US Patent and Trademark Office
`Teva v. Corcept Therapeutics
`
`Page 1
`UNITED STATES PATENT AND TRADEMARK OFFICE
` ----------------------
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
` ----------------------
`
`FINAL - February 14, 2020
`Dr. David Greenblatt
`
`Page 3
`
`APPEARANCES:
`On behalf of the Petitioner:
` DEBORAH A. STERLING, Ph.D., ESQ.
` WILLIAM H. MILLIKEN, ESQ.
` Sterne, Kessler, Goldstein & Fox, P.L.L.C.
` 1100 New York Avenue, NW, Suite 600
` Washington, D.C. 20005-3934
` PHONE: (202) 772-8501 (Ms. Sterling)
` (202) 772-8854 (Mr. Milliken)
` FAX: (202) 371-2540
` EMAIL: dsterling@sternekessler.com
` wmilliken@skgf.com
`
`On behalf of the Patent Owner:
` ERIC STOPS, ESQ.
` DANIEL C. WIESNER, ESQ.
` Quinn Emanuel Urquhart & Sullivan, LLP
` 51 Madison Avenue, 22nd Floor
` New York, New York 10010
` PHONE: (212) 849-7561
` FAX: (212) 849-7100
` EMAIL: ericstops@quinnemanuel.com
` danielwiesner@quinnemanuel.com
`
`--------------------------------X
`TEVA PHARMACEUTICALS USA, INC., :
` :
` Petitioner, :
` :
`v. :
` :
`CORCEPT THERAPEUTICS, INC., :
` :
` Patent Owner. :
` :
`Case No. PCR2019-00048 :
`--------------------------------X
`
`VIDEO DEPOSITION OF
`Dr. David Greenblatt
`February 14, 2020
`Washington, D.C.
`Lead: Eric Stops, Esquire
`Firm: Quinn Emanuel Urquhart & Sullivan, LLP
`
`FINAL COPY
`JANE ROSE REPORTING 1-800-825-3341
`
` VIDEO DEPOSITION OF
` DAVID J. GREENBLATT, M.D.
`
`the witness, was called for examination by counsel
`for the Patent Owner, pursuant to notice, on
`Friday, February 14, 2020, commencing at
`9:03 a.m., at the law offices of Sterne, Kessler,
`Goldstein & Fox, P.L.L.C., 1100 New York Avenue,
`NW, Suite 600, Washington, D.C., before Dawn A.
`Jaques, CSR, CLR, and Notary Public in and for the
`District of Columbia.
`
`Page 2
`
`Page 4
`
` JANE ROSE REPORTING
` 74 Fifth Avenue
` New York, New York 10011
` PHONE: 1-800-825-3341
` EMAIL: janerose@janerosereporting.com
` WEB: www.janerosereporting.com
` Dawn Jaques, Court Reporter
` Nhat Pham, Videographer
`
`JANE ROSE REPORTING
`1-800-825-3341
`
`National Court-Reporting Coverage
`janerose@janerosereporting.com
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2059, Page 1
`
`

`

`US Patent and Trademark Office
`Teva v. Corcept Therapeutics
`
`FINAL - February 14, 2020
`Dr. David Greenblatt
`
`Page 5
`
`Page 7
`
` I-N-D-E-X
`
`WITNESS: PAGE:
`DAVID J. GREENBLATT, M.D.
`
`Examination by Mr. Stops .......... Page 6
`
`Reporter Certification................Page 239
`
`Notice to Read and Sign...............Page 237
`
`Index of Exhibits.....................Page 233
`
` P R O C E E D I N G S
`
`Page 6
`
` (The witness was administered the oath.)
`1
`2 Whereupon,
`3
` DAVID J. GREENBLATT, M.D.,
`4
` was called as a witness, after having been
`5
` first duly sworn by the Notary Public,
`6
` was examined and testified as follows:
`7
` EXAMINATION BY COUNSEL FOR THE PATENT OWNER
`8
` BY MR. STOPS:
`9
` Q Good morning, Dr. Greenblatt.
`10
` A Good morning.
`11
` Q Just a few instructions before we get
`12
`into it. We need your answers orally because the
`13
`court reporter cannot record nods of the head.
