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` IN THE UNITED STATES DISTRICT COURT FOR THE
` DISTRICT OF DELAWARE
`NOVARTIS PHARMACEUTICALS )
`CORPORATION and NOVARTIS AG, )
` )
` Plaintiffs, )
` )
` v. ) C.A. No. 14-1043-RGA
` )
`BRECKENRIDGE PHARMACEUTICAL, INC.,)
` )
` Defendant. )
`__________________________________)
`NOVARTIS PHARMACEUTICALS )
`CORPORATION and NOVARTIS AG, )
` )
` Plaintiffs, )
` )
` v. ) C.A. No. 14-1196-RGA
` )
`ROXANE LABORATORIES, INC., )
` )
` Defendant. )
`__________________________________)
`NOVARTIS PHARMACEUTICALS )
`CORPORATION and NOVARTIS AG, )
` )
` Plaintiffs, )
` )
` v. ) C.A. No. 14-1289-RGA
` )
`PAR PHARMACEUTICAL, INC., )
` )
` Defendant. )
` VIDEOTAPED DEPOSITION OF MARK J. RATAIN, M.D.
` Monday, April 11, 2016
` Chicago, Illinois
`Reporter by:
`Janice M. Kocek, CSR, CLR
`Job No. 105588
`
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`NOVARTIS EXHIBIT 2152
`Par v Novartis, IPR 2016-00084
`Page 1 of 23
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` IN THE UNITED STATES DISTRICT COURT FOR THE
` DISTRICT OF DELAWARE
`NOVARTIS PHARMACEUTICALS )
`CORPORATION and NOVARTIS AG, )
` )
` Plaintiffs, )
` )
` v. ) C.A. No. 14-1043-RGA
` )
`BRECKENRIDGE PHARMACEUTICAL, INC.,)
` )
` Defendant. )
`__________________________________)
`NOVARTIS PHARMACEUTICALS )
`CORPORATION and NOVARTIS AG, )
` )
` Plaintiffs, )
` )
` v. ) C.A. No. 14-1196-RGA
` )
`ROXANE LABORATORIES, INC., )
` )
` Defendant. )
`__________________________________)
`NOVARTIS PHARMACEUTICALS )
`CORPORATION and NOVARTIS AG, )
` )
` Plaintiffs, )
` )
` v. ) C.A. No. 14-1289-RGA
` )
`PAR PHARMACEUTICAL, INC., )
` )
` Defendant. )
` VIDEOTAPED DEPOSITION OF MARK J. RATAIN, M.D.
` Monday, April 11, 2016
` Chicago, Illinois
`Reporter by:
`Janice M. Kocek, CSR, CLR
`Job No. 105588
`
`TSG Reporting - Worldwide 877-702-9580
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` M. RATAIN, M.D.
` THE VIDEOGRAPHER: This is the start
`of DVD labeled Number 1 of the videotaped
`deposition of Mark J. Ratain, M.D., in the
`matter of Novartis Pharmaceuticals
`Corporation versus Breckenridge
`Pharmaceutical, Incorporated, Case Number
`14-1043-RGA; and Novartis Pharmaceuticals
`Corporation versus Roxane Laboratories,
`Incorporated, Case Number 14-1196-RGA;
`and Novartis Pharmaceuticals Corporation
`versus Par Pharmaceuticals, Incorporated,
`Case Number 14-1289-RGA in the United
`States District Court for the District of
`Delaware.
` This deposition is being held at
`Latham & Watkins, LLP, 330 North Wabash,
`Chicago, Illinois, on April 11, 2016, at
`approximately 9:35 a.m.
` My name is Renato Velarde. I'm the
`legal video specialist from TSG Reporting,
`Incorporated, headquartered at 747 Third
`Avenue, New York, New York. The court
`reporter is Janice Kocek in association
`with TSG Reporting.
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` M. RATAIN, M.D.
` Will counsel please introduce
` yourself?
` MS. JACOBSEN: Charlotte Jacobsen
` from Fitzpatrick on behalf of the
` plaintiffs; and with me is
` Susanne Flanders, also from Fitzpatrick.
` MS. DANEK: Brenda Danek from
` Latham & Watkins on behalf of Par.
