activity is the mechanism by which both
`
`ketoconazole and abiraterone acetate inhibit adrenal production of testosterone.
`
`(JSN 2037 (Serels Tr) page 59, lines 2-24). This was a reasonable approach to take
`and, in fact, one of the inventors of the ‘438 Patent, Dr. de Bono, characterized both
`
`ketoconazole and abiraterone acetate as treating prostate cancer by inhibiting adrenal
`
`androgen synthesis: “through the inhibition of key enzymes in the adrenal steroid
`
`biosynthesis pathways with agents such as ketoconazole or the CYP17 inhibitor
`
`abiraterone acetate.” (Vidal, AMG 1147, pp 7-8).
`
`9.
`
`I have read the rebuttal opinion of Dr. Dorin, Petitioners’ expert in the
`
`field of endocrinology.
`
`1 have considered Dr. Dorin’s explanation of the predicted
`
`impact of long-term administration ofabiraterone acetate at dosages to treat patients’
`
`mCRPC. (AMG 1093 (Dorin) e.g., W 15, 16, 22-26.) As a result, I understand that
`
`the potential adverse effects of the predicted cortisol deficiency and increased ACTH
`
`drive in such patients would have been understood by an expert in the field of
`
`endocrinology to include both adrenal insufficiency (as is the case with the long-
`
`term administration of ketoconazole to treat patients with mCRPC) and secondary
`
`mineralocorticoid excess. (AMG 1093 (Dorin) e.g., W 20-27, 31-35, 69, 70.)
`
`10.
`
`I have reviewed the steroid synthesis pathways as discussed in my
`
`deposition and now more fully appreciate the differences and that mineralocorticoid
`
`excess would not occur with ketoconazole.
`
`Nevertheless,
`
`this additional
`
`Page 6
`
`
`
`understanding does not change my opinion that cortisol deficiency would have been
`
`expected to have significant negative clinical impact in mCRPgC patients treated with
`
`abiraterone based on the disclosures in O’Donnell (AMG 1003) and Barrie (AMG
`
`1005).
`
`It also does not change my opinion that a POSA would have been motivated
`
`to co-administer a glucocorticoid, and in particular prednisone, as a first choice to
`
`suppress predicted ACTH drive in patients administered abiraterone acetate to treat
`
`mCRPC.
`
`III. Overstatement of Gerber According to Dr. Chodak
`
`1 l.
`
`I have read the declaration of Dr. Chodak (JSN 2042) and understand
`
`that he now states that the conclusion of Gerber (AMG 1004), an article on which
`
`he is a co-author, is overstated. According to Dr. Chodak, the conclusion, “there
`
`appears to be a small subgroup of patients who will derive significant benefit from
`
`the combination of ketoconazole and glucocorticoid replacement
`
`therapy,”
`
`overstates the results.
`
`I question the relevance of this “overstatement” to a POSA
`
`reading the article because a POSA would be sufficiently capable of reviewing the
`
`article critically and not just rely on the conclusions. Further, based on my review
`
`of Gerber (AMG 1004), a later publication by Dr. Chodak as a letter to the editor of
`
`the journal in which Gerber was published (JSN 2049), and his explanation of the
`
`“overstatement” made during his deposition (AMG 1148), the conclusion a POSA
`
`would take from Gerber is not changed.
`
`Page 7
`
`
`
`
`
`12. With respect to Dr. Chodak’s assertion that Gerber “overstated the
`
`observed outcomes,” a POSA reading Gerber would exercise his/her judgment,
`
`including determining whether or not any conclusions were supported by the results.
`
`As a POSA, I believe that a fair reading of Gerber would lead a POSA to reach the
`
`same conclusion that Dr. Chodak made when he submitted Gerber for publication.
`
`13.
`
`In the medical community we give a lot of credence to what is published
`
`in a peer reviewed journal. If an author decides that an article contains inaccuracies
`
`that author should withdraw the article and publish a revised account of the data. To
`
`my knowledge, this has not been done with Gerber and the medical community
`
`would have relied on Gerber for what it disclosed. Dr. Chodak’s attempt now to
`
`reorient his article for purposes of this legal proceeding does not affect how the
`
`medical community in 2006 would have viewed his article.
`
`14.
`
`However, in 1992 in response to a letter to the editor by Dr. Clyde
`
`Blackard in the same journal of Gerber, Dr. Chodak reaffirmed the conclusion of his
`
`original article by arguing that “the observations by others as well as our own
`
`findings suggest that more investigation with ketoconazole or its analog appears to
`
`be warranted, since the drug does appear to have some clinical benefit in these
`
`patients in addition to its effect on serum PSA.” (JSN 2049)
`
`15.
