Marc B. Garnick, M.D.
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`******** * * *:r ** * * * * * ** ** * * * * ** ** * **** **
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`MYLAN PHARMACEUTICALS INCORPORATED,
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`Petitioner
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`vs.
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`JANSSEN ONCOLOGY, INC.,
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`Patent Owner
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`******* * * * * * * * * * * * * * * * * * * * * * * * * * * * * * **
`
`CASE IPR2016 -01332
`
`U.S. Patent No. 8,822,438
`
`******* * * * * * * * * * * * * * * * * * * * * * * * * * * * * * **
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`VIDEOTAPED DEPOSITION of MARC B. GARNICK, M.D.
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`Thursday, February 16, 2017
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`9:02 a.m.
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`Held at: Eliot Hotel
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`360 Commonwealth Avenue
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`Boston, Massachusetts
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`JZEXHIB
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`h In
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`Date
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`Megan M. Castro, RPR, Court Reporter
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`Golkow Technologies, Inc.
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`Page 1 (1)
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`JANSSEN EXHIBIT 2016
`Wockhardt v. Janssen IPR2016-01582
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`

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`Marc B. Garnick, M.D.
`Page 2
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`Page 4
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`INDEX
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`Page
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`Page
`104
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`Witness
`MARC B. GARNICK, M.D.
`Direct Examination by Mr. Krause
`EXHIBITS
`Number
`Description
`Exhibit JSN2009 Article entitled
`"Eligibility and
`Response Guidelines for
`Phase II Clinical
`Trials in
`Androgen- Independent
`Prostate Cancer:
`Recommendations From
`the Prostrate -Specific
`Antigen Working Group"
`by Glenn J. Bubley, et
`13
`al.
`14 Exhibit JSN2010 Declaration of Scott R. 109
`Serels, M.D.
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`a
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`9
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`1 APPEARANCES:
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`2 PERKINS COIE
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`3 Bryan D. Beel, Ph.D.
`Shannon M. Bloodworth, Esquire - VIA TELECONFERENCE
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`4
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`S
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`6
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`7
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`1120 NW Couch Street
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`10th Floor
`Portland, Oregon 97209 -4128
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`503- 727 -2116
`8
`9 bbeel @perkinscoie.com
`lo
`sbloodworth @perkinscoie.com
`on behalf of the Petitioner
`11
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`12
`13 SIDLEY AUSTIN, LLP
`14 Todd L. Krause, Esquire
`787 Seventh Avenue
`15
`16 New York, New York 10019
`212- 839 -5696
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`17
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`tkrause @sidley.com
`on behalf of the Patent Owner
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`Page 3
`1 APPEARING VIA TELECONFERENCE:
`2 WINSTON & STRAWN, LLP
`3 Ryan B. Hauer, Esquire
`35 W. Wacker Drive
`4
`Chicago, Illinois 60601 -9703
`312- 558 -8116
`rhauer @winston.com
`on behalf of Apotex, Inc.
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`ALSO PRESENT:
`Marissa DeMonte, videographer
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`Exhibit JSN2011 Two -page document from
`The Journal of Urology
`dated December 1991
`
`184
`
`PROCEEDINGS
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`Page 5
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`THE VIDEOGRAPHER: We are now on the
`record. My name is Marissa DeMonte, and I am a
`4
`5 videographer for Golkow Technologies.
`Today's date is February 16, 2017, and
`6
`7 the time is 9:02 a.m. This video deposition is
`8 being held in Boston, Massachusetts, in the
`9 matter of Mylan Pharmaceuticals Incorporated
`versus Janssen Oncology, Inc., for the United
`10
`States Patent and Trademark Office, before the
`Patent Trial and Appeal Board.
`The deponent is Marc B. Garnick, M.D.
`Counsel will be noted on the stenographic record.
`The court reporter is Megan Castro. She will now
`swear in the witness and we can proceed.
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`MARC B. GARNICK, M.D., first having been
`satisfactorily identified by the production of
`his driver's license and duly sworn by the Notary
`Public, testified under oath as follows in answer
`to direct examination by MR. KRAUSE:
`
`Q. Good morning, sir. Can you please state
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`Golkow Technologies, Inc.
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`Page 2 (2 - 5)
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`Marc B. Garnick, M.D.
`Page 6
`1 your name and home address for the record?
`A. Marc Bennett Gamick, G- A- R- N- I -C -K,
`2
`3 289 Marlborough Street, Boston, Massachusetts
`4 02116.