`14
` Do you understand?
`15
` A I do.
`16
` Q And if you don't answer a question, I
`17
`need you to ask me for a clarification before you
`18
`answer. If you do answer, that means you
`19
`understood the question. Do you agree?
`20
` A Yes, I agree.
`21
` Q You've been deposed before, correct?
`22
` A Yes.
`23
` Q How many times?
`24
` A I don't have an exact number, but I
`25
`estimate on average either a court or a deposition
`
`Page 8
`appearance, on average, one to two times a year
`1
`for the last 45 years.
`2
` Q Okay. And you've put in expert
`3
`reports or expert declarations in the past,
`4
`correct?
`5
` A Yes.
`6
` Q You submitted one declaration in this
`7
`8 matter, correct?
`9
` A Correct.
`10
` Q Have you prepared any documents for
`11
`this action beyond that declaration?
`12
` MS. STERLING: I'm going to object to
`13
`the extent that that gets to privileged
`14
`information.
`15
` You may answer yes or no, but not
`16
`discuss any substance of any of the conversations
`17
`you've had or any of the actions you've taken with
`18
`your counsel.
`19
` THE WITNESS: No.
`20
` BY MR. STOPS:
`21
` Q Who retained you for this case?
`22
` A The Sterne Kessler firm.
`23
` Q Have you worked with Teva before?
`24
` A Yes.
`25
` Q How many times?
`National Court-Reporting Coverage
`janerose@janerosereporting.com
`
`1
`
`23
`
` THE VIDEOGRAPHER: We are now on the
`record. Here begins the video deposition of David
`4
`J. Greenblatt, M.D., taken in the matter of
`5
`Teva Pharmaceuticals USA, Inc., v. Corcept
`6
`Therapeutics, Inc. Today's date is February 14,
`7
`2020. The time is 9:03.
`8
` This deposition is being held at
`9
`1100 New York Avenue, Northwest, in
`10
`11 Washington, D.C. Our court reporter is
`12
`Dawn Jaques. My name is Nat Pham, both on behalf
`13
`of Jane Rose Reporting.
`14
` Will counsel please state your
`15
`appearance for the record?
`16
` MR. STOPS: Eric Stops and Daniel
`17 Wiesner from Quinn Emanuel for Patent Owner,
`18
`Corcept.
`19
` MS. STERLING: Deborah Sterling and
`20 Will Milliken from Sterne, Kessler,
`21
`Goldstein & Fox for Teva Pharmaceuticals USA, Inc.
`22
` THE VIDEOGRAPHER: Will the court
`23
`reporter please swear in the witness?
`24
` THE REPORTER: Raise your right hand,
`25
`sir.
`JANE ROSE REPORTING
`1-800-825-3341
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2059, Page 2
`
`

`

`US Patent and Trademark Office
`Teva v. Corcept Therapeutics
`
`FINAL - February 14, 2020
`Dr. David Greenblatt
`
`Page 9
`
` A I don't have a number on it, but over
`1
`the last decade, I served as a scientific
`2
`consultant.
`3
` Q And have you worked with the
`4
`Sterne Kessler law firm before?
`5
` A Yes.
`6
` Q How many times?
`7
` A That I don't know. I'd have to --
`8
` Q Okay.
`9
` A Without looking at the records, but
`10
`sure, yeah.
`11
` Q What was the context? Was it a
`12
`deposition like this?
`13
` A You know, apparently I can't trust my
`14
`15 memory on that, so ...
`16
` Q Understood. Just so we keep the
`17
`record clear, if I use the abbreviation PK for
`18
`pharmacokinetics and PD for pharmacodynamics,
`19
`you'll know what I mean, right?
`20
` A Yes.
`21
` Q And I've heard pharmacokinetics
`22
`defined roughly as what a -- what your body does
`23
`to a drug, and pharmacodynamics as what a drug
`24
`does to your body.
`25
` Are those simplified definitions in
`
`Page 11
` Q So a specific CYP3A subfamily member,
`1
`such as CYP3A4, would be an isoform; is that
`2
`right?
`3
` A Yes.
