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`Paper No. ___
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`Date Filed: January 30, 2017
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________
`
`AMERIGEN PHARMACEUTICALS LIMITED,
`ARGENTUM PHARMACEUTICALS LLC,
`
`Petitioner
`
`v.
`
`JANSSEN ONCOLOGY, INC.,
`Patent Owner
`________________
`
`Case IPR2016-002861
`________________
`
`Patent No. 8,822,438 B2
`
`
`
`PATENT OWNER’S MOTION FOR OBSERVATIONS ON
`CROSS-EXAMINATION
`
`
`1 Case IPR2016-01317 has been joined with this proceeding.
`
`
`
`IPR2016-00286
`U.S. Patent 8,822,438
`
`Deposition of Dr. Ratain
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`I. Mechanism of Abiraterone Acetate Observations
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`1. In Exhibit 2124, on p. 48, l. 3 through p. 49, l. 11, the witness testified:
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`Q. Let’s shift gears a little bit. Abiraterone acetate and ketoconazole are
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`different compounds, right?
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`A. Yes.
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`Q. And they have different mechanisms of action?
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`A. Well, they – they have different properties, that’s for sure.
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`Q. And what do you mean by that?
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`A. Well, they’re different – different drugs and they each have multiple
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`targets.
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`Q. And they – abiraterone acetate and ketoconazole inhibit different
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`activities, is that right?
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`MR. CASIERI: Object to form.
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`THE WITNESS: Well, they – they have some targets in common and they
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`have some different targets.
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`This testimony is relevant to Dr. Ratain’s opinions at paragraphs 30, 37 and 39 of
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`his declaration. See Ex. AMG 1091 (analogizing the activity of abiraterone acetate
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`to that of ketoconazole). Further, this testimony is relevant to Dr. Serels’s opinions
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`at paragraphs 23 and 33-36 of his declaration. See Ex. AMG 1002 (analogizing the
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`1
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`IPR2016-00286
`U.S. Patent 8,822,438
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`activity of abiraterone acetate to that of ketoconazole). This testimony is relevant
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`to Patent Owner’s arguments regarding the mechanisms of action of abiraterone
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`acetate and ketoconazole. See Paper 33, Patent Owner Response (“PO Resp.”), 13-
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`17.
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`2. In Exhibit 2124, p. 48, l. 22, through p. 49, l. 11, the witness testified:
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`Q. What are the key components of the steroid synthesis pathway that are
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`inhibited by abiraterone acetate?
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`A. I wasn’t asked to provide opinions regarding that.
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`Q. So, you don’t know. Is that fair to say?
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`A. I wouldn’t answer that without having the documents in front of me. It’s
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`not in my declaration.
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`Q. And what are the key components of the steroid synthesis pathway that
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`are inhibited by ketoconazole?
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`A. Same answer.
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`This testimony is relevant to Dr. Ratain’s opinions at paragraphs 30, 37 and 39 of
`
`his declaration. See Ex. AMG 1091 (analogizing the activity of abiraterone acetate
`
`to that of ketoconazole). This testimony is also relevant because it is consistent
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`with Dr. Serels’s testimony at paragraphs 8 and 10 of Dr. Serels’s Reply
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`Declaration (Ex. AMG 1095) and to Patent Owner’s arguments regarding the
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`2
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`IPR2016-00286
`U.S. Patent 8,822,438
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`understanding of Petitioners’ experts concerning the differences in the mechanisms
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`of action between abiraterone acetate and ketoconazole. See PO Resp., 13-17.
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`II. Prior-Art Drugs Observations
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`3. In Exhibit 2124, on p. 50, l. 13 through p. 51, l. 1, the witness testified:
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`Q. And a person of ordinary skill in the art in August of 2006 would have
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`appreciated that no survival benefit in prostate cancer patients had been
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`demonstrated with ketoconazole, is that right?
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`MR. CASIERI: Object to form.
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`THE WITNESS: That’s correct.
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`MR. KRAUSE: And even as of today ketoconazole is not approved for the
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`treatment of prostate cancer and has not been shown to confer a survival
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`benefit, right?
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`A. That’s correct.