`Q. There are a few points I would like to
`5
`6 review before we get started. If I ask a
`7 question that is not clear or you didn't hear me,
`please let me know so I can ask the question
`9 again. If you answer, I will assume you
`10 understood and heard my question. Okay?
`A. Yes.
`11
`Q. And we have a court reporter taking down
`12
`13 your answers to my questions, so please try to
`14 give verbal answers to my questions. Okay?
`A. Yes.
`15
`Q. We will try to take breaks about every
`16
`17 hour or so, but please let me know if you need a
`18 break, and I will finish whatever question I am
`19 on and we can take a break.
`Is there any reason you cannot give
`20
`21 complete and accurate testimony here today?
`22
`A. No.
`(Handing document to the witness.)
`Q. I have handed you a document that has
`
`23
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`24
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`Page 8
`A. This basically represents the steroid
`1
`2 pathway from cholesterol to various other
`3 steroids, such as cortisol, aldosterone, and the
`4 sex steroids.
`Q. And the biosynthesis of all steroids
`5
`6 begins with the cleavage of the side chain of
`7 cholesterol to form pregnenolone; is that
`8 correct?
`MR. BEEL: Objection to form.
`9
`A. Yes.
`10
`11 BY MR. KRAUSE:
`Q. So if the conversion of cholesterol to
`12
`13 pregnenolone is blocked, so is the biosynthesis
`14 of all the steroids; is that correct?
`A. It would have to be a complete block, I
`15
`16 would assume.
`Q. But if one had a complete block, that
`17
`18 would block the production of all of the steroids
`19 in the pathways; correct?
`MR. BEEL: Objection. Foundation.
`'20
`A. I would assume so.
`21
`22 BY MR. KRAUSE:
`Q. Some arrows in the diagram have the word
`23
`24 "CYP17" over them. What is CYP17?
`
`Page 9
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`Page 7
`1 been marked as Mylan Exhibit 1002. Is this your
`2 declaration?
`(Witness viewing document.)
`A. Yes, it is.
`Q. Is that your signature on the last page
`5
`6 of the declaration?
`A. Yes, it is, page 57.
`7
`Q. Yes, sir. Thank you.
`Is the declaration marked as Mylan 1002
`10 an accurate statement of the opinions that you
`11 have reached in this case?
`A. Yes, it is.
`12
`Q. We will be talking about a person of
`13
`14 ordinary skill in the art a lot today. When I
`15 refer to a person of ordinary skill in the art,
`16 will you understand that I am referring to a
`17 person's knowledge as of -- that person's
`18 knowledge as of August 25, 2006?
`19
`A. Yes.
`MR. BEEL: Objection to form.
`20
`21 BY MR. KRAUSE:
`Q. Please turn to the diagram following
`22
`23 paragraph 37 in your declaration. What does this
`24 represent?
`
`8
`
`A. It is -- my understanding is that is an
`1
`2 enzyme complex that includes 17 alpha -hydroxylase
`3 and 17,20 -lyase, part of the cytochrome P450
`4 system.
`Q. Is it fair to say that these two
`5
`6 activities are represented in the diagram but not
`7 specifically labeled?
`A. I would assume so, yes.
`Q. And paragraph 38 of your declaration
`9
`10 notes the 17 alpha -hydroxylase activities as a
`11 hydroxyl group, OH, to pregnenolone and
`12 progesterone at carbon 17 of the steroid D ring,
`13 converting both to their 17- hydroxy forms. This
`14 is represented in the horizontal arrows between
`15 the first and second columns of the diagram; is
`16 that correct?
`. A. Yes.
`17
`Q. Can you please circle those arrows for me
`in your declaration and label them
`19
`20 "17 alpha- hydroxylase "?
`(Witness marking document.)
`21
`A. They are not on the diagram.
`Q. There are horizontal arrows between
`23
`24 pregnenolone and 17- hydroxy pregnenolone, as well
`
`18
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`22
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`Marc B. Garnick, M.D.
`Page 10
`1 as progesterone and 17- hydroxy progesterone?
`A. Correct.
`2
`Q. And don't those -- I believe you just
`3
`4 testified that those horizontal arrows represent
`5 the 17 alpha -hydroxylase activity; is that
`6 correct?
`A. My understanding is that it is
`7
`8 incorporated into the CYP17 nomenclature,
`9 C -Y -P 17.
`Q. So the activity that is being represented
`10
`11 by those arrows is the 17 alpha -hydroxylase
`12 activity of CYP17; is that correct?
`13
`A. Yes.
