`
`BEFORE THE PA a
`
`TRIAL AND APPEAL BOARD
`
`Amerigen Pharmaceuticals Limited and Argentum Pharmaceuticals LLC
`
`Petitioners
`
`v.
`
`Janssen Oncology, Inc.
`
`Patent Owner
`
`U.S. Patent No. 8,822,438 to Auerbach et al.
`Issue Date: September 2, 2014
`Title: Methods and Compositions for Treating Cancer
`
`Inter Partes Review No. 2016-00286'
`
`DECLARATION OF DR. SCOTT R. SERELS, M.D.
`
`I declare that all statements made herein on my own knowledge are true and that
`all statements made on information and belief are believed to be true, and
`further, that these statements were made with the knowledge that willful false
`statements and the like so made are punishable by fine or imprisonment, or
`both, under Section 1001 of Title 18 of the United States Code.
`/
`
`Scott R. Serels, M.D.
`
`Date
`
`Case IPR2016 -01317 has been joined with this proceeding.
`
`AMERIGEN 1095
`
`JANSSEN EXHIBIT 2019
`Wockhardt v. Janssen IPR2016-01582
`
`
`
`
`
`Table of Contents
`I. Introduction
`II. Mechanism of Action of Ketoconazole and Abiraterone Acetate
`III. Overstatement of Gerber According to Dr. Chodak
`IV. Secondary Considerations Do Not Indicate that the Claims of the `438 Patent
`Are Non -Obvious
`12
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`3
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`4
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`7
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`Page 2
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`I, Scott R. Serels, M.D., do hereby declare:
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`I. Introduction
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`1.
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`My qualifications are generally described in Section A, paragraphs 4-
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`7, of my declaration submitted on December 5, 2015, (AMG 1002).
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`2.
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`I am making
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`this declaration at
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`the
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`request of Amerigen
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`Pharmaceuticals, Ltd., in the matter of the Inter Partes Review (IPR) of U.S. Patent
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`No. 8,822,438 (the '438 Patent "), as set forth in the above caption.
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`3.
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`I am being compensated for my work in this matter at the rate of
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`$500.00 per hour. My compensation in no way depends on the outcome of this
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`proceeding. The opinions I set forth herein are my own, and are based on the
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`education, experience, training and skill that I have accumulated in the course of my
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`career as a practicing urologist and researcher, as well as the materials I have
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`reviewed in connection with this case.
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`4.
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`For this declaration, I was asked to review and discuss the declarations
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`of Patent Owner's experts, Dr. Chodak (JSN 2042), Dr. Auchus (JSN 2040) and Dr.
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`Vellturo (JSN 2044). I have reviewed their declarations and the transcripts of their
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`depositions in this matter. I have also reviewed the declarations of Dr. Dorin (AMG
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`1093) and Dr. Ratain (AMG 1091).
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`5.
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`Initially, I note that the Petition states that a person of ordinary skill in
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`AMERIGEN 1095
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`
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`the art ( "POSA ") would be a physician specializing in urology or oncology, or
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`holding a Ph.D
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`in pharmacology, biochemistry or a related discipline with
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`additional experience substituting for the advanced degree.
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`I understand that the
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`Patent Owner has disagreed with this definition because "it includes `a Ph.D. in
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`pharmacology, biochemistry or a related discipline' and a physician `specializing in
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`urology or oncology' who does not treat or study prostate cancer." My opinion
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`would not change whether we use the Patent Owner's definition of a POSA or the
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`definition according to the Petition.
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`6.
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`I have reviewed the declaration of Dr. Auchus (JSN 2040) and
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`understand that he asserts that a POSA, a urologist or oncologist with experience
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`treating patients with prostate cancer, would work in a team or setting that includes
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`access to one or more or individuals who have expertise in, endocrinology,
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`biochemistry, pharmacology, and/or molecular biology or a related field of science.
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`I agree that a POSA would not be an endocrinologist but would have access to an
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`endocrinologist, to the extent needed.
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`II. Mechanism of Action of Ketoconazole and Abiraterone Acetate
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`7.
