Matthew B Rettig , M.D.
`
`March 31, 2017
`
`Page 1
`
` UNITED STATES PATENT AND TRADEMARK OFFICE
`
` BEFORE THE PATENT TRIAL AND APPEAL BOARD
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` --------------------------------------
`
` MYLAN PHARMACEUTICALS INC,
`
` Petitioner,
`
` v.
`
` JANSSEN ONCOLOGY, INC.,
`
` Patent Owner.
`
` Case No. IPR2016-01332
`
` U.S. Patent No. 8,822,438
`
` --------------------------------
`
` WOCKHARDT BIO AG,
`
` Petitioner,
`
` v.
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` JANSSEN ONCOLOGY, INC.,
`
` Patent Owner.
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` Case IPR2016-01582
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`15
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` U.S. Patent No. 8.822,438 B2
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`16
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` VIDEOTAPED DEPOSITION OF MATTHEW
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` B. RETTIG, M.D., a Witness herein, taken
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` by Petitioners, at the offices of Sidley
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` Austin, 787 Seventh Avenue, New York, New
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` York, on Friday, March 31, 2017, at 9:08
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` a.m., before DEBRA STEVENS, Certified
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` Realtime and Registered Professional
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` Reporter and Notary Public within and for
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` the State of New York.
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`VERITEXT LEGAL SOLUTIONS
`202-803-8830
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`MYLAN PHARMS. INC. EXHIBIT 1135 PAGE 1
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`

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`Matthew B Rettig , M.D.
`
`March 31, 2017
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`Page 2
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`Page 4
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` E X A M I N A T I O N S
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` Witness Page
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`1 2
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`3
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`4
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` M. Rettig
`5 By Mr. White 8
` By Ms. Donovan 95
`6 By Mr. Gallo 99
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`7 8 9
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` E X H I B I T S
`10 Mylan
` Exhibit Description Page
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` Exh 1085 Potter article 37
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` Exh 1086 Attard 2012 article 41
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`11
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`12
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`13
`14
`15
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` Wockhardt
`16 Exhibit Description Page
`17 Exh 1082 Montgomery,Eisenberger, 128
` Rettig article, 2016
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`18
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`19
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` Exh 1083 Nishimura article 141
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` Exh 1084 Rettig declaration in 152
`20 Amerigen
`21 Exh 1085 Rettig declaration in 152
` Mylan
`
`22
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` Exh 1086 Garnick declaration in 153
`23 Mylan
`24
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` (Continued)
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` E X H I B I T S (Continued)
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` PRIOR MARKED AND REFERENCED HEREIN
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`Page 5
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` Mylan 1001 '438 Patent
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` Mylan 1005 '213 Patent
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` Mylan 1023 Attard 2005 article
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` Mylan 1003 O'Donnell article
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` Janssen 2014 Attard 2008 article
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` Janssen 2133 Ryan article
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` WCK 1035 Potter article
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` WCK 1036 Fakih article
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` WCK 1005 O'Donnell article
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` WCK 1002 Godley declaration
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`25
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`1 2
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`3
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`4
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`5
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`6
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`Page 3
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` A P P E A R A N C E S :
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`1 2
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`3 4
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` PERKINS COIE LLP
` Attorneys for Petitioner Mylan
`5 Pharmaceuticals Inc.
` 700 Thirteenth Street, N.W., Suite 600
`6 Washington, DC 20005-3960
`7 BY: BRANDON M. WHITE, ESQ.
` bmwhite@perkinscoie.com
`
`8
`
` MARIE STUBBINGS, ESQ.
`9 mstubbings@perkinscoie.com
`10
`11
`
` STERNE, KESSLER, GOLDSTEIN & FOX P.L.L.C
`12 Attorneys for Petitioner
` Wockhardt Bio AG
`13 1100 New York Ave. NW, Suite 600
` Washington DC 20005
`
`14
`
` BY: CHRISTOPHER M. GALLO, ESQ.
`15 cgallo@skgf.com
`16 DENNIES VARUGHESE, ESQ.
` dvarughe@skgf.com
`
`17
`18
`19 SIDLEY AUSTIN LLP
` Attorneys for Patent Owner Mylan
`20 Pharmaceuticals Inc.