`Q. Could you circle those arrows and label
`14
`15 them "17 alpha -hydroxylase" for me?
`MR. BEEL: Objection to form and
`16
`17 foundation.
`A. I am not sure I understand what you want
`18
`19 me to do.
`20 BY MR. KRAUSE:
`Q. I am trying to identify the activity in
`21
`22 this diagram that is associated with the
`23 17- hydroxylase activity.
`A. It is incorporated into the CYP17.
`24
`
`MR. BEEL: Objection to form and
`1
`2 foundation.
`THE WITNESS: Should I hear your
`3
`4 objection before I answer?
`MR. BEEL: If you can pause for a second.
`THE WITNESS: Okay.
`6
`7 BY MR. KRAUSE:
`Q. And can you please label those arrows
`8
`9 "17,20- lyase "?
`MR. BEEL: Objection to form and
`10
`11 foundation.
`(Witness marking document.)
`12
`13 BY MR. KRAUSE:
`Q. Let's talk first about the 17- hydroxylase
`14
`15 activity of CYP17. What does that do?
`A. My understanding is it adds a hydroxy
`16
`17 group to pregnenolone.
`Q. So if you completely block the
`18
`19 17- hydroxylase, you do not get any production of
`20 cortisol or testosterone; is that correct?
`MR. BEEL: Objection to form.
`21
`A. I would assume that you have to have
`22
`23 complete blockage to have that.
`24 BY MR. KRAUSE:
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`Page 11
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`1
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`Page 13
`Q. So if one has complete blockage, is it
`true that you would not get any production of
`2
`3 cortisol and testosterone?
`A. That is a question for basically an
`4
`5 endocrine biochemist or enzymologist. That is
`6 not an expertise that I have, whether it is
`7 completely blocked or incompletely blocked, to
`a answer your question accurately.
`Q. But my question was with reference to a
`9
`10 complete blockage. If one completely blocks that
`11 activity, that is, the 17- hydroxylase activity,
`12 one does not get any production of cortisol or
`13 testosterone; is that correct?
`MR. BEEL: Objection to form and
`14
`15 foundation.
`A. I don't really know what you mean by
`16
`17 "completely blocked."
`18 BY MR. KRAUSE:
`Q. If there is a total absence of
`19
`20 17- hydroxylase activity, cortisol and
`21 testosterone are not produced; is that correct?
`MR. BEEL: Same objection.
`22
`A. Of 17- hydroxylase?
`23
`24 BY MR. KRAUSE:
`
`4
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`5
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`6
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`7
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`Q. Correct.
`A. Okay.
`Q. And that is represented by these
`horizontal arrows between the first and second
`columns in the diagram; is that correct?
`A. Yes, correct.
`Q. So I am simply trying to ask you --
`A. Want me to put 17 alpha -hydroxylase
`8
`9 there?
`Q. Yes, sir. And just circle the arrows
`10
`11 that are correlated with that.
`MR. BEEL: Objection to form and
`12
`13 foundation.
`(Witness marking document.)
`14
`15 BY MR. KRAUSE:
`Q. And I believe in your declaration,
`16
`17 paragraph 38, you note that 17,20 -lyase activity
`18 splits the side chain off of 17- hydroxy
`19 progesterone and 17- hydroxy pregnenolone?
`20
`A. Yes.
`Q. This is represented by the horizontal
`21
`22 arrows between the second and third columns of
`23 the diagram; is that correct?
`24
`A. Yes.
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`Golkow Technologies, Inc.
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`Marc B. Garnick, M.D.
`Page 14
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`Page 16
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`Q. Yes, sir.
`A. I am not sure that is correct.
`Q. And if you get some but not complete
`3
`4 blocking of 17- hydroxylase, one could get some
`5 cortisol and testosterone, but it would be less
`6 than if it were completely blocked; is that
`7 correct?
`A. You are asking questions that are really
`s
`9 better addressed to a steroid biochemist or a
`10 steroid enzymologist, in terms of the degree of
`11 blockage, complete blockage versus incomplete
`12 blockage. I am not really equipped to answer
`13 those questions because I really don't know what
`14 complete "blockage means" and what "incomplete
`15 blockage" means.
`Q. Okay. Now let's talk about 17,20 -lyase
`16
`17 activity. What does 17,20 -lyase do?
`MR. BEEL: Objection. Foundation.
`18
`A. My understanding is that it basically is
`19
`20 involved in the pathway going to the sex
`21 steroids.