`4
` Q And the metabolism by the liver before
`5
`a substrate reaches the rest of the body is
`6
`referred to as first-pass metabolism, correct?
`7
` A That is one of the terms that's used.
`8
`This -- and this refers to oral dosage.
`9
` Q Understood, because -- and it refers
`10
`to oral dosage because IV dosing will bypass --
`11
`bypass first-pass metabolism, correct?
`12
` MS. STERLING: Objection, foundation.
`13
` THE WITNESS: The second statement is
`14
`correct, yes.
`15
` BY MR. STOPS:
`16
` Q Oh, the second statement being IV
`17
`dosing will bypass first-pass metabolism?
`18
` A Correct.
`19
` MS. STERLING: Same objection.
`20
` BY MR. STOPS:
`21
` Q Thank you. I'm sorry.
`22
` Is it -- is it proper to refer to the
`23
`24 metabolism in the intestines and the first-pass
`25
`liver metabolism collectively as presystemic
`
`Page 10
`
`Page 12
`
`accordance with your understanding?
`1
` A Those are simplified definitions. I
`2
`would point to the declaration for more detailed
`3
`discussion.
`4
` Q Okay. Enzymes in the cytochrome P4503A
`5
`family are often referred to as just CYP3A, right?
`6
` A That is often the case, yes.
`7
` Q And if I call that CYP3A, you'll know
`8
`what I mean, right?
`9
` A Yes, I will.
`10
` Q And a CYP3A is also written as
`11
`P450-3A, correct?
`12
` A That's correct.
`13
` Q Okay. And there is a CYP3A enzyme in
`14
`the intestines, correct?
`15
` A That is correct.
`16
` Q There's also a CYP3A enzyme in the
`17
`liver, correct?
`18
` A Correct.
`19
` Q How would you define a CYP3A isoform?
`20
` MS. STERLING: Objection, form.
`21
` THE WITNESS: It is one of the
`22
`specific proteins or enzymes in the cytochrome
`23
`P4503A subfamily.
`24
`25
` BY MR. STOPS:
`JANE ROSE REPORTING
`1-800-825-3341
`
`1 metabolism?
`2
` MS. STERLING: Objection.
`3
` BY MR. STOPS:
`4
` Q Can I -- I'll rephrase that.
`5
` Is it proper to collectively refer to
`6 metabolism in the intestines and the first-pass
`7
`liver metabolism as presystemic extraction?
`8
` A That -- that is partly -- partly
`9
`correct.
`10
` Q Okay. What was incorrect?
`11
` A Well, the -- when a drug is given
`12
`orally and incompletely reaches the systemic
`13
`circulation, we collectively call that presystemic
`14
`extraction or the first-pass effect. It can be
`15
`due to metabolism, or there can be other things
`16
`causing it.
`17
` Q Other things such as transporters?
`18
` A That's one of --
`19
` MS. STERLING: Objection, foundation.
`20
` THE WITNESS: Yes, that is one of the
`21
`other things.
`22
` BY MR. STOPS:
`23
` Q Okay. And just so I'm clear on
`24
`terminology, I had always thought first-pass
`25 metabolism referred to just the liver.
`National Court-Reporting Coverage
`janerose@janerosereporting.com
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2059, Page 3
`
`

`

`US Patent and Trademark Office
`Teva v. Corcept Therapeutics
`
`FINAL - February 14, 2020
`Dr. David Greenblatt
`
`Page 13
`
`Page 15
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
` Does first-pass metabolism also
`encompass the metabolism in the intestines?
` A When it's used in that context, yes.
`It's a -- it's a combination of enteric and liver.
` Q Would you agree that the most
`important mechanism of presystemic extraction is
`the first-pass hepatic metabolism?
` MS. STERLING: Objection to form,
`scope.
` THE WITNESS: No.
` BY MR. STOPS:
` Q Why do you disagree?
` A It could be enteric metabolism, it
`could be hepatic metabolism, a combination of the
`two, or other factors preventing reaching of the
`systemic circulation.
` Q So it depends on the context; is that
`correct?
` MS. STERLING: Objection, form, scope.