` 787 Seventh Avenue
`21 New York, New York 10019
`22 BY: BINDU DONOVAN, ESQ.
` bdonovan@sidley.com
`
`23
`
` ALYSSA B. MONSEN, ESQ.
`24 amonsen@sidley.com
`25
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` (Continued)
`
` A P P E A R A N C E S:
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`1 2
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`3
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` FINNEGAN EUROPE LLP
`4 Attorneys for Patent Owner BTG
` 16 Old Bailey
`5 London EC4M 7EG
` United Kingdom
`
`6
`
` BY: ANTHONY C. TRIDICO, ESQ.
`7 anthony.tridico@finnegan.com
`
` ALSO PRESENT:
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` Tony Dolan, BTG
`
`8 9
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`10
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`11
`12 * * *
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
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`VERITEXT LEGAL SOLUTIONS
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`2 (Pages 2 - 5)
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`MYLAN PHARMS. INC. EXHIBIT 1135 PAGE 2
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`

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`Matthew B Rettig , M.D.
`
`March 31, 2017
`
`Page 6
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`Page 8
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`1 2
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` MR. DOLAN: Tony Dolan, BTG.
`3 VIDEOGRAPHER: Our court
`4 reporter, Deb Stevens, also from
`5 Veritext, will now swear in the
`6 witness and we can proceed.
`7 Whereupon,
`8 M A T T H E W R E T T I G,
`9 having been first duly sworn/affirmed,
`10 was examined and testified as follows:
`11 EXAMINATION BY
`12 MR. WHITE:
`13 Q. Good morning, Doctor.
`14 A. Morning.
`15 Q. My name is Brandon White and I
`16 am here on behalf of Mylan to ask you some
`17 questions today.
`18 Would you state your name for
`19 the record?
`20 A. Matthew Rettig.
`21 Q. Where are you currently
`22 employed?
`23 A. I am currently employed at the
`24 UCLA School of Medicine and Department of
`25 Veterans Affairs of West Los Angeles.
`
`1 2
`
` THE VIDEOGRAPHER: This is the
`3 beginning of file number one. We are
`4 going on the record at approximately
`5 9:08 a.m. My name is Kevin Gallagher,
`6 representing Veritext, New York. The
`7 date today is the 31st of March, 2017.
`8 The deposition is being held at Sidley
`9 Austin, located at 787 Seventh Avenue,
`10 New York, New York.
`11 The caption of the case is Mylan
`12 Pharmaceuticals vs. Janssen Oncology,
`13 Inc. and also Wockhardt et al. vs.
`14 Janssen Oncology Inc. The case is
`15 filed in the U.S. Patent and Trademark
`16 Office, Case Number IPR2016-01332.
`17 The name of our witness this morning
`18 is Matthew Rettig.
`19 At this time attorneys present
`20 in the room will identify themselves
`21 for the record.
`22 (Brief interruption)
`23 VIDEOGRAPHER: Off the record at
`24 9:09 a.m.
`25 (Recess.)
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`Page 7
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`Page 9
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`1 M. Rettig
`2 Q. You are the same Dr. Rettig who
`3 submitted declarations and was deposed in
`4 the Amerigen IPR a few months ago?
`5 A. Yes.
`6 Q. You have before you the
`7 declaration that you submitted in response
`8 to the Mylan papers. Is that right?
`9 A. Yes.
`10 Q. If I just refer to that as your
`11 Mylan declaration, will you know what I am
`12 referring to?
`13 A. Yes.
`14 MS. DONOVAN: I would like to
`15 state for the record that it is
`16 Janssen's position that Petitioner's
`17 examination of Dr. Rettig will be
`18 limited to the scope of the
`19 declaration that he has submitted in
`20 the Mylan IPR.
`21 MR. WHITE: I understand your
`22 position and you can object to our
`23 questions if you believe they are
`24 outside the scope. We take no
`25 position on your statement.
`
`1 2
`
` VIDEOGRAPHER: We are going back
`3 on the record approximately 9:10 a.m.
`4 This is the beginning of File B.