` MS. BIRBACH: Naomi Birbach from
` Goodwin Procter on behalf of Roxane
` Laboratories.
` THE VIDEOGRAPHER: Will the court
` reporter please swear in the witness?
` (Witness sworn.)
`M A R K J. R A T A I N , M. D. ,
` called as a witness, having been duly
` sworn by a Notary Public, was examined
` and testified as follows:
`EXAMINATION BY
`MS. JACOBSEN:
` Q. Good morning.
` A. Good morning.
` Q. Can you state your full name for the
`record?
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` M. RATAIN, M.D.
` Q. Okay. Why did you never publish
`them?
` A. I couldn't get results that I felt
`were publishable quality. I also did some in
`vitro studies with hydroxyurea in combination
`with etoposide, which I did publish.
` Q. And what does it mean to be of
`publishable quality?
` A. Something that I really felt told a
`story.
` Q. Which story were you trying to tell?
` A. I was trying to understand why --
`you know, why there were differences between
`vincristine and vinblastine, because the two
`drugs were very similar, yet vincristine had
`more neurotoxicity than vinblastine and
`vinblastine had more myelosuppression than
`vincristine.
` And, and, you know, that was really
`something that I thought was important -- that,
`that was of interest to me to try and
`understand that.
` Q. Are there differences in the side
`effects of vincristine and vinblastine?
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`BY MS. JACOBSEN:
` Q. I'm asking you about -- well, let's
`take a step back. Strike that.
` So as I understood your testimony,
`you were saying that activity means evidence of
`some shrinkage in some patients, and that was a
`reference to humans; is that correct?
` A. Yes. You can talk about activity
`also in a different context, activity in, in
`models of cancer, but that's not the same as
`activity in cancer X. So, you know, they're
`different, different meanings of the word
`"activity."
` Q. Can you demonstrate activity in
`cancer X by running a test in models of cancer?
` A. That would demonstrate activity of,
`of the drug in a model of cancer X.
` Q. It would not demonstrate activity in
`cancer X?
` A. No.
` Q. Okay. Can we look at your expert
`report at paragraph 16. And there you state as
`one example, "I designed and led the Phase II
`randomized discontinuation trial of sorafenib,
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`everolimus has confirmed clinical efficacy in
`the treatment of postmenopausal woman with
`advanced hormone receptor-positive,
`HER2-negative breast cancer in combination with
`exemestane after failure of treatment with
`letrozole or anastrozole?
` A. I'm not disputing that.
` Q. And everolimus was the first mTOR
`inhibitor approved by the FDA for the
`everolimus breast cancer indication?
` A. Yes.
` Q. And everolimus is still today the
`only mTOR inhibitor approved by the FDA for the
`treatment of breast cancer?
` A. Yes.
` Q. And in your reply report, you don't
`dispute that as of October 1992 rapamycin was
`not approved by the FDA for the same breast
`cancer indication as everolimus?
` A. That's correct.
` Q. And as of today, rapamycin is still
`not approved by the FDA for the same breast
`cancer indications as everolimus?
` A. That's right.
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` Q. Do you disagree with me that you
`don't dispute Dr. Burris' description of the
`therapies available as of October 1992 for the
`treatment of advanced breast cancer?
` A. I agree.
` Q. You don't dispute that as of October
`1992 there was a long-felt, unmet need for a
`safe and effective therapy for advanced breast
`cancer?
` A. I agree.
` Q. And you don't dispute as of October
`1992 that resistance to hormonal therapy was a
`recognized problem in the treatment of advanced
`breast cancer?
` A. I agree.
` Q. And you don't dispute that -- that
`everolimus has been demonstrated in a Phase III
`clinical trial to overcome hormonal resistance
`in postmenopausal woman with advanced hormone
`receptor-positive, HER2-negative breast cancer?
` A. I agree.
` Q. You don't dispute that as of October
`1992 others had tried and failed to develop new
`treatments for advanced breast cancer?
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` A. Well, there have been many failures
`and successes for the treatment of breast
`cancer.
` Q. And in your reply report, you don't
`dispute Dr. Burris' opinions with respect to
`the failures of others to develop new
`treatments for advanced breast cancer?