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`I have read the declaration of Dr. Auchus and understand that he
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`disagrees with part of a conclusion in my declaration (AMG 1002, ¶ 34) that
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`ketoconazole "was known to reduce cortisol levels and potentially result in
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`mineralocorticoid excess." (JSN 2040 (Auchus Declaration) ¶ 36.) While he agrees
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`Page 4
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`with my explanation that ketoconazole was known to reduce cortisol levels, he
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`disagrees that ketoconazole potentially results in mineralocorticoid excess. As I
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`explained in my declaration at paragraph 33, ketoconazole is a non -specific inhibitor
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`of 17 -a hydroxylase, an enzyme critical to steroid synthesis. In my declaration I
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`contrasted the non -specificity of ketoconazole with that of abiraterone acetate, which
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`is a selective CYP17 inhibitor (paragraphs 26, 45). Although both compounds were
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`known to reduce cortisol levels and therefore would have been expected to share
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`common adverse effects because of those reduced levels, e.g., increased ACTH
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`drive, the lack of specificity of ketoconazole will result in additional effects that are
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`not seen with abiraterone acetate. Nonetheless, the common inhibitory effect on
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`cortisol production and resulting increase in ACTH as a consequence of
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`administering either abiraterone acetate or ketoconazole would have plainly and
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`sufficiently suggested to a POSA the use of a glucocorticoid, such as prednisone,
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`with both compounds as glucocorticoid replacement therapy.
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`8.
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`At the time I prepared my declaration, I did not fully consider the
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`various mechanisms by which ketoconazole was known to inhibit adrenal steroid
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`synthesis beyond that of inhibiting CYP 17 enzyme activity.
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`In forming my
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`opinions, I relied primarily on the disclosures in the prior art regarding the inhibition
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`by ketoconazole of CYP 17 enzymatic activity, including the specific disclosures in
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`O'Donnell (AMG 1003 at 2318) and Barrie (AMG 1005 at col. 24, lines 61 -62),
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`Page 5
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`because inhibition of CYP 17 enzymatic activity is the mechanism by which both
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`ketoconazole and abiraterone acetate inhibit adrenal production of testosterone.
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`(JSN 2037 (Serels Tr) page 59, lines 2 -24). This was a reasonable approach to take
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`and, in fact, one of the inventors of the `438 Patent, Dr. de Bono, characterized both
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`ketoconazole and abiraterone acetate as treating prostate cancer by inhibiting adrenal
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`androgen synthesis: "through the inhibition of key enzymes in the adrenal steroid
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`biosynthesis pathways with agents such as ketoconazole or the CYP17 inhibitor
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`abiraterone acetate." (Vidal, AMG 1147, pp 7 -8).
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`9.
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`I have read the rebuttal opinion of Dr. Dorin, Petitioners' expert in the
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`field of endocrinology. I have considered Dr. Dorin's explanation of the predicted
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`impact of long -term administration of abiraterone acetate at dosages to treat patients'
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`mCRPC. (AMG 1093 (Dorin) e.g., ¶¶ 15, 16, 22 -26.) As a result, I understand that
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`the potential adverse effects of the predicted cortisol deficiency and increased ACTH
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`drive in such patients would have been understood by an expert in the field of
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`endocrinology to include both adrenal insufficiency (as is the case with the long-
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`term administration of ketoconazole to treat patients with mCRPC) and secondary
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`mineralocorticoid excess. (AMG 1093 (Dorin) e.g., IT 20 -27, 31 -35, 69, 70.)
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`10.
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`I have reviewed the steroid synthesis pathways as discussed in my
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`deposition and now more fully appreciate the differences and that mineralocorticoid
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`excess would not occur with ketoconazole. Nevertheless,
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`this additional
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`Page 6
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`understanding does not change my opinion that cortisol deficiency would have been
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`expected to have significant negative clinical impact in mCRPC patients treated with
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`abiraterone based on the disclosures in O'Donnell (AMG 1003) and Barrie (AMG
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`1005). It also does not change my opinion that a POSA would have been motivated
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`to co- administer a glucocorticoid, and in particular prednisone, as a first choice to
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`suppress predicted ACTH drive in patients administered abiraterone acetate to treat
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`mCRPC.