`5 MR. WHITE: This is Brandon
`6 White from Perkins Coie, on behalf of
`7 Petitioner Mylan.
`8 MS. STUBBINGS: Marie Stubbings,
`9 also from Perkins Coie, on behalf of
`10 Petitioner Mylan.
`11 MR. GALLO: Christopher Gallo
`12 from Sterne Kessler Goldstein & Fox,
`13 on behalf of Petitioner Wockhardt.
`14 MR. VARUGHESE: Dennies
`15 Varughese, Sterne Kessler Goldstein
`16 Fox, on behalf of Petitioner
`17 Wockhardt.
`18 MS. DONOVAN: Bindu Donovan on
`19 behalf of Patent Owner Janssen
`20 Oncology Inc.
`21 MS. MONSEN: Alyssa Monsen, on
`22 behalf of Patent Owner Janssen
`23 Oncology Inc.
`24 MR. TRIDICO: Anthony Tridico on
`25 behalf of Patent Owner BTG.
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`MYLAN PHARMS. INC. EXHIBIT 1135 PAGE 3
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`

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`Matthew B Rettig , M.D.
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`March 31, 2017
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`Page 10
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`Page 12
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`1 M. Rettig
`2 Q. I just want to go over the rules
`3 so we are on the same page for the
`4 deposition. I am sure you have probably
`5 heard these before.
`6 I will ask you ask you some
`7 questions. After I ask my question,
`8 Ms. Donovan may object. Unless she
`9 instructs you not to, you should try to
`10 answer my question if you can.
`11 We should try not to talk over
`12 each other for the reporter's sake. You
`13 should give your attorney time to object,
`14 again for the court reporter's sake. If I
`15 cut you off, it is inadvertent. Please
`16 tell me, and I will happily let you finish
`17 your answer. Again, I ask that you let me
`18 finish my question. Sometimes we can get
`19 conversational and you think you know
`20 where I am going with a question and start
`21 answering. It can make for a difficult
`22 record.
`23 If there is something I ask you
`24 that you don't understand or you need to
`25 see something, please let me know and I
`
`1 M. Rettig
`2 MR. WHITE: Can we stipulate
`3 that the witness is here in response
`4 to our deposition notices filed in the
`5 IPR's?
`6 MS. DONOVAN: That's fine.
`7 Q. What did you do to prepare for
`8 your deposition today?
`9 A. I communicated with counsel and
`10 collaborated on the generation of my
`11 declaration.
`12 Q. Other than your meetings with
`13 counsel, did you speak to anyone else?
`14 A. No.
`15 Q. At any time have you spoken with
`16 any of the other witnesses for Janssen?
`17 A. No.
`18 Q. Did you ever speak with
`19 Dr. Vellteuro?
`20 A. No.
`21 Q. Did you review any materials to
`22 prepare for your deposition today?
`23 A. Yes.
`24 Q. What did you review?
`25 MS. DONOVAN: I will caution the
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`Page 11
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`Page 13
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`1 M. Rettig
`2 will try to clarify the question or
`3 provide you materials to the extent I can.
`4 Understood?
`5 And you should try to give
`6 verbal answers and not head nods or other
`7 gesturing. The court reporter can't take
`8 that down.
`9 MS. DONOVAN: Before we continue
`10 further --
`11 THE VIDEOGRAPHER: Off the
`12 record at 9:14 a.m.
`13 (Pause.)
`14 THE VIDEOGRAPHER: Back on the
`15 record at approximately 9:15 a.m.,
`16 beginning of file C.
`17 BY MR. WHITE:
`18 Q. As we finish up the rules, if at
`19 any time you need a break, feel free to
`20 let me know and I am happy to take a
`21 break.
`22 Do you believe there is any
`23 reason you can't give honest and truthful
`24 testimony today?
`25 A. No.
`
`1 M. Rettig
`2 witness, you may respond generally
`3 without disclosing the specifics of
`4 attorney-client privileged
`5 communications.
`6 A. I reviewed many of the exhibits
`7 related to this case.
`8 Q. Those are the materials that you
`9 cited in your declaration?
`10 A. Correct.
`11 Q. Did you review anything that you
`12 hadn't included in your declaration?