`22 BY MR. KRAUSE:
`Q. And if one completely blocks the
`23
`24 17,20 -lyase activity, no testosterone is
`
`1
`
`6
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`MR. BEEL: Objection to form.
`A. That is another enzyme involved in
`2
`3 steroid synthesis.
`4 BY MR. KRAUSE:
`Q. What does that do?
`5
`MR. BEEL: Objection. Foundation.
`A. It takes it from DOC to corticosterone,
`7
`a from deoxy -corticosterone to corticosterone.
`9 BY MR. KRAUSE:
`Q. So is it true that if there is no
`10
`11 11- beta -hydroxylase activity, cortisol would not
`12 be produced?
`MR. BEEL: Objection to form and
`13
`14 foundation.
`A. My answer is the same answer that I have
`15
`16 given you previously to the other quantitative
`17 analyses of blockage or inhibition.
`18 BY MR. KRAUSE:
`Q. So is it your testimony that you have no
`19
`20 opinion with respect to a relative degree of
`21 blockage of any of the enzymatic activities
`22 represented on this diagram?
`MR. BEEL: Objection to form.
`23
`A. I definitely have opinions on that.
`
`24
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`Page 15
`1 produced, but cortisol could be produced; is that
`2 correct?
`MR. BEEL: Objection to form and
`3
`4 foundation.
`A. That would be incorrect because
`5
`6 testosterone is produced other places as well.
`7 BY MR. KRAUSE:
`Q. Well, with respect to the pathway that we
`8
`9 have in front of us, isn't it true that if
`10 one blocks the 17,20 -lyase activity, the
`11 production of testosterone would be blocked?
`A. I guess my best answer to that question
`12
`is you are asking terms that I am really not
`13
`14 terribly familiar with. When you say "complete
`15 block," "incomplete block," those questions are
`16 really better addressed to an enzymologist.
`Q. So is it fair to say you don't know the
`17
`18 answer to those questions?
`A. I don't know what the term "blockage"
`19
`20 means. In strict enzymology, I don't understand
`21 what that term means, complete versus incomplete
`22 blockage.
`Q. Okay. The diagram also has the word
`23
`24 "CYPI IB 1" near a couple of arrows. What is that?
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`Page 17
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`2
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`1 BY MR. KRAUSE:
`Q. Well, what are your views with respect to
`the relative degrees of blockage and the
`3
`4 potential production of steroids in light of
`5 those relative degrees?
`A. So I have been asked to be an expert
`6
`7 on -- and provide expert testimony on this
`6 related to the clinical understanding of the way
`in which pharmaceuticals are utilized in the
`9
`10 management of patients with prostate cancer that
`11 affects steroid synthesis and sex steroid
`12 synthesis.
`So my opinions on agents that block
`13
`14 either 17- hydroxylase activity or 17,20 -lyase
`15 activity are agents which are commonly used --
`16 which I commonly use in my day -to -day practice of
`17 medicine, and the sequelae of those activities of
`18 these particular enzymes relate -- result in
`19 clinical activities and clinical sequelae that I
`20 understand and treat.
`So that is my understanding of the
`21
`22 opinions. I am not an expert in providing for
`23 you specific enzymatic characteristics,
`24 equilibrium characteristics. That would be
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`Golkow Technologies, Inc.
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`Marc B. Garnick, M.D.
`Page 18
`1 better suited for a biochemical enzymologist.
`Q. In your answer, you just referred to
`2
`3 block. What degree of blockage were you
`4 referring to?
`A. If I said "block," I meant inhibition or
`5
`6 anything that decreases the production of
`7 cortisol, mineralocorticoids, or sex steroids.
`Q. So what degree of inhibition are you
`8
`9 referring to?
`A. Inhibition that results in a clinical
`10
`11 result or a clinical sequelae. And,
`12 quantitatively, I can't tell you that, the degree
`13 of that inhibition.
`Q. But there could be different degrees of
`14
`15 inhibition; is that fair to say?
`A. I would say so, yes.
`16
`Q. But you are not prepared to discuss any
`17
`18 particular degree of inhibition?
`A. I am not qualified to discuss the degree
`19
`20 of inhibition.
`21
`Q. Is it fair to say that the steroids
`22 synthesis pathway is very complex?
`MR. BEEL: Objection to form.
`23
`A. That is an unanswerable question.
`24
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`Page 20
`Q. And the inhibition of different enzymes
`1
`2 in the pathways can affect the production of
`3 different reaction products downstream; is that
`4 correct?
`A. In general, yes.