` THE WITNESS: Well, many factors
`determine the contributions or the determinants of
`first-pass metabolism or presystemic extraction.
` BY MR. STOPS:
` Q So sometimes the intestinal metabolism
`would be most important, sometimes the hepatic
`Page 14
`1 metabolism is the most important, sometimes it
`2
`will be something else; is that right?
`3
` MS. STERLING: Objection, form.
`4
` THE WITNESS: Partially correct, but
`5
`the point is that presystemic extraction or
`6
`first-pass metabolism can be either hepatic or
`7
`enteric biotransformation metabolism, it could be
`8
`transport, and maybe other factors as well.
`9
` BY MR. STOPS:
`10
` Q Okay. And in all of the first-pass
`11 metabolism or the presystemic extraction, the
`12
`common result is that some portion of the drug is
`13
`biotransformed before reaching systemic
`14
`circulation, correct?
`15
` MS. STERLING: Objection, foundation,
`16
`form.
`17
` THE WITNESS: When there is first-pass
`18 metabolism or presystemic extraction, some
`19
`fraction fails to reach the circulation after oral
`20
`dosage.
`21
` BY MR. STOPS:
`22
` Q A POSA would have known prior to the
`23
`critical date that for CYP3A substrates that
`24
`ordinarily undergo high systemic -- sorry, high
`25
`presystemic extraction after oral dosage, CYP3A
`JANE ROSE REPORTING
`1-800-825-3341
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
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`13
`14
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`25
`
`1
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`
`inhibition may profoundly increase oral
`bioavailability through the impaired presystemic
`extraction, resulting in large substrate plasma
`concentrations, correct?
` MS. STERLING: Objection, form,
`foundation.
` THE WITNESS: A POSA would have known
`that after oral dosage of a CYP3A substrate, that
`inhibition of CYP3A could lead to increased
`systemic exposure in amounts ranging from small to
`very large.
` BY MR. STOPS:
` Q And a POSA would have known that such
`interactions may be clinically hazardous, correct?
` MS. STERLING: Objection, form,
`foundation.
` THE WITNESS: A POSA would have known
`that such interactions could be clinically
`beneficial, could be of no effect at all, or could
`be hazardous. All three are possible.
` BY MR. STOPS:
` Q In drug interactions, the drug causing
`the interaction can be referred to as the
`perpetrator, correct?
` A It has been referred to as that, yes.
`
`Page 16
` Q And the drug being interacted with can
`be referred to as the victim or the substrate,
`correct?
` A That is correct.
` Q And the perpetrator can be, for
`example, an inhibitor of the victim's metabolism,
`correct?
` A That is one possibility among many.
` Q One of the references you refer to in
`your declaration is the -- is a 2006 draft FDA
`guidance, correct?
` A I believe you're correct, that that's
`among the documents.
` Q And it's your opinion that POSAs will
`follow FDA guidances, correct?
` A My opinion is that a POSA could
`consider FDA guidance. Whether they follow it, I
`can't say.
` Q Why can't you say?
` A Because I don't know if they would
`follow it. Depends on what the objective is and
`what the clinical or scientific problem is.
` Q In your opinions for this matter, is
`it your opinion that POSAs would follow the 2006
`draft FDA guidance?
`National Court-Reporting Coverage
`janerose@janerosereporting.com
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2059, Page 4
`
`

`

`US Patent and Trademark Office
`Teva v. Corcept Therapeutics
`
`FINAL - February 14, 2020
`Dr. David Greenblatt
`
`Page 17
`
`Page 19
`
` MS. STERLING: Objection, form.
`1
` THE WITNESS: I think I just answered
`2
`that.
`3
` BY MR. STOPS:
`4
` Q I was making sure you weren't
`5
`answering the question in the abstract versus a
`6
`different opinion for this case in particular.
`7
` A Okay. Well, my answer would then be
`8
`the same. I think if -- if -- depending on the
`9
`specific problem in question, they might consider
`10
`the guidance; and whether they would follow it, I
`11
`don't know.
`12
` Q You'd agree that the impact of a
`13
`drug-drug interaction on the clearance of a victim
`14
`drug is greatest when that drug is extensively
`15
`16 metabolized and a single CYP isoform mediates
`17
`clearance, correct?