`13 MS. DONOVAN: You may answer
`14 that "yes" or "no."
`15 A. Not that I recall.
`16 Q. How much time did you spend in
`17 preparing the Mylan declaration?
`18 A. I don't have the exact number of
`19 hours, but many hours.
`20 Q. And that is many hours that were
`21 spent unique to the Mylan declaration and
`22 not as part of your work with the Amerigen
`23 case?
`24 A. Correct.
`25 Q. Do you have an understanding of
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`MYLAN PHARMS. INC. EXHIBIT 1135 PAGE 4
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`Matthew B Rettig , M.D.
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`March 31, 2017
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`Page 14
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`Page 16
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`1 M. Rettig
`2 what this dispute is about?
`3 A. Yes.
`4 Q. You understand you are here to
`5 talk about your opinions with respect to
`6 the '438 patent?
`7 A. Yes.
`8 Q. You understand what the '438
`9 patent is?
`10 A. Yes.
`11 Q. Other than your deposition in
`12 the Amerigen case, have you been deposed
`13 before?
`14 A. No.
`15 Q. Have you served as an expert
`16 witness other than in the Amerigen case?
`17 MS. DONOVAN: Objection to form.
`18 A. Can you clarify the specifics of
`19 what you mean by "expert witness"?
`20 Q. Sure. Other than with respect
`21 to your declarations with respect to the
`22 '438 patent that are in the Amerigen,
`23 Wockhardt and Mylan cases, have you been
`24 an expert witness in any litigations?
`25 A. So, I have been retained as an
`
`1 M. Rettig
`2 A. No.
`3 Q. Did you have any involvement
`4 with the development of abiraterone
`5 acetate?
`6 MS. DONOVAN: Object to the form
`7 of the question as vague.
`8 A. So, can you please specify what
`9 you mean by "development of abiraterone
`10 acetate"?
`11 Q. Prior to the FDA approval of
`12 abiraterone acetate did you have any
`13 involvement with abiraterone acetate?
`14 A. Yes. I did serve as an
`15 investigator in the clinical trials that
`16 led up to the approval of abiraterone
`17 acetate.
`18 Q. Which clinical trials were you
`19 involved with?
`20 A. So, the Phase III studies, both
`21 the -- as I recall, both the
`22 post-chemotherapy and pre-chemotherapy
`23 studies. I may have been a
`24 subinvestigator on one of the earlier
`25 phase studies, but I can't recall.
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`Page 15
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`Page 17
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`1 M. Rettig
`2 expert witness but was never deposed, and
`3 the cases were settled prior to my direct
`4 involvement.
`5 MS. DONOVAN: Let me just state
`6 for the record, we have disclosed
`7 Dr. Rettig under the protective order
`8 in the District Court litigation
`9 related to the '438 patent. So you
`10 may want to just clarify your
`11 question.
`12 Q. I understand you have been
`13 disclosed with respect to the '438 patent,
`14 so nothing with respect to the '438
`15 patent.
`16 Was that -- the other case that
`17 you referenced, was that public? Was your
`18 disclosure public?
`19 A. They were not just one case, but
`20 I don't know the disclosure status of
`21 those cases. They were tort claims.
`22 Q. So they weren't patent cases?
`23 A. No.
`24 Q. Have you ever testified at trial
`25 before?
`
`1 M. Rettig
`2 Q. Do you remember what the
`3 treatment arms were in the studies you
`4 were involved with?
`5 MS. DONOVAN: Objection to form.
`6 A. For these -- if you are
`7 referring to the Phase III studies?
`8 Q. Mm-hmm.
`9 A. Yes, I do recall the treatment.
`10 Q. What were they?
`11 A. It was -- there were two arms in
`12 both of the studies. It was abiraterone
`13 acetate plus prednisone versus placebo
`14 plus prednisone.
`15 Q. What were what were your
`16 responsibilities as an investigator in
`17 those clinical trials?
`18 A. So, as an investigator there
`19 were some standard requirements and duties
`20 to generally oversee the conduct of the
`21 study, to make sure that appropriate
`22 persons who are involved in the study are
`23 trained, to make sure that the execution
`24 of the clinical trials and procedures is
`25 done accurately and that data are reported
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`VERITEXT LEGAL SOLUTIONS
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`MYLAN PHARMS. INC. EXHIBIT 1135 PAGE 5
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`Matthew B Rettig , M.D.