`
`Beyond his surprising attempt to reinterpret his conclusion in Gerber, I
`
`note that when I read Dr. Chodak’s deposition 1 was surprised to see that he was
`
`Page 8
`
`
`
`commenting on my declaration without even having read the declaration.
`
`2 3
`2 4
`
`Q. Ol<a_\'. Sorrfv. Ol<a_v.
`Did jvou re\'ie\\' the clepossition
`
`Page 18
`
`1
`
`2
`3
`
`4
`
`5
`6
`7
`
`8
`9
`1 O
`
`1 1
`1 2
`1 3
`
`14
`1 5
`1 6
`
`A.
`
`3110.
`
`l;)id you review the cleclaratioii
`Q. No?’
`of1")r. Serels‘?
`
`A. No.
`
`Q. Did you review -— do fizou lmow who
`Scott Serels is ii;1tl1is case‘?
`A. Na‘),
`
`is it --
`l\«IS. Z\—'I(fi)N.‘3EZ\5' Pm sorry (j)l*>je-ction
`to form.
`
`Is it fair to sax’ that you didn't
`Q.
`review the references 3 cited in im
`de<:la1’atiox1‘?
`
`(")l>jecIic'»1i. form.
`.‘\/l(f)NSF§T\E:
`l\~lf%§.
`I don'tl<i1owwl1e11 what refereiices
`A.
`are in his cleclziration.
`
`AMG 1148 (Chodak Tr.) page 14, line 23 through page 15, line 16.
`
`16.
`
`I also find it surprising that Dr. Chodak only became aware of his
`
`“overstatement” after Patent Owner’s attorneys asked him to review the paper and
`
`that he never communicated this “overstatement” to his co—author, Dr. Gerber.
`
`Page 9
`
`
`
`9
`1 O
`1 1
`1 2
`1 3
`1 4
`1 S
`1 6
`1 '7
`18
`1 9
`
`2 0
`
`Q. C)l«:av. So this overstatement. the
`sentence tl.1at\\'e’r'e referi‘iiig to. wliere the
`word "signif1ca11t" is iised in the last
`pa1'agrapl1, wlieii did j<;ou 136601116 aware ofthe
`ox‘er:statement. this ovexstateinent seiiterice in
`the article‘?
`
`M(f)NSl3N: Objection to form.
`\Vl1€11 I xx’:/195 asked to review the
`paper. 13ecau.se 1 never revisited it again.
`Q. Ol«:a_\1 Did you coiiniiuiiicate with
`Dr. (jerber about this o\'er‘state1iient in the
`
`article‘?
`
`A. New.
`2 1
`Q. And did yc>u send aiijvtliiiig like a
`2 2
`l'€I§1.”2‘1CIlO11
`to the Journal of l_§i‘olog_\x to
`2 3
`com:-ct this overstateriieiit‘?
`2 4
`.%..§......,................,......l.§:l..?§.;....1§:1.£;m.>ifl.;:....1?1:iss1és2i1§s:.i§<.¢m2.a..,s.W.W1.W
`Page 43
`
`1
`
`A. There would be no need to do Ilia‘-it.
`
`AMG 1148 (Chodak Tr.) page 42, line 9 through page 43, line 1.
`
`Dr. Chodak indicates that he was not aware of the overstatement because he was
`
`never asked to revisit the article again, although he revisited the article more than a
`
`one year after its publication when he replied to the letter to the editor from Dr.
`
`Clyde Blackard commenting on the original Gerber article.
`
`17.
`
`I also note that in an article published in 2004, almost fifteen years after
`
`he published the Gerber article, Dr. Chodak still believed that ketoconazole could
`
`still be used to treat prostate cancer: “there appears to be a reasonable number of
`
`patients with hormone refractory prostate cancer who may derive some benefit from
`
`Page 10
`
`
`
`intermediate-dose ketoconazole.” [AMG 1077, Abstract, page 584 Wilkinson]
`
`In
`
`this study, Dr. Chodak administered ketoconazole to mCRPC patients with
`
`replacement hydrocortisone, a corticosteroid.
`
`In his deposition, Dr. Chodak
`
`admitted that hydrocortisone was given with the ketoconazole for the same reasons
`
`that prednisone was given with ketoconazole in Gerber — to prevent the side effects
`
`of adrenal insufficiency.