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`III. Overstatement of Gerber According to Dr. Chodak
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`11.
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`I have read the declaration of Dr. Chodak (JSN 2042) and understand
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`that he now states that the conclusion of Gerber (AMG 1004), an article on which
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`he is a co- author, is overstated. According to Dr. Chodak, the conclusion, "there
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`appears to be a small subgroup of patients who will derive significant benefit from
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`the combination of ketoconazole and glucocorticoid replacement therapy,"
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`overstates the results. I question the relevance of this "overstatement" to a POSA
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`reading the article because a POSA would be sufficiently capable of reviewing the
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`article critically and not just rely on the conclusions. Further, based on my review
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`of Gerber (AMG 1004), a later publication by Dr. Chodak as a letter to the editor of
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`the journal in which Gerber was published (JSN 2049), and his explanation of the
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`"overstatement" made during his deposition (AMG 1148), the conclusion a POSA
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`would take from Gerber is not changed.
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`Page 7
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`12. With respect to Dr. Chodak's assertion that Gerber "overstated the
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`observed outcomes," a POSA reading Gerber would exercise his/her judgment,
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`including determining whether or not any conclusions were supported by the results.
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`As a POSA, I believe that a fair reading of Gerber would lead a POSA to reach the
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`same conclusion that Dr. Chodak made when he submitted Gerber for publication.
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`13.
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`In the medical community we give a lot of credence to what is published
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`in a peer reviewed journal. If an author decides that an article contains inaccuracies
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`that author should withdraw the article and publish a revised account of the data. To
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`my knowledge, this has not been done with Gerber and the medical community
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`would have relied on Gerber for what it disclosed. Dr. Chodak's attempt now to
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`reorient his article for purposes of this legal proceeding does not affect how the
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`medical community in 2006 would have viewed his article.
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`14. However, in 1992 in response to a letter to the editor by Dr. Clyde
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`Blackard in the same journal of Gerber, Dr. Chodak reaffirmed the conclusion of his
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`original article by arguing that "the observations by others as well as our own
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`findings suggest that more investigation with ketoconazole or its analog appears to
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`be warranted, since the drug does appear to have some clinical benefit in these
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`patients in addition to its effect on serum PSA." (JSN 2049)
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`15. Beyond his surprising attempt to reinterpret his conclusion in Gerber, I
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`note that when I read Dr. Chodak's deposition I was surprised to see that he was
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`Page 8
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`commenting on my declaration without even having read the declaration.
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`2 3=
`24
`25
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`1
`2
`3
`4
`5
`6.
`7
`9
`9
`1.0
`11
`12
`13
`14
`15
`16
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`Q. Okay. Sony. Okay.
`Did you review the deposition
`testimony of Dr. Scott Serels?'
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`Page 15
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`A. No.
`Q. No? Did you review the declaration
`of Dr. Serels?
`A. No.
`Q Did you review -- do you know who
`Scott Serels is in this ease?
`A. No.
`Q Is it
`MS. MONSEN- I'm sorry Objection
`to form_.
`Q. Is it fair to say that you didn't
`review the references a cited in his
`declaration?
`MS. MONSEN: Objection, form.
`A. I don't know when what references
`are in his declaration.
`
`AMG 1148 (Chodak Tr.) page 14, line 23 through page 15, line 16.
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`16.
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`I also find it surprising that Dr. Chodak only became aware of his
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`"overstatement" after Patent Owner's attorneys asked him to review the paper and
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`that he never communicated this "overstatement" to his co- author, Dr. Gerber.
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`Page 9
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`Q. Okay. So this overstatement, the
`9
`sentence that we're referring to, where the
`1 o
`11 word "significant' is used in the last.
`paragraph, when did you become aware of the
`12
`13
`overstatement, this overstatement sentence in.
`14
`the article ?'
`15
`MS. MONSEN: Objection to form.
`A. Whenl was asked to review the
`16
`17
`paper. Because I never revisited it again.
`18
`Q Okay. Did you communicate with
`19
`Dr_ Gerber about this overstatement in the
`20
`article?
`21
`A. No.
