`
`
` - VOLUME 2 -
`IN THE UNITED STATES DISTRICT COURT
`IN AND FOR THE DISTRICT OF DELAWARE
`- - -
`
`CIVIL ACTION
`
`NO. 15-474 (RGA)
`
`:::::::::::::
`
`NOVARTIS PHARMACEUTICALS
`CORPORATION, and
`NOVARTIS AG,
`Plaintiffs,
`
`vs.
`WEST-WARD
`PHARMACEUTICALS
`INTERNATIONAL LIMITED,
`Defendant.
`
`
` - - -
`Wilmington, Delaware
`Thursday, September 14, 2017
`8:30 o'clock, a.m.
`
` - - -
`BEFORE: HONORABLE RICHARD G. ANDREWS, U.S.D.C.J.
`- - -
`
`
`
`APPEARANCES:
`
`McCARTER & ENGLISH
`BY: DANIEL M. SILVER, ESQ.
`
`-and-
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`APPEARANCES (Continued):
`
`173
`
`FITZPATRICK, CELLA, HARPER & SCINTO
`BY: NICHOLAS KALLAS, ESQ.,
` CHARLOTTE JACOBSEN, ESQ. and
` CHRISTINA SCHWARZ, ESQ.
` (New York, New York)
`
`Counsel for Plaintiffs
`
`POTTER, ANDERSON & CORROON LLP
`BY: DAVID E. MOORE, ESQ. and
` BINDU A. PALAPURA, ESQ.
`
`-and-
`
` GOODWIN PROCTER LLP
` BY: KEITH A. ZULLOW, ESQ.,
` MICHAEL B. COTTLER, ESQ.,
` MARTA E. GROSS, ESQ.,
` NATASHA DAUGHTREY, ESQ. and
` CINDY CHANG, ESQ.
` (New York, New York)
`
` Counsel for Defendant
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`P R O C E E D I N G S
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`174
`
`(Proceedings commenced in the
`courtroom beginning at 8:30 a.m.)
`
`THE COURT: All right. Good
`morning. Everyone, please be seated.
`Dr. Cho, wherever you are.
`MS. JACOBSEN: Good morning, your
`Honor. We have cross-examination booklets for
`the Court and for the witness.
`THE COURT: All right.
`MS. JACOBSEN: May we approach?
`THE COURT: Sure.
`(Binders handed to the Court and
`to the witness.)
`... DR. DANIEL CHANG CHO,
`having previously been duly sworn as a
`witnesses, was examined and testified as
`follows ...
`
`CROSS-EXAMINATION4.
`
`BY MS JACOBSEN:
`Good morning, Dr. Cho.
`Q.
`Hello.
`A.
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`
`Cho - cross
`Dr. Cho, as of February 2001,
`Q.
`there was a need for new treatments for advanced
`RCC; is that right?
`Yes, I would agree with that
`A.
`statement.
`And you agree that attempts to use
`Q.
`cytotoxic chemotherapy to treat advanced RCC had
`failed prior to 2001; is that right?
`I don't actually know what the
`A.
`word "failed" means. There were responses seen
`to different cytotoxic chemotherapy regimens. I
`think the sense in the field was it was not
`effective.
`And attempts to use hormonal
`Q.
`therapy to treat advanced RCC had been
`unsuccessful prior to February 2001; is that
`correct?
`A.
`successful.
`All right. And I would like to
`Q.
`discuss your definition of a POSA, so let's have
`a look at your slide No. 6, and we've added some
`highlighting.
`Now, in your opinion, a POSA would
`
`Yes, hormonal therapy had not been
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`Cho - cross
`have had experience conducting preclinical,
`clinical and/or laboratory research relating,
`among other things, to rapamycin and its
`analogs. Right, Dr. Cho?
`That is correct.
`A.
`And the only class of drugs you
`Q.
`identified in your POSA definition was rapamycin
`and its analogs; is that right?
`Yes, in the context of this
`A.
`definition, what we're referring to as this
`amongst other things as an example.
`Right. But that's the only
`Q.
`example you provided in your definition of a
`POSA; right?
`Yes, that's the only example we
`A.
`included.
`Several novel classes of therapies
`Q.
`were being developed for cancer therapy in
`February 2001; right?
`Yes, several classes were being
`A.
`developed.
`And more specifically, many
`Q.
`approaches were being considered to find new
`treatments for advanced RCC in February 2001;
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`Cho - cross
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`177
`
`right?
`
`Yes, I would agree with that.
`A.
`And you also agree that a POSA in
`Q.