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`March 31, 2017
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`Page 18
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`Page 20
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`1 M. Rettig
`2 in a timely and accurate fashion.
`3 Q. Were you involved in the
`4 development of the protocol for those
`5 clinical trials?
`6 A. No.
`7 Q. In preparing your declaration
`8 did you do any independent review or
`9 search of the prior art?
`10 A. So, as I stated, I reviewed
`11 exhibits associated with my declaration,
`12 besides my declaration. In my experience
`13 in the field I have reviewed literature
`14 that is related to the issues in this
`15 case, but I did not do a specific
`16 literature search related to the Mylan
`17 case.
`18 Q. Now I would -- maybe we can
`19 clarify some nomenclature so we are on the
`20 same page for the deposition. Do you
`21 understand that abiraterone acetate and
`22 abiraterone are two distinct compounds?
`23 A. Yes, I do.
`24 Q. And abiraterone acetate is the
`25 ingredient in the -- is it a capsule or
`
`1 M. Rettig
`2 MS. DONOVAN: I will just note
`3 for the record, the witness is
`4 speaking without the '438 patent in
`5 front of him.
`6 Q. Just so you have a copy in front
`7 of you, before you is what was marked in
`8 the Mylan IPR as Exhibit 1001. It should
`9 be a copy of the '438 patent. Feel free
`10 to look at that if you need to.
`11 How does -- how does an
`12 anticancer effect -- how is that evidenced
`13 clinically? How do you know if
`14 abiraterone has an anticancer effect?
`15 A. So, there are a number of
`16 metrics that can be used to assess the
`17 anticancer effect. Some of the ones
`18 commonly used would be a reduction in
`19 tumor burden as detected on imaging
`20 studies.
`21 So, if a patient has a
`22 measurable metastasis, something that can
`23 be seen and measured on a CT scan, for
`24 example, one can assess the changes in the
`25 size of a particular lesion, tumor, over
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`Page 19
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`Page 21
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`1 M. Rettig
`2 tablet that the patient takes? Is that
`3 right?
`4 A. Abiraterone acetate is the
`5 active ingredient in the tablet the
`6 patients take.
`7 Q. And that becomes abiraterone in
`8 the body?
`9 A. Correct.
`10 Q. And that's what has the clinical
`11 effect?
`12 A. That's the active form of the
`13 drug; yes.
`14 Q. With respect to the '438 patent
`15 you understand the word "treatment" or
`16 "treating" has a special meaning?
`17 A. Yes.
`18 Q. What is your understanding of
`19 that meaning?
`20 A. My understanding is that "treat"
`21 specifically refers to an anticancer
`22 effect. For example, eradicating the
`23 primary tumor, reducing tumor burden,
`24 improving clinical outcomes such as
`25 survival.
`
`1 M. Rettig
`2 time in response to a therapy.
`3 Another example would be a
`4 change in outcome such as cancer-specific
`5 survival, overall survival, radiographic
`6 progression-free survival.
`7 Q. Overall radiographic
`8 progression-free survival?
`9 A. No. There is something called
`10 overall survival, which is death due to
`11 any cause, including death due to cancer
`12 but it could be death due to heart attack.
`13 There is cancer-specific or
`14 disease-specific survival, which are
`15 deaths that are attributable to the cancer
`16 and exclude non-cancer related deaths.
`17 Then there are other types of
`18 survival end points. Another one would be
`19 radiographic progression-free survival,
`20 which is itself a composite between
`21 radiographic progression and death due to
`22 any cause -- or death due to any cause.
`23 Q. Does PSA level show an
`24 anticancer effect?
`25 A. It really depends on the
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`Matthew B Rettig , M.D.
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`March 31, 2017
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`Page 22
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`Page 24
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`1 M. Rettig
`2 situation. It's a hypothetical situation,
`3 so I'd really need to know the context in
`4 which the PSA is being measured in order
`5 to assess whether or not it has an
`6 anticancer effect.
`7 Q. What type of contextual
`8 information would you need?