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`This testimony is relevant to Petitioners’ assertions in this IPR proceeding. See
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`Reply at 1, 9 (arguing that ketoconazole was considered “safe and effective in
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`treating human patients with hormone-refractory advanced prostate cancer”). This
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`testimony is relevant to the disclosure of Wilkinson. See Ex. 1077 at p. 583
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`(“Disappointingly, a survival benefit could not be demonstrated in our study
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`population. This is consistent with other efficacy trials of ketoconazole….”). This
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`3
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`IPR2016-00286
`U.S. Patent 8,822,438
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`testimony is also relevant to Patent Owner’s arguments regarding the use of
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`“ketoconazole and prednisone” for “treating prostate cancer.” PO Resp., 37.
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`4. In Ex. 2124, at p. 90, l. 13-16, the witness testified:
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`Q. Is it true that prednisone monotherapy has never been shown to provide a
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`survival benefit for the treatment of prostate cancer?
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`A. Yes.
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`This testimony is relevant to Dr. Ratain’s declaration at paragraphs 42 and 43. See
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`Ex. AMG 1091 (opining, respectively, that corticosteroids “were specifically
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`approved by the FDA for the treatment of prostate cancer – in combination with
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`docetaxel” and that there was “extensive literature regarding the treatment of
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`mCRPC with corticosteroids”). This testimony is also relevant to Petitioners’ and
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`Patent Owner’s assertions regarding the use of prednisone in the treatment of
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`cancer. See Petition, 14; PO Resp., 47.
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`5. In Ex. 2124, at p. 101, l. 11-16, the witness testified:
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`Q. Okay. And dexamethasone monotherapy has not been shown to improve
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`any survival measure for the treatment of prostate cancer, is that right?
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`A. Not in any published trials that I’ve seen. I don’t know if whether there
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`could be unpublished data.
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`This testimony is relevant to Dr. Ratain’s declaration at paragraph 43. Ex. AMG
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`1091 (opining that there was “extensive literature regarding the treatment of
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`4
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`IPR2016-00286
`U.S. Patent 8,822,438
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`mCRPC with corticosteroids”). This testimony is also relevant to Petitioners’
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`Reply at 15 (asserting that dexamethasone was an effective monotherapy treatment
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`for prostate cancer). Further, this testimony is relevant to Patent Owner’s
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`arguments regarding how one of ordinary skill in the art would have viewed the
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`results of the dexamethasone extension study. See PO Resp, 56-57.
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`6. In Ex 2124, at p. 90, l. 7-16, the witness testified:
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`Q. My question is that this sentence immediately after the sentence that you
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`have quoted in your declaration, “This seems unlikely,” that undermines the
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`thrust of the sentence that you’ve cited in your declaration, is that correct?
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`A. Yes.
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`This testimony is relevant to Dr. Ratain’s declaration at paragraph 44. See Ex.
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`AMG 1091 (referring to a sentence in AMG 1022 in support of his opinion that
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`corticosteroids, including prednisone, may have a survival benefit as a
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`monotherapy. The next sentence in AMG 1022, p. 1511 states: “[t]his seems
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`unlikely because with prednisone or hydrocortisone alone, the rate of PSA
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`response in large phase 3 studies was in the range of 16 to 24 percent and was
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`generally transient…Intensive treatment with dexamethasone was reported to have
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`no effect on hormone-refractory prostate cancer in one small study.”).
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`III. Expertise Observations
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`7. In Exhibit 2124, on p. 24, l. 17-21, the witness testified:
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`5
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`IPR2016-00286
`U.S. Patent 8,822,438
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`Q. Do you regularly treat patients with prostate cancer?
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`MR. CASIERI: Object to form.
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`THE WITNESS: No.
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`This testimony is relevant to Dr. Ratain’s declaration at paragraphs 3-17. Ex.
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`AMG 1091 (describing Dr. Ratain’s oncology background). This testimony is
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`relevant because it relates to Dr. Ratain’s experience in treating prostate cancer and
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`the weight that should be given to his testimony regarding the treatment of prostate
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`cancer.
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`Deposition of Dr. Dorin
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`I. ACTH Stimulation (“Synacthen”) Test
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`8. In Exhibit 2125, on p. 97, l. 11-16, the witness testified:
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`Q. And when you refer to the historical use of a delta cortisol, do you mean
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`that use was before 2006, but as of 2006 the standard of care was to use the
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`absolute value of cortisol?