`
`2 1
`2 2
`2 3
`
`2 4
`
`2 5
`
`1
`
`2
`3
`4
`5
`6
`7
`8
`9
`1 O
`1 1
`12
`
`Q. So fl}cf."\' were treated \\'l{lt1
`ketoconazole with l1jvc11‘<:>co1"tisoi1e; is that
`correct‘?
`
`A. Yes.
`
`Q.
`
`Is. h}”ch*oco1*tis0i1e it cortico:~sIer<.wicl‘f’
`
`A. Yes.
`
`Q. Would you have 21C.l11ll1llSI€1'C’(;l
`l‘1_vd1‘ocortisone l1€‘i’€
`jttst for the same 1'€8.‘SC)11
`you would sidiriiriister prednisoiie‘7
`MONSEN: Objection. form.
`H_v<;lro<:<;>1'Iiso11e was Ltsetl here
`A.
`to prevent sicie effects of aclrenal
`i11suff1cie11c}'.
`Q. Wlrat would p1‘eclmE's«:>1f1e l12‘t\’ti’ beeii
`acl111inisterecl. for‘?
`l\*ION’fSEN:
`A. Saine.
`
`(j)bjectioi1. form.
`
`Page 54
`
`AMG 1148 (Chodak Tr.) page 53, line 21 through page 54_. line 12.
`
`18. During his deposition, Dr. Chodak also admitted that at the time he
`
`Page 1 1
`
`
`
`submitted the article, “given the knowledge that we had, it seemed like a reasonable
`
`thing to write.”
`
`is it fair to asstiiiie that if
`Q. C)l<ay,
`1 '7
`ifou c1.i¥.;agreecl\.x'itli a sentence 7;otiwou1d:1i’t
`1 8
`ha\'e been czoinfortable subniittiiig it for
`1 9
`publication‘?
`2 O
`MS. M(I)NSE‘:\1: Olojeetioii, form.
`2 1
`lfl xvas stibiiiittiiig the paper toclay
`A.
`2 2
`1 woiilcl Write it clifferemlv. Tliat cloes not
`2 3
`iiiemi that it \m:s -- it \V'21S again an
`24
`(}\'€1‘Si2'ii€111€11i
`like the Ci€l'l3$i;%l}a§:iARw§:1:“:&_¥ But at
`2 S
`hVaw«»«Aa»teuw»vv~mA»wNo«M»v««aa»«mvwo«w-Mv»ms<w<u¢v»wvwaw»-wI¢»mvrnwz1mou~A\vn«Vv9r»wvnxmmuwmww/m>%wh&Amwn«/»Mwk4.Jwwu««sammzmiwwwa
`
`it
`
`the time. given the ldiowleclge 1i1&1t\‘.’€l1?tCl..
`1
`sseeiiied like :1 1‘t1‘Ei$_iL“)11E‘tl‘>l<2 thing to W“I.'1'[<;‘.
`In
`2
`retmszpiect, 1 wouldirt write it that way. It
`3
`cioemft retlect reall};w1iz1t we l<how Abtizlli the
`4
`effects of lietoeoriazole on p1'0Si8i€ czaneer.
`5
`6 which that it cloes not iiiiprove rstirvival.
`7 We l1:§i\'€1”iQ real good exfidence £1121: it plays a
`8
`role. amd again. the C(.")1‘1lE<3Xi\\}':‘!f%§ we had no
`9
`otlier approxed treatment tliat \voi.tlz;l iiicrease
`O
`surx'ix'al at the 1i111€Il1€‘Es€
`papers; were
`
`1
`
`written.
`
`AMG 1148 (Chodak Tr.) page 60, line 17 through page 61, line 11.
`
`IV. Secondary Considerations Do Not Indicate that the Claims of the ‘438
`Patent Are Non—Obvious
`19.
`I disagree with Dr. Vellturo’s assertion at paragraph 49 that
`
`an $33(IQ
`
`(D ,_ |\)
`
`
`
`administering the combination of abiraterone acetate and prednisone to treat prostate
`
`cancer patients “indicates that the therapeutic effects ofthe two drugs in combination
`
`reflects more than the simple additive effects of each drug individually.” JSN 2044
`
`1] 49.
`
`I disagree.
`
`I write both prescriptions to avoid the side effects that are set out
`
`in the prescribing information of Zytiga®. The FDA prescribing information
`
`provides Warnings and Precautions at Section 5, which state that use of Zytiga “may
`
`cause hypertension, hypokalemia and fluid retention as a consequence of increased
`
`mineralocorticoid levels resulting from CYPI7 inhibition.
`
`Co-administration of
`
`a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in
`
`a reduction in the incidence and severity of these adverse reactions." AMG 1018.
`
`Page 13
`
`
`
`