`5
`Q. And the action of any given enzyme in the
`6
`7 pathways can be affected by other enzymes and
`8 components in the pathways?
`A. Yes. In general, yes.
`Q. And the pathways and the effects of
`10
`11 enzyme inhibition can also be affected by the
`12 expression and inactivity of individual enzymes
`13 as well as by environmental factors, which can
`14 vary between individuals; is that correct?
`MR. BEEL: Objection to form, foundation.
`15
`A. That is an all- encompassing question. I
`16
`17 didn't get all of the details of the question.
`18 BY MR. KRAUSE:
`Q. Sure. I will be happy to ask it again.
`19
`Isn't it true that the pathways and
`20
`21 effects of enzyme inhibition can also be affected
`22 by the expression and activity of individual
`23 enzymes as well as environmental factors, which
`24 can vary between individuals?
`
`9
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`Page 19
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`Page 21
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`1 BY MR. KRAUSE:
`Q. Why?
`2
`A. Well, if you were a steroid biochemist
`3
`4 and studied enzyme machinology..::.mechanisms,
`5 that would probably be something that is
`6 understandable and something that someone does.
`7 The word "complex" is a very far -reaching and
`8 all- encompassing word.
`Q. Would a POSA view the steroid synthesis
`9
`10 pathway as complex?
`11
`MR. KRAUSE: Sorry. Strike that.
`12 BY MR. KRAUSE:
`Q. Would a person of ordinary skill in the
`13
`14 art view the steroid synthesis pathway as very
`15 complex?
`MR. BEEL: Objection to form.
`16
`A. Qualitatively, yes. Quantitatively,
`17.
`18 probably not.
`19 BY MR. KRAUSE:
`Q. And is it true that enzymes operate at
`20
`21 various steps in the biochemical pathways to
`22 regulate the step -by -step biosynthesis of
`23 steroids?
`24
`A. In general, yes.
`
`MR. BEEL: Objection to form and
`1
`2 foundation.
`A. Again, I can't answer that question
`3
`4 because I don't know what you mean by
`5 "environmental factors."
`6 BY MR. KRAUSE:
`Q. Well, isn't it true that environmental --
`7
`8 that drugs or other agents in the environment can
`9 impact enzymatic activity?
`A. Again, I can't answer your question
`10
`11 because when you say drugs or other factors in
`12 the environment, you would have to be more
`13 specific. Clearly, if a patient is taking
`14 another drug -- preferably, it wasn't in the
`15 environment but it was given as a pharmaceutical,
`16 as a pharmaceutical to the patient -- that could
`17 potentially influence these things.
`Q. Can diet affect enzymatic activity?
`18
`MR. BEEL: Objection to form and
`19
`20 formation.
`A. I think I would have to know the
`21
`22 particular component of the diet that you are
`23 referring to.
`24 BY MR. KRAUSE:
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`Marc B. Garnick, M.D.
`Page 22
`Q. In general, to your knowledge, can diet
`1
`2 in any way affect enzymatic activity?
`MR. BEEL: Objection to form.
`3
`A. In the case of abiraterone, for example,
`4
`5 my assumption is that the enzymatic activity is
`6 influenced by food because there is strict
`7 instructions that the drug should be taken on an
`8 empty stomach.
`So under those circumstances, given the
`9
`to activity of abiraterone clinically, my
`11 understanding is that the activity is definitely
`12 different if food is ingested with a product as
`13 opposed to on an empty stomach. So to that
`14 matter, I would say yes.
`15 BY MR. KRAUSE:
`Q. And is it true that a number of steroids
`16
`17 have overlapping functions that can compensate
`18 for one another?
`MR. BEEL: Objection to form.
`19
`20
`A. That is an unanswerable question in its
`21 current form.
`22 BY MR. KRAUSE:
`Q. Why is that?
`23
`A. Which particular steroids are you
`24
`
`1 inhibitor of?
`A. I am very happy to answer your question,
`2
`3 but I need a little bit more precision in your
`4 question.
`Q. Okay. Well, is it true that a person of
`5
`6 ordinary skill in the art knew that ketoconazole
`7 was a nonspecific inhibitor of
`8 17 alpha -hydroxylase?
`A. I would assume that a person that used
`9
`10 ketoconazole would know that, yes.
`Q. And among other things, a person of
`11
`12 ordinary skill would also have known that
`13 ketoconazole was known to inhibit the conversion
`14 of cholesterol to pregnenolone; is that correct?
`15
`MR. BEEL: Objection to form.