`18
` MS. STERLING: Objection, form --
`19
` THE WITNESS: I can't --
`20
` MS. STERLING: -- foundation.
`21
` THE WITNESS: I'm sorry.
`22
` I can't agree with that. That's just
`23
`not enough information.
`24
` MR. STOPS: Okay. So I'm going to
`25
`continue the numbering from the last exhibit in
`Page 18
`
`the 2000 range that we put in. I think that's
`1
`consistent with normal practice. So this is going
`2
`to be --
`3
` MS. STERLING: It is.
`4
` MR. STOPS: Thank you. I think I'm
`5
`going -- I'm going to mark this exhibit as 2049,
`6
`please.
`7
` (Exhibit 2049 was marked
`8
` for identification.)
`9
` BY MR. STOPS:
`10
` Q Doctor, I'm handing you an exhibit
`11
`that is marked as 2049.
`12
` MS. STERLING: I'm going to object to
`13
`the exhibit for authentication, scope, hearsay,
`14
`relevance, and there may be others depending on
`15
`where the questioning goes.
`16
` BY MR. STOPS:
`17
` Q Sure. Dr. Greenblatt, have you seen
`18
`this Exhibit 2049 before?
`19
` A I have seen it, not in the context of
`20
`the exhibit, but the internal part is a chapter
`21
`written by me a number of years ago.
`22
` Q Sure. So after the first page, which
`23
`is the cover of a -- cover of a book, the
`24
`25
`Chapter 24, which begins on page 625 of the
`JANE ROSE REPORTING
`1-800-825-3341
`
`exhibit, is a book chapter that you wrote,
`1
`correct?
`2
` A That's correct. I see that.
`3
` Q Okay. And you recognize the book
`4
`chapter?
`5
` A I do, yes.
`6
` Q And the book chapter is entitled
`7
`"Clinical Studies of Drug-Drug Interactions:
`8
`Design and Interpretation," correct?
`9
` A That is correct.
`10
` Q If you would turn to page 634 of
`11
`Exhibit 2049, let me know when you're there,
`12
`please.
`13
` A Yes, I see it. I'm there.
`14
` Q In the second full paragraph -- I'll
`15
`direct you to the second full paragraph on the
`16
`page. Do you see the first sentence, "The impact
`17
`of a DDI on the clearance of a victim drug is
`18
`greatest when that drug is extensively
`19
`20 metabolized, and a single CYP isoform mediates
`21
`clearance"?
`22
` A Yes, I see those words.
`23
` Q And you wrote those words, correct?
`24
` A That's correct. Also many other
`25
`things in the -- in the chapter.
`
`1
`2
`3
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`
`Page 20
`
` Q In that same paragraph, the last
`sentence states, "Concern is augmented when the
`substrate victim has high clearance, and undergoes
`significant presystemic extraction after oral
`dosage." Do you see that?
` A I see those words, yes.
` Q And do you agree with those words?
` A Well, I agree with the whole chapter,
`and I agree with the words in the context of the
`whole chapter, but not out of context. It's not
`relevant.
` MS. STERLING: Excuse me. Sorry,
`Eric, I don't mean to interrupt your line. Our
`realtime has stopped.
` MR. MILLIKEN: Mine stopped also.
` THE VIDEOGRAPHER: Off the record,
`9:23.
` (Pause in the proceedings.)
` THE VIDEOGRAPHER: Back on the record
`at 9:24.
` BY MR. STOPS:
` Q Mifepristone is metabolized entirely,
`or almost entirely, by CYP3A, correct?
` MS. STERLING: Objection, foundation.
` THE WITNESS: My understanding is that
`National Court-Reporting Coverage
`janerose@janerosereporting.com
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2059, Page 5
`
`

`

`US Patent and Trademark Office
`Teva v. Corcept Therapeutics
`
`FINAL - February 14, 2020
`Dr. David Greenblatt
`
`Page 21
`
`the majority of clearance is accounted for by
`1
`action of CYP3A.