`9 A. The stage and state of the
`10 disease, the type of treatment that is
`11 being implemented would be examples.
`12 Q. For abiraterone acetate plus
`13 prednisone, would a PSA response indicate
`14 antitumor effect?
`15 A. Again, it --
`16 MS. DONOVAN: Allow me to
`17 object. Object to the form of the
`18 question. Calls for speculation.
`19 A. Yeah; again, I think I would
`20 need to know the specifics of the clinical
`21 trial context or clinical context in order
`22 to make that assessment.
`23 Q. Have you seen any clinical data
`24 in preparing your report where you believe
`25 a PSA response showed an anticancer effect
`
`1 M. Rettig
`2 You may answer.
`3 A. So, it really -- generally what
`4 we are talking about would be endocrine
`5 therapies that are used after castration.
`6 Q. In that same sentence it says
`7 "improve the clinical outcomes of the
`8 patients with mCRPC." What is meant by
`9 "improve the clinical outcomes"?
`10 A. Clinical outcomes can refer to a
`11 number of different measures, objective
`12 measures of the response to treatment, and
`13 some of them are the ones that I listed
`14 for you in terms of assessing anticancer
`15 effects. "Improve" would mean make
`16 better.
`17 As an example, if one is looking
`18 at objective responses -- in other words
`19 does the tumor shrink -- "improve" would
`20 mean a reduction in tumor burden. And
`21 there are some standardized ways of
`22 establishing the extent of the response,
`23 and those are specific criteria that are
`24 used for clinical trials.
`25 Q. You have previously used
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`Page 23
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`Page 25
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`1 M. Rettig
`2 with the treatment of abiraterone acetate
`3 plus prednisone?
`4 A. So, changes in PSA are -- a
`5 change in PSA is a poor surrogate for
`6 changes in tumor burden. So while it is
`7 plausible that change in PSA correlates
`8 with changes in tumor burden, there can be
`9 a disconnect between what the PSA is doing
`10 and what the overall tumor burden is
`11 doing.
`12 Q. I want to get your understanding
`13 of some of the terms used in your report.
`14 I turn you to 38 of your report, your
`15 Mylan declaration.
`16 A. Okay.
`17 Q. I am going to talk about the
`18 last portion on page 24.
`19 MS. DONOVAN: Do you have a copy
`20 for me?
`21 Q. It is the end of paragraph 58,
`22 second to last sentence. You mention
`23 secondary form of therapies. What is
`24 meant by that term?
`25 MS. DONOVAN: Object to form.
`
`1 M. Rettig
`2 ketoconazole with a steroid to treat
`3 patients. Is that right?
`4 MS. DONOVAN: Object to the form
`5 of the question. You may answer.
`6 A. Yes, I have. Not recently.
`7 Q. When is the last time you used
`8 that therapy?
`9 A. I don't recall exactly but it's
`10 been years.
`11 Q. Did you believe that therapy
`12 improved the clinical outcome for
`13 patients?
`14 MS. DONOVAN: Object to the form
`15 of the question.
`16 A. My usage of ketoconazole -- and
`17 I would say this is not necessarily
`18 restricted to ketoconazole. When there is
`19 an absence of therapies that I believe to
`20 improve clinical outcomes and a patient is
`21 left with no options but is in a suitable
`22 functional state, sometimes as
`23 oncologists, as I do and many oncologists
`24 do in practice, is we give the patient a
`25 therapy that has not been shown to, in a
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`Matthew B Rettig , M.D.
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`March 31, 2017
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`1 M. Rettig
`2 rigorous fashion, to improve a clinical
`3 outcome.
`4 Q. In your experience in providing
`5 that therapy to patients, did you believe
`6 it improved their clinical outcome for the
`7 patients?
`8 A. I would just stick with my
`9 answer and just add that I had no evidence
`10 that ketoconazole by itself or in
`11 combination with anything else had an
`12 established effect on clinical outcome.
`13 So, that's how I would answer the
`14 question.
`15 Q. When you prescribed ketoconazole
`16 did you always prescribe it with a
`17 steroid?
`18 A. Yes.
`19 Q. What steroids did you use?