`A. A person may or may not have known that.
`16
`17 BY MR. KRAUSE:
`Q. And what is the basis for whether the
`18
`19 person may or may not have known that?
`20
`A. A person would know that ketoconazole
`21 when used as an anticancer agent inhibited the
`22 production of steroids. And I think
`23 17 alpha -hydroxylase and the 17,20- Iyase, to me,
`24 were the things that were probably best known.
`
`Page 23
`
`1 referring to?
`Q. Well, I am just asking in the general
`2
`3 sense, in your view.
`A. I can't -- I can't answer that question.
`4
`5 If you give me a specific steroid, I will say
`6 yes, it can, or it can't, or I don't know.
`Q. For example, cortisol had some weak
`7
`9 mineralocorticoid activity, and corticosterone,
`9 which is a weak mineralocorticoid, had some
`10 glucocorticoid activity?
`A. In general, I would agree with that, yes.
`11
`Q. So isn't it true that one could
`12
`13 compensate for the other to a certain degree?
`MR. BEEL: Objection to form.
`14
`A. I don't know.
`15
`16 BY MR. KRAUSE:
`Q. Your declaration discusses ketoconazole;
`17
`is that right?
`A. Yes, it does.
`Q. And a person of ordinary skill knew that
`20
`21 ketoconazole was a nonspecific inhibitor; is that
`22 right?
`A. An inhibitor of what?
`23
`Q. Well, can you tell me what it was an
`24
`
`18
`19
`
`11
`
`9
`10
`
`Page 25
`Q. Well, isn't it true that ketoconazole was
`1
`2 known to inhibit the biosynthesis of all
`3 steroids?
`MR. BEEL: Objection to form and
`4
`5 foundation.
`A. Of all?
`6
`7 BY MR. KRAUSE:
`Q. Steroids.
`8
`A. Of all steroids?
`Q. Yes, sir.
`A. Of all steroids? I don't know.
`A person skilled in the art who utilized
`12
`13 ketoconazole for fungal disease would be one set
`14 of experiences, and the person skilled in the art
`15 that used ketoconazole for the management of
`16 patients with prostate cancer would probably have
`17 another set of knowledge that would allow that
`18 person to use that drug.
`Q. So you are saying that there are
`19
`20 different persons of ordinary skill in the art
`21 that would have different sets of knowledge?
`22
`A. It depends on the indication that
`23 ketoconazole was being used in.
`Q. Well, I think the person of ordinary
`24
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`1
`
`5
`
`6
`7
`
`Marc B. Garnick, M.D.
`Page 26
`1 skill in the art that we are talking about here
`2 today is with respect to the patent in the
`3 lawsuit.
`A. Okay.
`4
`Q. And you have provided opinions with
`6 respect to the knowledge of that person; is that
`7 correct?
`A. That's correct, yes.
`Q. And just so I understand, are you
`9
`10 testifying that there could be people within your
`11 definition of a person of ordinary skill that
`12 would have different skill sets or different sets
`13 of knowledge?
`MR. BEEL: Objection to form.
`14
`A. I think a person skilled in the art that
`15
`16 used ketoconazole for the treatment of patients
`17 with prostate cancer would have the following
`18 knowledge: They would know that it inhibits
`19 steroid production; they would know that it
`20 inhibits sex steroid production.
`21
`And in so doing, a person skilled in the
`22 art that utilized ketoconazole would know that
`23 there was an obligation to replace
`24 glucocorticoids when ketoconazole is used for the
`
`Page 28
`
`Page 29
`
`A. Yes.
`Q. Would a person of ordinary skill in the
`2
`3 art have been familiar with O'Donnell?
`A. In what year?
`4
`Q. As of August 25, 2006.
`(Handing document to the witness.)
`A. Well, a person in 2006, since abiraterone
`was -- since this paper deals with abiraterone,
`9 would not have access to abiraterone. So a
`10 person skilled in the art in 2006 would probably
`11 not be familiar with the O'Donnell paper.
`Q. Let me ask you to turn to -- well, I have
`12
`13 handed you a document that bears the label
`14 Amerigen 1003, which is an exhibit.
`15
`A. Yes, okay.
`Q. And this is O'Donnell; correct?
`MR. BEEL: Objection to form.
`17
`Did you say Amerigen 1003?
`18
`19 BY MR. KRAUSE:
`Q. Sorry. I meant Mylan 1003. I apologize.
`20
`This exhibit is marked Mylan 1003;
`21
`22 correct?
`23
`A. Yes.