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`A. Yes.
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`This testimony is relevant to Dr. Dorin’s declaration at paragraphs 40 and 50-59.
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`See Ex. AMG 1093 (opining that the delta, or change in, cortisol would be a useful
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`parameter for diagnosing adrenal insufficiency). This testimony is relevant to
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`Patent Owner’s arguments regarding how one skilled in the art would have
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`6
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`IPR2016-00286
`U.S. Patent 8,822,438
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`interpreted ACTH-Stimulation (or “Synacthen”) test results as of the priority date.
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`See PO Resp., 19-20.
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`9. In Exhibit 2125, on p. 93, l. 17 through p. 94, l. 16, the witness testified:
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`Q. The Synacthen test doesn’t reflect the total amount of glucocorticoids
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`being produced in a patient, does it?
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`A. No.
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`Q. And in fact, it only measures the patient’s cortisol levels in response to
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`stress; is that right?
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`A. It only measures cortisol concentrations. That’s true. In response to stress,
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`no. In response to a stimulus of cortisol secretion.
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`Q. Better put. Thank you. The Synacthen test doesn’t measure corticosterone
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`levels, does it?
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`A. It does not.
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`Q. And corticosterone is another steroid with glucocorticoid activity; isn’t
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`that right?
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`A. That’s correct. But to qualify that, very weak glucocorticoid activity in
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`human beings.
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`Q. But we agree that it provides some glucocorticoid activity?
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`A. Yes.
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`7
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`IPR2016-00286
`U.S. Patent 8,822,438
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`This testimony is relevant to Patent Owner’s arguments regarding how one skilled
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`in the art would have interpreted Synacthen test results as of the priority date. PO
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`Resp., 21.
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`10. In Exhibit 2125, on p. 104, l. 1-5, the witness testified:
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`Q. And are you aware that the next study with abiraterone acetate was not
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`performed with concomitant glucocorticoids?
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`A. No.
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`This testimony is relevant to Dr. Dorin’s opinions at paragraphs 31-35 of his
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`declaration. See Ex. AMG 1093 (opining on IRB (Institutional Review Board)
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`approval of abiraterone acetate clinical trials and its impact on the use of
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`concomitant steroids in light of O’Donnell). This testimony is relevant to Patent
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`Owner’s arguments concerning the next clinical trial of abiraterone acetate. PO
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`Resp., 41.
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`II. Effect of Treatment with Exogenous Glucocorticoids Observations
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`11. In Exhibit 2125, on p. 30, l. 19 through p. 31, l. 1-4, the witness testified:
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`Q. And how could the HPA axis be suppressed?
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`A. A common way is by exogenous glucocorticoids at doses and durations
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`that are sufficient to suppress corticotropin-releasing hormone and ACTH.
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`Q. And those doses could be as low as about 5 to 10 MGs per day; isn’t that
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`correct?
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`8
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`IPR2016-00286
`U.S. Patent 8,822,438
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`A. Yes.
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`Q. And what happens when the HPA axis is suppressed?
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`A. What you can measure is that ACTH levels are decreased for any given
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`concentration of cortisol and that the cortisol response to ACTH is
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`subnormal.
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`Q. Anything else?
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`A. No.
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`Q. Can HPA axis suppression result in adrenal insufficiency?
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`A. This is a slightly complicated question. So do you mean adrenal
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`insufficiency while you’re on glucocorticoids or once you stop the
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`glucocorticoids?
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`Q. Why don’t we take it both ways.
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`A. Uh-huh. So when you’re on replacement glucocorticoids, it would be
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`unusual to develop adrenal insufficiency.
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`Q. And –
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`A. And –
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`Q. Sorry.
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`A. And if – if you had suppressed the HPA axis and then stopped the
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`exogenous glucocorticoids, there would be a risk of adrenal insufficiency.
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`Q. And can HPA axis suppression lead to adrenal crisis?
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`9
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`IPR2016-00286
`U.S. Patent 8,822,438
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`A. In the setting of concurrent stress, yes.
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`This testimony is relevant to at least paragraphs 28 and 29 of Dr. Dorin’s
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`declaration. See Ex. AMG 1093 (opining on the risks of concomitant
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`administration of replacement glucocorticoids). This testimony is relevant to
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`Patent Owner’s views concerning concomitant administration of glucocorticoids.