`20 A. Typically -- I used a
`21 glucocorticoid, and that would have been
`22 either hydrocortisone or prednisone, most
`23 commonly hydrocortisone.
`24 Q. And you would have given the
`25 hydrocortisone and prednisone even prior
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`1 M. Rettig
`2 the time or treated prostate cancer at the
`3 time to add back steroids that can replace
`4 the activities that are diminished as a
`5 consequence of ketoconazole.
`6 Q. You did not wait until you saw a
`7 clinical manifestation of adrenal
`8 insufficiency before you provided the
`9 steroids to the patients; correct?
`10 MS. DONOVAN: I object to the
`11 form of the question.
`12 A. The corticosteroids or the
`13 hydrocortisone and prednisone were
`14 generally prescribed at the outset along
`15 with the ketoconazole.
`16 Q. If you could turn to your Mylan
`17 declaration at page 41, please?
`18 A. Okay.
`19 Q. On page 41 there are two
`20 figures, Figure 4 and Figure 5. I see you
`21 have a black and white copy. I have a
`22 color copy if that is helpful for you to
`23 review.
`24 A. Sure. Okay.
`25 Q. Did you prepare these figures?
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`1 M. Rettig
`2 to seeing a clinical manifestation of a
`3 need for either of those glucocorticoid
`4 therapies?
`5 MS. DONOVAN: I object to the
`6 form of the question.
`7 A. Can you clarify what you mean by
`8 "need"?
`9 Q. Why was the glucocorticoid given
`10 in conjunction with ketoconazole?
`11 A. Ketoconazole has a mechanism of
`12 action whereby it inhibits the
`13 biosynthesis of all adrenal steroids.
`14 These are steroids such as
`15 mineralocorticoids, glucocorticoids and
`16 adrenal androgens.
`17 While ketoconazole can be and
`18 has been published to be used by itself as
`19 a monotherapy, the frequency with which
`20 patients who get ketoconazole monotherapy
`21 of adrenal insufficiency and complicated
`22 related to the absence of or reduction in
`23 mineralocorticoid and glucocorticoid,
`24 homo-concentrations prompted me and most
`25 oncologists who treat prostate cancer at
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`1 M. Rettig
`2 A. I worked with my counsel to
`3 generate these figures. Well, to bring
`4 these figures in. So, that's what I did.
`5 I didn't actually make the original
`6 figure.
`7 Q. These were kind of developed
`8 with your guidance?
`9 A. Correct.
`10 Q. What do the X's, the red X's
`11 shown with Figures 4 and 5 represent?
`12 A. Those indicate the principal
`13 sites of enzyme inhibition by the
`14 respective drugs.
`15 Q. And why are the X's different
`16 sizes? Are you trying to show something
`17 with that?
`18 A. Yes. The X's are different
`19 sizes to indicate the extent, the relative
`20 extent, on a schematic level, to which the
`21 respective drugs inhibit the indicated
`22 enzymes.
`23 Q. So, the larger X would indicate
`24 that something is a more potent
`25 inhibitor --
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`Matthew B Rettig , M.D.
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`March 31, 2017
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`1 M. Rettig
`2 A. Yes. The larger X indicates
`3 that the drug has a greater impact on
`4 inhibiting the enzyme associated with the
`5 larger X.
`6 Q. For ketoconazole, what evidence
`7 do you have that desmolase is a more
`8 potent inhibitor than -- that ketoconazole
`9 is a more potent inhibitor of the
`10 desmolase enzyme than 17 hydroxylase and
`11 17,20-lyase?
`12 A. So, there is literature that
`13 looked at the effects of ketoconazole and
`14 these enzymes. For example, one of the
`15 articles that is sited in the Mylan
`16 petition, the Sonino reference,
`17 specifically described the effects of
`18 ketoconazole on these different enzymes
`19 within the adrenal steroid synthesis
`20 pathways.
`21 Q. What was the reference?
`22 A. I believe it was the Sonino
`23 reference.
`24 Q. In your figure, should there be
`25 an X on the line from progesterone to 17
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`1 M. Rettig
`2 inhibition of the desmolase enzyme?
`3 MS. DONOVAN: Objection to form.