`Q. And this is the O'Donnell reference?
`
`16
`
`24
`
`Page 27
`1 treatment of patients with prostate cancer. That
`is what a person skilled in the art would know.
`2
`3 BY MR. KRAUSE:
`Q. Well, a person of ordinary skill in the
`4
`5 art as you have defined it would be familiar with
`the references that you referred to in your
`6
`7 declaration; is that correct?
`A. A person skilled in the art would know of
`8
`9 publications that identified the utility of
`10 ketoconazole.
`Q. I am not sure what you are trying to
`11
`12 parse. My question was: A person with ordinary
`13 skill in the art as you have defined it would be
`14 familiar with the references that you cited in
`is your declaration; is that correct?
`MR. BEEL: Objection to form.
`16
`A. I think a person skilled in the art,
`17
`18 i.e., a practicing physician who treated patients
`19 with ketoconazole, would know some but not
`20 necessarily all of the references in my
`21 declaration.
`22 BY MR. KRAUSE:
`Q. One of the key references in your
`23
`24 declaration was O'Donnell; is that correct?
`
`1
`
`4
`s
`
`A. Yes, it is.
`Q. And this is one of the key references in
`2
`3 your declaration; correct?
`A. That's correct, yes.
`Q. Can I ask you to tum to page 2318? Look
`in the left column, the first full paragraph,
`6
`7 second line. There is a statement, "Ketoconazole
`is relatively unselective, inhibiting both
`8
`9 cholesterol side chain cleavage and
`10 11 -beta- hydroxylation. ".
`Do you see that?
`11
`A. Yes, I do.
`Q. Would that statement be consistent with
`13
`14 how a person of ordinary skill in the art would
`15 view ketoconazole's activity?
`MR. BEEL: Objection to form.
`16
`17
`A. I don't know.
`18 BY MR. KRAUSE:
`Q. Do you believe that this statement in
`19
`20 O'Donnell would inform a person of ordinary skill
`21 in the art's knowledge about the activity of
`22 ketoconazole?
`A. In 2006 or when?
`23
`Q. In 2006.
`
`12
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`24
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`Marc B. Garnick, M.D.
`Page 30
`A. I believe a person skilled in the art in
`1
`2 2006 would probably not have access -- would
`3 not -- a person skilled in the art who is
`4 utilizing ketoconazole for the management of
`5 patients with prostate cancer would probably not
`6 be aware of this paper.
`Q. Would a person of ordinary skill in the
`7
`a art in 2006 have any reason to doubt that
`9 ketoconazole inhibited cholesterol side chain
`10 cleavage?
`A. No, there would be no reason why they
`11
`12 would think that.
`Q. And cholesterol side chain cleavage, as I
`13
`14 believe we discussed earlier, is the cleavage
`15 that occurs on the side chain from cholesterol
`16 that produces pregnenolone; is that correct?
`A. Yes.
`17
`(Handing document to the witness.)
`Q. And I handed you another document. This
`19
`20 one is marked Mylan Exhibit 1004. Do you
`21 recognize this document?
`(Witness viewing document.)
`22
`A. Yes, I do.
`Q. And is this the Gerber reference that you
`
`18
`
`23
`
`24
`
`Page 32
`Q. Well, I am asking you how a person of
`1
`2 ordinary skill in the art would view that
`3 statement.
`A. A person of ordinary skill in the art
`4
`5 would say, okay, ketoconazole for the use in
`6 patients with prostate cancer inhibits gonadal,
`7 which would be testosterone as a steroid, and
`8 adrenal steroid synthesis. That could be
`9 mineralocorticoids; it could be glucocorticoids;
`10 it could be a variety of other things. Your term
`11 was "all."
`Q. Is it fair to say that this could be
`12
`13 referring to the fact that it blocks any or all
`14 of the steroids?
`1s
`MR. BEEL: Objection to form and
`16 foundation.
`A. Any or all? No, okay. As opposed to
`17
`18 all. So that is what a person skilled in the
`19 art -- a person that would understand who is
`20 using ketoconazole.
`21 BY MR. KRAUSE:
`Q. And would a person of ordinary skill in
`22
`23 the art as of August 25, 2006, be aware of this
`24 reference?
`
`Page 31
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`1 talk about in your declaration?
`A. Yes, it is.
`2
`Q. If I could ask you to look in the first
`3
`4 paragraph under the abstract on the left column.
`And the first couple of sentences there, it
`5
`indicates that ketoconazole is a potent inhibitor
`of gonadal and adrenocortical steroid synthesis;
`is that correct?