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`PO Resp., 31 (“In addition, and paradoxically, evidence now presented to the Panel
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`also shows that administration of glucocorticoids to a patients would have been
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`understood to have the potential to actually incapacitate the adrenal gland, thereby
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`impairing a patient’s ability to mount a cortisol response during times of stress
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`[i.e., lead to adrenal crisis].”).
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`III. CYP17 Deficiency Observations
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`12. In Exhibit 2125, on p. 52, l. 15-21, the witness testified:
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`Q. Okay. And there can be a wide range of genetic mutations that are
`
`associated with those deficiencies; is that right?
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`A. That’s correct.
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`Q. And as I think as we just said, the clinical symptoms are variable?
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`A. Yes.
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`This testimony is relevant to Dr. Dorin’s declaration at paragraphs 15, 17, 20, 25,
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`26, 61, and 66. See AMG Ex. 1093 (characterizing the symptoms observed in
`
`patients with congenital deficiencies of the 17α-hydroxylase/17,20 lyase enzyme).
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`IPR2016-00286
`U.S. Patent 8,822,438
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`13. In Exhibit 2125, on p. 29, l. 12-23, the witness testified:
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`Q. And have you ever treated a patient with P450c17 deficiency syndrome?
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`A. No.
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`Q. Have you ever published on P450c17 deficiency syndrome?
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`A. I have not.
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`Q. And you don’t have any patents related to P450c17 syndrome?
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`A. That’s correct.
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`Q. Is it fair to say that you’re not an expert in P450c17 deficiency
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`syndromes?
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`A. Yes.
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`14. In Exhibit 2125, on p. 38, l. 10-13, the witness testified:
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`Q. And do you know if there are guidelines with respect to the diagnosis of
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`P450c17 deficiency syndromes?
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`A. I do not.
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`This testimony is relevant to at least paragraphs 15-19 of Dr. Dorin’s declaration.
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`See Ex. AMG 1093 (generally describing P450C17 deficiency syndromes and their
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`clinical presentation). This testimony is relevant to the weight that should be given
`
`to Dr. Dorin’s testimony regarding the range of presentations and symptoms
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`associated with congenital CYP17 deficiency syndromes, as well as the appropriate
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`clinical management of such patients. This testimony is relevant to the disclosure
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`11
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`of Van den Akker. See Ex. 1155 at 5719 (“All of our patients had normal basal
`
`cortisol serum levels, but insufficient response to stimulation by ACTH. No
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`guidelines are available for the hydrocortisone substitution treatment in these
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`patients. In our view, daily hydrocortisone substitution treatment is not needed
`
`when there are no complaints, but in case of stress, a hydrocortisone stress dose is
`
`advised. Nevertheless, some of our patients underwent uneventful surgery without
`
`a hydrocortisone stress scheme”).
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`IV. Expertise Observations
`
`15. In Exhibit 2125, on p. 25, l. 20-24, the witness testified:
`
`Q. Okay. Have you ever treated a patient for prostate cancer?
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`A. No. I’ve treated patients with prostate cancer, but not for the cancer.
`
`In Exhibit 2125, on p. 26, l. 21-24, the witness testified:
`
`Q. So it’s fair to say, isn’t it, that you’re not an expert in the treatment of
`
`prostate cancer?
`
`A. Oh, yes.
`
`This testimony is relevant to paragraphs 3 – 8 of Dr. Dorin’s declaration. See Ex.
`
`AMG 1093 (describing Dr. Dorin’s education and professional background). This
`
`testimony is relevant because it relates to the witness’s level of experience in
`
`treating prostate cancer and the weight that should be given to Dr. Dorin’s
`
`testimony regarding the treatment of prostate cancer.
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`12
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`Deposition of Dr. Serels
`
`
`I. Person of Skill in the Art Observations
`
`16. In Exhibit JSN 2127, p. 8, l. 23, through p. 9, l. 7, the witness testified:
`
`Q. And do you agree that a urologist is generally not an expert in
`
`endocrinology?
`
`A. Correct.
`
`MR. CASIERI: Object to form.
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`MR. ZEGGER: And do you agree that an oncologist is generally not an
`
`expert in endocrinology?