`2
` BY MR. STOPS:
`3
` Q Are you aware of any other CYP enzyme
`4
`5 metabolizing mifepristone?
`6
` A At this point, I'm not sure that that
`7
`can be said because I think the topic has not been
`8
`studied since 1996, so can't be certain about
`9
`that.
`10
` Q Okay. But you haven't seen any --
`11
`anything that would indicate that there's another
`12
`cytochrome P450 enzyme involving mifepristone
`13 metabolism, correct?
`14
` A Partly true, but I have also not seen
`15
`anything that would exclude it. I have not seen
`16
`the question addressed since 1996.
`17
` Q And so as of the last time the
`18
`question was addressed, you're not aware of
`19
`anything that would indicate that there is another
`20
`cytochrome P450 enzyme involved in the metabolism
`21
`of mifepristone, correct?
`22
` A Well, as I said, the last data that I
`23
`know of is dated 1996, and I -- I don't know
`24
`whether we can confirm or exclude the possible
`25
`participation in other -- of other CYPs at this
`
`Page 22
`
`point.
`1
` Q Is it your opinion that every CYP
`2
`enzyme would need to be individually tested to
`3
`exclude it from having a contribution to
`4
`5 mifepristone's metabolism?
`6
` MS. STERLING: Objection, form.
`7
` THE WITNESS: I have trouble
`8
`interpreting your question.
`9
` BY MR. STOPS:
`10
` Q So right now we're in a world where
`11
`there is no evidence that any other CYP enzyme is
`12
`involved in mifepristone's metabolism, but you're
`13
`saying we can't exclude the possibility, correct?
`14
` A I believe that you've at least partly
`15
`characterized my answer.
`16
` Q So my question is that in order to
`17
`exclude the possibility that another CYP enzyme is
`18
`involved in mifepristone's metabolism, we would
`19
`have to individually test each enzyme; is that
`20
`right?
`21
` MS. STERLING: Objection, form.
`22
` THE WITNESS: It doesn't quite work
`23
`that way. There are ways of addressing the
`24
`question that are not in vitro that are not that
`25
`complicated. You don't have to test each enzyme.
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`Page 23
`You can look at overall metabolism and look at the
`1
`extent of inhibition by other so-called
`2
`perpetrators.
`3
` BY MR. STOPS:
`4
` Q And in terms of metabolism, the known
`5
`6 metabolites of mifepristone are the result of
`7
`CYP3A metabolism, correct?
`8
` MS. STERLING: Objection, foundation.
`9
` THE WITNESS: My understanding is that
`10 metabolic products are largely explained by the
`11
`action of CYP3A.
`12
` BY MR. STOPS:
`13
` Q And that would be another data point
`14
`confirming that the enzyme responsible for
`15 mifepristone metabolism is CYP3A, correct?
`16
` MS. STERLING: Objection, form.
`17
` THE WITNESS: I think the second
`18
`question is not necessary. The first answer
`19
`already encompasses that.
`20
` BY MR. STOPS:
`21
` Q What first answer were you referring
`22
`to?
`23
` A Well, I believe my answer was that the
`24
`formation of the metabolites is largely explained
`25
`by the action of CYP3A.
`
`Page 24
` Q Okay. As of the 2017 critical date, a
`1
`POSA would consider mifepristone to be a
`2
`relatively pure substrate for CYP3A, correct?
`3
` MS. STERLING: Objection, form,
`4
`foundation.
`5
` THE WITNESS: I don't think that's
`6
`correct. I -- the -- the application of "pure" I
`7
`think is not necessarily correct, and I believe
`8
`that I've already answered that.
`9
` BY MR. STOPS:
`10
` Q So with no evidence to the contrary, a
`11
`person of skill in the art would not consider
`12
`13 mifepristone to be a pure CYP3A substrate?
`14
` MS. STERLING: Objection, form.
`15
` THE WITNESS: No, I didn't say that.
`16
` BY MR. STOPS:
`17
` Q You agree there's -- there is no
`18
`evidence showing that mifepristone is not a pure
`19
`CYP3A substrate, correct?
`20
` MS. STERLING: Objection.
`21
` THE WITNESS: Well, again, I don't
`22
`know how to interpret "pure."