` A. I don't dispute Dr. Burris'
`statements in that regard.
` Q. And you don't dispute that
`everolimus satisfied a long-felt, unmet need
`for a safe and effective therapy for advanced
`breast cancer?
` MS. DANEK: Objection. Form.
` THE WITNESS: I do dispute that.
`BY MS. JACOBSEN:
` Q. And where do you dispute that in
`your reply report?
` A. Paragraph 48.
` Q. And what is the basis on which you
`dispute that opinion?
` A. That rapamycin has -- rapamycin met
`that long-felt need first.
` Q. Is there a reason why you dedicated
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`failure of treatment with sunitinib or
`sorafenib, correct?
` A. Yes.
` Q. And if I refer to that as the
`everolimus RCC indication, will you understand
`what I mean?
` A. Yes.
` Q. And you don't dispute that
`everolimus has confirmed clinical efficacy in
`the treatment of advanced renal cell carcinoma
`after failure of treatment with sunitinib or
`sorafenib?
` A. I agree.
` Q. And the fact that the FDA approved
`everolimus for use after failure of treatment
`with sunitinib or sorafenib means that
`everolimus is approved for use in second or
`later lines of therapy?
` A. That's correct.
` Q. Everolimus is not approved as a
`first-line therapy in RCC?
` A. That's correct.
` Q. And in your reply report, you don't
`dispute that as of October 1992 rapamycin was
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`not approved by the FDA for the same RCC
`indication as everolimus?
` A. I agree.
` Q. And as of today, rapamycin is not
`approved by the FDA for the same RCC indication
`as everolimus?
` A. I agree.
` Q. And you don't dispute that as of
`October 1992 temsirolimus was not approved by
`the FDA for the same RCC indication as
`everolimus?
` A. I agree.
` Q. And as of today, temsirolimus is
`still not approved by the FDA for the same RCC
`indication as everolimus?
` A. I disagree.
` Q. What is the basis for you
`disagreeing?
` A. If you look at the label for, for
`Torisel, it's approved for advanced RCC
`regardless of prior therapy.
` Q. Is temsirolimus approved as a
`first-line therapy in RCC?
` A. It just says advanced RCC. It
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`publication in support of your opinion that
`rapamycin had been shown to have anticancer and
`antitumor activity in a range of cancer models
`as of October 1992, correct? Paragraph 33 of
`your reply report.
` A. Yes.
` Q. You actually cited this publication
`in support of your opinion that rapamycin had
`been shown to have anticancer and antitumor
`activity in a range of cancer models as of
`October 1992?
` A. Yes.
` Q. All right. So at least as of 1981,
`there were published reports that rapamycin had
`some in vivo antitumor activity; is that
`correct?
` A. I'm just having trouble sorting out
`whether these results in Table 21 are -- yeah,
`I guess this is in vivo because it's got the
`optimal dose. So yes.
` Q. Okay. So the, the NCI tested the
`activity of rapamycin against different tumor
`models in vivo?
` A. That's what they did in the study.
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` Q. Okay. And those are tumor cells
`that have grown in tissue culture and
`transplanted into the animals?
` A. Yes.
` Q. And they're not tumors; they're
`tumor cells?
` A. I'm sorry?
` Q. They're not tumors; they're tumor
`cells?
` A. That's right.
` Q. And they're not spontaneously
`arising cancers that have developed in the
`animals?
` A. These are not. I mean, there are
`models like that. But these are not those
`types of models.
` Q. And the cell lines that were tested
`by the NCI are all derived from malignant
`tumors, not benign tumors; is that correct?
` A. That's right.
` Q. Okay. And can we look at page 63,
`which is the first page of Douros? Are you
`there?
` A. Yes.
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`basic, you know, chemical structure and
`preserving what was believed to be the, the
`primary pharmacophore necessary for the
`anticancer activity.
` Q. What was that word you used, the
`pharma- --
` A. Pharmacophore.
` Q. Yes. What's that?
` A. Pharmacophore is the part of the
`molecule that is pharmacologically active for
`the desired effect.
` Q. Okay. And then you go on in
`paragraph 30 to discuss various, various
`chemotherapeutic -- or chemotherapies; is that
`correct?