`22
`Q And did you send anything like a
`retraction to the Journal of Urology to
`23
`24
`correct this overstatement?
`MS. MONSEN: Objection to foil.
`25
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`1
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`A. There would be no need to do that.
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`AMG 1148 (Chodak Tr.) page 42, line 9 through page 43, line. 1.
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`Page 43
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`Dr. Chodak indicates that he was not aware of the overstatement because he was
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`never asked to revisit the article again, although he revisited the article more than a
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`one year after its publication when he replied to the letter to the editor from Dr.
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`Clyde Blackard commenting on the original Gerber article.
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`17.
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`I also note that in an article published in 2004, almost fifteen years after
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`he published the Gerber article, Dr. Chodak still believed that ketoconazole could
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`still be used to treat prostate cancer: "there appears to be a reasonable number of
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`patients with hormone refractory prostate cancer who may derive some benefit from
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`Page 10
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`intermediate -dose ketoconazole." [AMG 1077, Abstract, page 584 Wilkinson] In
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`this study, Dr. Chodak administered ketoconazole to mCRPC patients with
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`replacement hydrocortisone, a corticosteroid.
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`In his deposition, Dr. Chodak
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`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
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`of adrenal insufficiency.
`21
`2 2
`23
`2 4
`2 5
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`Q. So they were treated with
`ketoconazole with hydrocortisone; .is. that
`correct?
`A. Yes..
`Q. Is hydrocortisone a corticosteroid?
`
`Pagé:54
`
`1
`2
`3.
`4
`S
`6
`7
`a
`9
`1.0
`11
`12
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`A. Yes.
`Q. Would you have administered
`hydrocortisone here just for the same reason
`you would administer prednisone?
`MS. MONSEN: Objection, form.
`A. No. Hydrocortisone was used here
`to prevent side effects of adrenal.
`.insufficiency.
`Q. What would prednisone have been
`administered for?
`MS MONSEN: Objection, form
`A. Same.
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`AMG 1148 (Chodak Tr.) page 53, line 21 through page 54, line 12.
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`18. During his deposition, Dr. Chodak also admitted that at the time he
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`Page 11
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`
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`submitted the article, "given the knowledge that we had, it seemed like a reasonable
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`thing to write."
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`Q. Okay_ Is it fair to assume that if
`17
`you disagreed with a sentence you wouldn't
`18;
`19
`have been comfortable submitting it for
`publication'?
`2 0'
`21
`MS. MONSEN Objection, form.
`A If I was submitting the paper today
`22
`23
`I would write it differently. That does not
`24 mean that it was -- it was again an
`25
`overstatement like the Gerber paper: But at
`Page 61
`the time, given the knowledge that we had, it
`1
`seemed like a reasonable thing to write. In
`2
`retrospect, I wouldn't write it that way. It.
`3
`4
`doesn't reflect really what we know about the
`5
`effects of ketoconazole on prostate cancer,
`which is that it does not improve survival'
`6
`7 We have no real good evidence that it plays a
`s
`role, and again the context was we had no
`other approved treatment that would increase
`9
`survival at the time these papers were
`10'
`11
`written.
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`AMG 1148 (Chodak Tr.) page 60, line 17 through page 61, line 11.
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`IV. Secondary Considerations Do Not Indicate that the Claims of the `438
`Patent Are Non -Obvious
`
`19.
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`I disagree with Dr. Vellturo's assertion at paragraph 49
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`that
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`Page 12
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`
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`administering the combination of abiraterone acetate and prednisone to treat prostate
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`cancer patients "indicates that the therapeutic effects of the two drugs in combination
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`reflects more than the simple additive effects of each drug individually." JSN 2044
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`If 49. I disagree. I write both prescriptions to avoid the side effects that are set out
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`in the prescribing information of Zytiga®. The FDA prescribing information
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`provides Warnings and Precautions at Section 5, which state that use of Zytiga "may
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`cause hypertension, hypokalemia and fluid retention as a consequence of increased
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`mineralocorticoid levels resulting from CYP17 inhibition. ... Co- administration of
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`a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in
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`a reduction in the incidence and severity of these adverse reactions." AMG 1018.
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`Page 13
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`