`23
` BY MR. STOPS:
`24
` Q Okay.
`25
` A The data from 1996 shows that CYP3A is
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2059, Page 6
`
`

`

`US Patent and Trademark Office
`Teva v. Corcept Therapeutics
`
`FINAL - February 14, 2020
`Dr. David Greenblatt
`
`Page 25
`
`Page 27
`
`a major participant in the metabolism of
`1
`2 mifepristone, and I think data available then and
`3
`to the present does not either confirm or exclude
`4
`the possible participation of other CYP3A -- CYP
`5
`enzymes.
`6
` Q The knowledge that CYP3A is a major
`7
`participant in the metabolism of mifepristone
`8
`would have suggested to a POSA that the likelihood
`9
`of drug-drug interactions subsequent to long-term
`10
`administration of the compound would be -- would
`11
`exist, correct?
`12
` MS. STERLING: Objection, form.
`13
` THE WITNESS: I think my answer is
`14
`that a POSA would have known that because
`15 mifepristone is mainly metabolized by CYP3A, there
`16
`would be a possibility or probability of a drug
`17
`interaction, causing increased exposure to
`18 mifepristone, if a CYP3A inhibitor were
`19
`administered at the same time.
`20
` BY MR. STOPS:
`21
` Q I'm not sure I asked this already.
`22
` Mifepristone is subject to extensive
`23
`first-pass metabolism, correct?
`24
` MS. STERLING: Objection, foundation.
`25
` THE WITNESS: I do not believe that
`
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` A I do, yes.
` Q Do you see the second sentence states
`that mifepristone "undergoes first-pass effect in
`the liver and gets partially metabolized and
`eventually its bioavailability is reduced to 40%
`in human beings"?
` A I do see those words, yes.
` Q And that indicates that mifepristone
`is -- or that states mifepristone is subject to
`extensive first-pass metabolism, correct?
` MS. STERLING: Objection, form.
` THE WITNESS: Well, the sentence says
`"it undergoes first-pass effect in the liver and
`gets partially metabolized and eventually its
`bioavailability is reduced to 40% in human
`beings." Those are the words.
` BY MR. STOPS:
` Q Right. And you would agree that
`that's -- that is extensive first-pass metabolism,
`correct?
` A No. First of all, extensive, I'm
`not -- that's a qualitative term, so I don't know
`if that's applicable or not.
` And secondly, I don't know about the
`level of credibility of the data, nor how they
`
`Page 26
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`Page 28
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`that is known.
`1
` MR. STOPS: I'd like to mark the next
`2
`exhibit as 2050.
`3
` (Exhibit 2050 was marked
`4
` for identification.)
`5
` BY MR. STOPS:
`6
` Q I'm handing you a document that was
`7
`8 marked as 2050. This is --
`9
` MS. STERLING: I'm going to, sorry,
`10
`object to the document for relevance, scope,
`11
`authenticity, hearsay, and there may be more
`12
`depending on how the conversation goes.
`13
` BY MR. STOPS:
`14
` Q Exhibit 2050 is an article by author
`15
`last name Sarkar entitled "Mifepristone:
`16
`bioavailability, pharmacokinetics and
`17
`use-effectiveness," published in the European
`18
`Journal of Obstetrics & Gynecology and
`19
`Reproductive Biology in 2002, correct?
`20
` A Yes, I do see that.
`21
` Q Have you seen this publication before?
`22
` A I believe I have, yes.
`23
` Q On the bottom of the front page
`24
`there's a section entitled "Absorption, metabolism
`25
`and tissue update." Do you see that?
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`actually calculated bioavailability, so I would
`1
`have to see that information.
`2
` Q What do you understand the word
`3
`"extensive" to mean in this context?
`4
` A I -- I do not have an idea in mind.
`5
` Q So you don't know what it means to
`6
`undergo extensive first-pass metabolism?
`7
` MS. STERLING: Objection, form.
`8
` THE WITNESS: Again, I don't know the
`9
`10 meaning of "extensive" in a quantitative
`11
`scientific context.
`12
` BY MR. STOPS:
`13
` Q You understand the term "significant
`14
`first-pass metabolism"?