` A. That's right.
` Q. And one of those is daunorubicin?
` A. That's right.
` Q. And that's a cytotoxic chemotherapy?
` A. Yes.
` Q. Okay. And doxorubicin?
` A. Yes.
` Q. And that's a cytotoxic chemotherapy?
` A. Yes.
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`known that there was a change in the law that
`was coming?
` A. Well, it was known that there were
`major lobbying efforts in the legislation, and
`I don't know exactly what stage the legislation
`was in October 1992. But it was pretty clear
`that this effort was being pushed for by both
`patient groups and physician groups as well as,
`obviously, the pharmaceutical industry.
` Q. But as of October of 1992, there
`were cancer drugs that were approved by the FDA
`that were available only as oral formulations,
`correct?
` A. That's correct.
` Q. Okay. And I'd like to look at one
`of the references that you cite in this
`paragraph. It's the Muggia reference. I'm
`going to mark that.
` (Ratain Deposition Exhibit 8
` was marked for identification.)
`BY MS. JACOBSEN:
` Q. I'm handing you a document that's
`been marked Ratain Exhibit 8.
` Do you recognize that document?
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`development, that something new and bad could
`happen due to a modification that one thought
`was benign, one could end up with, with a
`problem.
` Q. Okay. And so you test to find out
`whether or not that's the case?
` A. Well, you try. You can't -- you
`know, cardiac toxicity was not really observed
`in Phase I trials of doxorubicin as I recall.
`It's really only something that observes --
`that, that occurs with cumulative use of the
`drug. So if you saw cardiac toxicity acutely
`with a new anthracycline, you'd be very
`concerned about it.
` Q. Okay. So it's possible that the
`doxorubicin analog would be more toxic than
`doxorubicin?
` A. Anything's possible.
` Q. And it's also possible that the
`doxorubicin analog will be less toxic than
`doxorubicin?
` A. Yes.
` Q. And you wouldn't actually know until
`you tested it?
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` A. That's true.
` Q. And if the doxorubicin analog had
`toxicity similar to or less than doxorubicin,
`this envisages that it would move on to a
`Phase II trial; is that correct?
` A. That's the suggestion here.
` Q. And it recognizes that it's possible
`that the doxorubicin analog will have no
`activity in doxorubicin-responsive tumors; is
`that right?
` A. Sure.
` Q. And it's possible that the
`doxorubicin analog will have activity in
`doxorubicin-unresponsive tumors?
` A. That's correct.
` Q. And you wouldn't know about that
`activity until you tested?
` A. That's right. You'd have to do
`the -- you know, and, you know, Dr. Carter
`proposes in 1980. As I said, I -- I think in
`1992 this would still be valid and would
`certainly be considered routine in 1992.
` Q. And then this envisages that the
`doxorubicin analogs would only -- would go on
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` toxicities. Okay? But it -- it also
` implies what the expectation would be. The
` expectation would be that you wouldn't have
` exceptional toxicities.
`BY MS. JACOBSEN:
` Q. And that expectation is not actually
`stated in this reference. That's your
`interpretation of this reference, correct?
` A. You can put it that way.
` Q. Okay. So let's have another look --
`look at another reference.
` (Ratain Deposition Exhibit 11
` was marked for identification.)
`BY MS. JACOBSEN:
` Q. You've been handed another document
`that's been marked Ratain Exhibit 11.
` Do you recognize this document?
` A. I do.
` Q. What do you recognize it to be?
` A. It's a paper by Brenda Foster from
`the National Cancer Institute in 1990 on a
`couple of platinum analogs.
` Q. Okay. And this is a reference that
`you have cited in your reply report?
`
`TSG Reporting - Worldwide 877-702-9580
`
`NOVARTIS EXHIBIT 2152
`Par v Novartis, IPR 2016-00084
`Page 17 of 23
`
`
`
`Page 303
`
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`
` M. RATAIN, M.D.
` A. Yes.
` Q. And I think you said this, but this
`reference relates to two cisplatin analogs,
`correct?
` A. That's correct.
` Q. One of those is called CBDCA; is
`that right?
` A. Carboplatin, yes.
` Q. And the another is -- other analog,
`or cisplatin, discussed in this reference is
`CHIP?