`
`MR. CASIERI: Object to form.
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`THE WITNESS: Correct.
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`This testimony is relevant to Dr. Dorin’s January 16, 2017 declaration at
`
`paragraphs 62 and 65. See AMG 1093 (describing what an “expert in
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`endocrinology” would recognize).
`
`II. Ketoconazole Observations
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`17. In Exhibit JSN 2127, p. 9, l. 24, through p. 10, l. 16, the witness testified:
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`Q. Now, at the time of your initial declaration, you did not fully consider the
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`various mechanisms by which ketoconazole was known to inhibit adrenal
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`steroid synthesis beyond inhibiting CYP17 enzyme synthesis; correct?
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`MR. CASIERI: Object to form.
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`13
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`U.S. Patent 8,822,438
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`THE WITNESS: Correct.
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`MR. ZEGGER: Okay. And particularly, you were focusing on one particular
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`mechanism of action; is that right?
`
`A. As it pertained to abiraterone, which was the compound that we were
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`most interested in.
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`Q. You agree that ketoconazole has mechanisms of action other than
`
`inhibiting CYP17 enzyme synthesis?
`
`A. I do agree.
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`This testimony is relevant to Dr. Serels’s January 16, 2017 declaration at paragraph
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`10. See Ex. AMG 1095 (stating that “mineralocorticoid excess would not occur
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`with ketoconazole”).
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`18. In Exhibit JSN 2127, p. 26, l. 17-24, the witness testified:
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`Q. Okay. And in the 2004 article of Chodak, he doesn’t say that there’s a
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`significant benefit to ketoconazole. Correct?
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`MR. CASIERI: Object to form.
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`THE WITNESS: He doesn’t use those exact terms.
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`This testimony is relevant to Dr. Serels’s January 16, 2017 declaration at paragraph
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`14. See Ex. AMG 1095 (opining that in 2004 Dr. Chodak reiterated his view that
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`ketoconazole could provide a benefit in the treatment of prostate cancer).
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`IPR2016-00286
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`Dated: January 30, 2017
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`Respectfully submitted,
`
`By: /Dianne B. Elderkin/
`Dianne B. Elderkin (Reg. No. 28,598)
`delderkin@akingump.com
`Barbara L. Mullin (Reg. No. 38,250)
`bmullin@akingump.com
`Ruben H. Munoz (Reg. No. 66,998)
`rmunoz@akingump.com
`AKIN GUMP STRAUSS HAUER &
`FELD LLP
`Two Commerce Square
`2001 Market Street, Suite 4100
`Philadelphia, PA 19103
`Tel: (215) 965-1200
`Fax: (215) 965-1210
`
`David T. Pritikin (pro hac vice)
`Bindu Donovan (pro hac vice)
`Paul J. Zegger (Reg. No. 33,821)
`Todd L. Krause (Reg. No. 48,860)
`S. Isaac Olson (pro hac vice)
`Alyssa B. Monsen (pro hac vice)
`SIDLEY AUSTIN LLP
`787 Seventh Avenue
`New York, NY 10019
`Tel.: (212) 839-5300
`Fax: (212) 839-5599
`ZytigaIPRTeam@sidley.com
`Counsel for Patent Owner
`
`
`
`
`
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`IPR2016-00286
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`CERTIFICATE OF SERVICE
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`The undersigned hereby certifies that a copy of the foregoing Patent
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`Owner’s Motion for Observations on Cross-Examination was served on counsel of
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`record on January 30, 2017 by filing this document through the End-to-End
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`System, as well as delivering a copy via electronic mail to counsel of record for the
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`Petitioners and Patent Co-Owner at the following addresses:
`
`William Hare - bill@miplaw.com
`Gabriela Materassi - materassi@miplaw.com
`
`Teresa Stanek Rea - TRea@Crowell.com
`Shannon M. Lentz - SLentz@Crowell.com
`
`Anthony C. Tridico - anthony.tridico@finnegan.com
`Jennifer H. Roscetti - jennifer.roscetti@finnegan.com
`
`
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`Date: Jan. 30, 2017
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`Respectfully submitted,
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`By: /Dianne B. Elderkin/
`Dianne B. Elderkin
`Registration No. 28,598
`Counsel for Patent Owner
`
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`16
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