`15
` A I have the same response to that.
`16
`"Significant" can mean statistically significant,
`17
`or it could mean -- it could be a qualitative term
`18
`which is undefined.
`19
` Q So you wouldn't use vague terms like
`20
`that in your publications?
`21
` A I might, but I would have an idea of
`22
`what the supporting numbers would be.
`23
` Q Will you look at the previous exhibit,
`24
`2049? If you go back to page 634 of Exhibit 2049,
`25
`in the first sentence of the second full paragraph
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`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
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`Corcept Ex. 2059, Page 7
`
`

`

`US Patent and Trademark Office
`Teva v. Corcept Therapeutics
`
`Page 29
`
`where you said the drug is extensively
`1
`2 metabolized, what did you mean by it there?
`3
` A Excuse me, where are we?
`4
` Q The first sentence of the second full
`5
`paragraph. It starts with, "The impact of a DDI."
`6
` A Yes.
`7
` Q In that sentence you state the drug is
`8
`extensively metabolized.
`9
` A Yes, I see the --
`10
` Q What did you --
`11
` A I see the words.
`12
` Q What did you mean by "extensively"
`13
`there?
`14
` A It would depend on the specific
`15
`context of which drug and how much it's
`16 metabolized, et cetera.
`17
` Q Why didn't you use a quantitative
`18
`number rather than the term "extensively" in this
`19
`article?
`20
` MS. STERLING: Objection, relevance.
`21
` THE WITNESS: I do not know.
`22
` BY MR. STOPS:
`23
` Q You agree it would have been more
`24
`precise to use a quantitative number?
`25
` MS. STERLING: Same objection.
`
`Page 30
` THE WITNESS: That would depend on the
`1
`context. Which drug? Which inhibitor? What
`2
`route of administration?
`3
` BY MR. STOPS:
`4
` Q In the last sentence of that same
`5
`paragraph where you state, "Concern is augmented
`6
`when the substrate victim has high clearance, and
`7
`undergoes presystemic extraction after oral
`8
`dosage," you also don't know what you meant by the
`9
`word "significant"?
`10
` MS. STERLING: Objection, misstates
`11
`his testimony, relevance.
`12
` THE WITNESS: Yeah, I didn't say that,
`13
`and it all depends on the numbers, which drug,
`14
`which route of administration, which inhibitor,
`15
`et cetera.
`16
` BY MR. STOPS:
`17
` Q Neither of the sentences that we just
`18
`looked at on page 634 of Exhibit 2049 are specific
`19
`to a drug. These are general statements in your
`20
`chapter, correct?
`21
` A Yes, that's the whole point.
`22
` Q I'm sorry, when you say yes, that's
`23
`the whole point, what's the whole point?
`24
`25
` A The whole point is that you take those
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`FINAL - February 14, 2020
`Dr. David Greenblatt
`
`Page 31
`sentences which you've pulled out of context and
`put it in the context of the entire article.
` So the article is trying to teach
`principles, and then the application of the
`principles gets down to the specific drugs, the
`route of administration, the specific inhibitor,
`and items like that.
` Q In this -- in this paragraph of 2049,
`the sentences do not state any specific substrate
`or perpetrator, correct?
` A And again, I answered that, but that's
`the whole point of the paragraph. It's part of
`teaching, it's in the context of understanding
`principles, and then they're subsequently applied
`to individual cases.
` Q Okay. So these are -- these are
`general principles; is that correct?
` A In the context of the entire chapter.
`They have to be placed in context.
` Q And the context of the chapter is
`drug-drug interactions, correct?
` A The chapter is entitled "Clinical
`Studies of Drug-Drug Interactions: Design and
`Interpretation."
` Q Right. So these are intended to be
`
`Page 32
`
`general principles that are applicable to
`drug-drug interactions, correct?
` A Sir --
` MS. STERLING: Objection, form.
` THE WITNESS: I believe I've already
`answered that, sir.
` BY MR. STOPS:
` Q So your answer is that these are
`teaching principles, correct?
` MS. STERLING: Objection, misstates
`testimony.
` THE WITNESS: That also is taken out
`of context