` A. Yes, iproplatin.
` Q. And if we can look at the end of the
`first paragraph under the heading "Mechanism of
`Action," on the page 395 of this reference, and
`it states that "all platinum 2 analogs,
`including CBDCA, include DNA shortening and
`superhelical conformational changes, whereas
`platinum(IV) compounds including CHIP produce
`DNA degradation."
` Do you see that?
` A. Yes.
` MS. DANEK: Objection.
` Mischaracterizes this document.
`
`TSG Reporting - Worldwide 877-702-9580
`
`NOVARTIS EXHIBIT 2152
`Par v Novartis, IPR 2016-00084
`Page 18 of 23
`
`
`
`Page 304
`
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` M. RATAIN, M.D.
`BY MS. JACOBSEN:
` Q. And so this indicates that CBDCA and
`CHIP have different mechanisms of action; is
`that correct?
` A. That's the implication.
` Q. Okay. So it's fair to say that not
`all analogs of a cancer drug have the same
`mechanism of action as its parent?
` MS. DANEK: Objection to form.
` THE WITNESS: I would agree with
` that.
`BY MS. JACOBSEN:
` Q. And can we look at your reply report
`now?
` You can put that one aside.
` Paragraph 31. And here you state
`"in general, however, these derivatives were
`expected to have similar activity and toxicity
`related to their mechanism until disproven by
`data."
` Do you see that?
` A. Yes.
` Q. And you've not cited any reference
`published prior to October of 1992 that states
`
`TSG Reporting - Worldwide 877-702-9580
`
`NOVARTIS EXHIBIT 2152
`Par v Novartis, IPR 2016-00084
`Page 19 of 23
`
`
`
`Page 320
`
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` M. RATAIN, M.D.
`they will have similar toxicity related to
`their mechanism?
` A. You need to know something about the
`pharmacology of the drug. So if you have
`absolutely no clue what part of the molecule
`binds to any target, you'd be lost. But if you
`have -- if you have a clue and so knowing --
`looking at everolimus versus rapamycin and you
`say, okay, this -- you know, if there's a part
`of the molecule that is believed to be the
`active part and that's a part I'm staying away
`from, one would expect that the mechanism
`related to toxicity would not be affected.
` Q. So you'd need to know what -- what
`part of the drug is involved in the mechanism
`of action; is that fair?
` A. Or at least binding to something,
`yes. You'd have to know where, where the
`action is on the molecule, what I, what I
`referred to as the pharmacophore in the -- in
`my previous testimony, the part of the molecule
`that, if you want to preserve activity of the
`compound, you don't mess with.
` Q. Okay. And so if you don't know
`
`TSG Reporting - Worldwide 877-702-9580
`
`NOVARTIS EXHIBIT 2152
`Par v Novartis, IPR 2016-00084
`Page 20 of 23
`
`
`
`Page 321
`
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` M. RATAIN, M.D.
`where the pharmacophore is, you can't form a
`reasonable expectation of similar activity and
`similar toxicity related to the mechanism?
` A. That's right.
` Q. Okay. Can we turn to paragraph 48
`of your report?
` And at the end of that paragraph,
`you say, "For this reason, the properties,
`approvals, and activities of everolimus that
`are cited by Novartis's experts represent
`merely a difference in degree rather than a
`difference in kind from the properties,
`approvals, and activities of the prior art
`rapamycin?"
` Do you see that?
` A. I see that.
` Q. What properties are you referring to
`there?
` A. The, the properties of rapamycin as
`an anticancer agent, the, the -- the properties
`of rapamycin as an immunosuppressive agent.
` Q. And are you here offering opinions
`with respect to immunosuppressant properties
`and expectations with respect thereto?
`
`TSG Reporting - Worldwide 877-702-9580
`
`NOVARTIS EXHIBIT 2152
`Par v Novartis, IPR 2016-00084
`Page 21 of 23
`
`
`
`NOVARTIS EXHIBIT 2152
`Par v Novartis, IPR 2016-00084
`Page 22 of 23
`
`
`
`NOVARTIS EXHIBIT 2152
`Par v Novartis, IPR 2016-00084
`Page 23 of 23
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