`4 A. What do you mean by "complete"?
`5 Q. Does it entirely block the
`6 activity of the desmolase enzyme?
`7 A. So, when we talk about
`8 inhibition we are talking about
`9 concentrations of the drug that -- the way
`10 it's typically reported is the
`11 concentration of the drug that inhibits
`12 50 percent of the activity; okay? And
`13 there is a range of concentrations,
`14 obviously, that a drug can -- that are
`15 required for a drug to inhibit a
`16 particular enzyme.
`17 So, "complete" to me sounds like
`18 100 percent. And while it
`19 predominantly -- ketoconazole
`20 predominantly inhibits that enzyme,
`21 desmolase, involved in the first step of
`22 steroid biosynthesis, I don't know it is
`23 100 percent. I don't know that we can say
`24 any drug inhibits something 100 percent in
`25 the concentrations that are achievable in
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`1 M. Rettig
`2 OH-progesterone?
`3 A. So, CYP17, it does also mediate
`4 the conversion of progesterone to 17
`5 hydroxyprogesterone. So it is the same
`6 enzyme that is converting pregnenolone to
`7 17 hydroxypregnenolone.
`8 So yes, this is a simplified
`9 version of that, but it is the same enzyme
`10 involved in the two steps, which is the 17
`11 alpha-hydroxylation.
`12 Q. So for abiraterone -- well, let
`13 me -- Figure 4, should that be abiraterone
`14 acetate, or abiraterone?
`15 A. It probably should be the active
`16 form of it, or could be. I think the
`17 point is that -- I think everyone
`18 understands what the point is, and that is
`19 the active form of the drug.
`20 Q. Are there differences in the
`21 activity between abiraterone acetate and
`22 abiraterone?
`23 A. Yes. Abiraterone is the active
`24 form of the compound. Yes.
`25 Q. Is ketoconazole a complete
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`1 M. Rettig
`2 a human being.
`3 Q. Do you know to what extent
`4 ketoconazole inhibits desmolase?
`5 A. Again, are you referring to
`6 the -- I don't know what you mean by "to
`7 what extent."
`8 Q. Do you know the IC50 value
`9 for ketaconazole --
`10 A. I don't know it offhand.
`11 (Brief interruption)
`12 Q. Do you know the IC50 value
`13 for desmolase?
`14 A. I don't recall the specific
`15 number.
`16 Q. Do you recall seeing the
`17 specific number in preparing your
`18 declaration?
`19 A. I can't recall.
`20 Q. Looking at Figure 4, with
`21 abiraterone, the pathway to cortisol is
`22 inhibited by abiraterone? All pathways to
`23 cortisol are inhibited by abiraterone; is
`24 that right?
`25 MS. DONOVAN: Object to the form
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`Matthew B Rettig , M.D.
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`March 31, 2017
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`1 M. Rettig
`2 of the question.
`3 A. The figure is not demonstrating
`4 or is meant to demonstration the --
`5 that -- it does not demonstrate the
`6 effects of abiraterone acetate on the
`7 concentrations of specific hormones.
`8 Q. Did the prior art teach that the
`9 administration of abiraterone acetate
`10 would cause a reduction in the level of
`11 cortisol?
`12 A. No.
`13 Q. Doctor, I have given you a copy
`14 of what has been marked in the Mylan IPR
`15 as Exhibit 1005. You may recognize that
`16 as the '213 patent or the Barrie patent.
`17 A. Yes.
`18 Q. That is something you reviewed;
`19 correct?
`20 A. Yes.
`21 Q. And one of the points you make
`22 from Barrie is that abiraterone has
`23 differential activity with respect to
`24 inhibition of lyase and hydroxylase. Is
`25 that right?
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`1 M. Rettig
`2 that were used to establish the effects of
`3 abiraterone on these enzymes.
`4 Q. Is that another way of saying
`5 you don't know if the data reported at the
`6 bottom of column 22 reflects the activity
`7 of abiraterone? Is that correct?
`8 MS. DONOVAN: Objection. Asked
`9 and answered.
`10 A. I don't know what the authors of
`11 this patent were indicating here. The way
`12 I interpret this is that abiraterone, the
`13 acti