`A. Yes.
`Q. So a person of ordinary skill in the art
`would understand from that statement that
`ketoconazole blocks the synthesis of all
`steroids; correct?
`MR. BEEL: Objection to form.
`A. No. What the article says is the drug is
`a potent inhibitor of gonadal and adrenocortical
`steroid synthesis. It doesn't say all steroids.
`That is what a person skilled in -- of ordinary
`skill in the art would know, would understand.
`19
`20 Exactly.
`21 BY MR. KRAUSE:
`Q. But that statement doesn't exclude any
`22
`23 types of steroids, does it?
`A. I have no idea.
`24
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`3
`
`Page 33
`A. I would assume, yes. I would assume so,
`1
`2 absolutely.
`(Handing document to the witness.)
`Q. I have handed you another document,
`4
`5 Exhibit 1020. Do you recognize this document?
`A. Yes, I do.
`6
`7 . Q. This is the Harris reference?
`A. Yes, it is.
`e
`Q. And this reference is referred to in your
`9
`10 declaration; is that correct?
`11
`A. Correct.
`Q. Would a person of ordinary skill in the
`12
`13 art be familiar with this reference?
`14
`A. Yes.
`Q. If I could ask you to look at page 544
`15
`16 and the right -hand column, the first full
`17 paragraph. There the paper says, "Ketoconazole
`18
`is a substituted imidazole that suppresses
`19 testicular and adrenal steroidogenesis by
`20 inhibition of the conversion of cholesterol to
`21 pregnenolone. Because ketoconazole is a potent
`22 inhibitor of all adrenal steroid synthetic
`23 pathways, replacement doses of hydrocortisone may
`24 be required."
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`1
`
`2
`
`Do you see that?
`A. Yes.
`Q. So would a person of ordinary skill in
`3
`4 the art understand from this statement that
`5 ketoconazole blocks the production of all adrenal
`6 steroid synthetic pathways?
`A. Yes.
`7
`Q. Would a person of ordinary skill in the
`s
`9 art have any reason to believe that this is not a
`10 true statement?
`11
`A. No.
`MR. BEEL: Objection to form on the last
`
`12
`
`13
`
`tWO.
`
`MR. KRAUSE: I will wait to let you go
`
`14
`15 first.
`16 BY MR. KRAUSE:
`Q. So would a person of ordinary skill
`17
`18 understand ketoconazole to block the biosynthesis
`19 of mineralocorticoids, glucocorticoids, and
`20 androgens?
`MR. BEEL: Objection to form and
`21
`22 foundation.
`A. A person skilled in the art who utilized
`23
`24 ketoconazole would know that ketoconazole
`
`Marc B. Garnick, M.D.
`Page 34
`
`3
`
`Page 36
`1 ketoconazole inhibited steroid production,
`2 including sex steroids and glucocorticoids, and,
`in so doing, needed to replace the glucocorticoid
`4 with another glucocorticoid. That is what a
`5 person skilled in the art would know.
`6 BY MR. KRAUSE:
`Q. Is it your testimony, Doctor, that a
`?
`a person of ordinary skill in the art would be
`9 ignorant of the fact that ketoconazole blocks
`10 this biosynthesis of mineralocorticoids?
`MR. BEEL: Objection to form.
`11
`A. Repeat the question, please.
`12
`(The pending question was then read
`13
`14 back.)
`A. No. I think a person would have a
`15
`16 general understanding of that.
`17 BY MR. KRAUSE:
`Q. And if a person of ordinary skill in the
`18
`19 art knew that ketoconazole blocked the
`20 biosynthesis of mineralocorticoids, they would
`21 understand that ketoconazole treatment does not
`22 lead to mineralocorticoid excess; is that
`23 correct?
`MR. BEEL: Objection to form and
`24
`
`Page 35
`
`Page 37
`
`1 decreases levels of testosterone and, in so
`2 doing, decreases levels of cortisol or inhibits
`3 some of the production of cortisol. And, in so
`4 doing, to achieve the desired pharmacological
`5 effect of decreasing testosterone, a person
`6 skilled in the art would know that replacement
`7 doses of glucocorticoid would have to be done.
`8 That is what a person skilled in the art who
`9 utilized ketoconazole would have to know or would
`10 know.
`11 BY MR. KRAUSE:
`Q. But a person of ordinary skill in the art
`12
`13 familiar with the Harris reference which we just
`14 looked at, which states that ketoconazole blocks
`15 all a