`February of 2001 would not have only considered
`mTOR inhibitors as a potential treatment for
`advanced RCC; right?
`No, I would agree that a POSA
`A.
`would not have only considered mTOR inhibitors.
`So let's have a look at your slide
`Q.
`number 13, titled scope of the prior art.
`Now, you discussed the development
`of mTOR inhibitors, but I would like to talk
`about some of the other potential approaches to
`the treatment of advanced RCC that were in
`clinical trials as of February 2001, Dr. Cho.
`Now, in February of 2001,
`immunotherapy was one approach being researched
`to find new treatments for advanced RCC; is that
`right?
`
`Yes, that was one active area of
`A.
`investigation.
`And in your direct, you did not
`Q.
`describe the state of the art as of
`February 2001 with respect to the
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`Cho - cross
`
`188
`
`to --
`
`Dr. Cho, I'm asking: You didn't
`Q.
`do that comparison?
`MR. COTTLER: Objection.
`THE COURT: He either did or he
`didn't and he said he didn't.
`MS. JACOBSEN: Okay.
`THE COURT: So let's move on.
`MS. JACOBSEN: Let's move on.
`BY MS. JACOBSEN:
`All right. So let's discuss what
`Q.
`was known about everolimus as of February 2001.
`Okay.
`
`Now, this is your slide 19, and in
`the first bullet you state that everolimus was
`described as useful as an immunosuppressant and
`antitumor agent. But as of February 2001, Dr.
`Cho, there was no clinical data on the antitumor
`activity of everolimus; right?
`That is correct. We are deriving
`A.
`that statement from the -- from what is taught
`by the '973 and '772 patents.
`All right. But there was no
`Q.
`clinical data on the antitumor activity of
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`Cho - cross
`everolimus in the prior art; is that correct?
`Yes. As I said in my direct,
`A.
`there was no clinical data towards that effect.
`All right. And the only
`Q.
`everolimus clinical data that you relied on was
`from Phase I dosing studies in transplant
`patients; right?
`The only clinical data that was
`A.
`available was in the transplant setting
`indicating the safety, which is how we used that
`data.
`
`And as of February 2001,
`Q.
`everolimus had not even shown preclinical
`activity against any model of RCC?
`That -- that type of data was not
`A.
`disclosed in the prior art.
`Okay. So turning to the other
`Q.
`mTOR inhibitors that were known as of
`February 2001, as of February 2001, no mTOR
`inhibitor had been FDA approved to treat any
`type of cancer; right?
`Yes. As of February 2001, no mTOR
`A.
`inhibitor had been FDA approved for any cancer.
`And if we focus on rapamycin, as
`Q.
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`Cho - cross
`of February 2001, there was also no clinical
`data on the antitumor activity of rapamycin;
`right?
`
`190
`
`As of 2001, there was no clinical
`A.
`data on the antitumor activity of rapamycin.
`And in preclinical testing,
`Q.
`rapamycin had not been shown to have activity in
`any RCC models; is that correct?
`There was no data specifically
`A.
`about rapamycin and RCC models.
`All right. May we have a look at
`Q.
`Sekulic’ 2000. That's JTX-27. And on page
`3512, this reference states, "Clearly,
`additional experiments are required to establish
`the relationship between deregulated PI3K/Akt
`activity and rapamycin sensitivity in human
`cancer cells."
`Do you see that, Dr. Cho?
`I do see the sentence, yes.
`A.
`Okay. And PI3K and Akt are
`Q.
`components of the larger PI3K, Akt, mTOR
`signaling pathway; right?
`Yes, it is.
`A.
`And this reference goes on to say,
`Q.
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`Cho - cross
`effective against cancer, I believe this does
`suggest that.
`Okay. Dr. Cho, you recall being
`Q.
`deposed in this case?
`I do.
`A.
`You have a copy of your deposition
`Q.
`transcript in front of you? Can you turn to
`page 297, line 16 to 21.
`I don't think I have a copy.
`A.
`
`Sorry.
`
`MS. JACOBSEN: May I approach?
`THE COURT: Yes.
`BY MS. JACOBSEN:
`So, Dr. Cho, at page 297, Lines 16
`Q.
`to 21, you were asked the question:
`"You don't contend that the '772
`patent contains any suggestion that everolimus
`would be effective for the treatment of RCC,
`correct?"
`
`And the answer you gave was:
`"I do not make that contention."
`Was that question you were asked
`and the answer you gave --
`MR. COTTLER: Objection.
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`Cho - cross
`
`195
`
`BY MS. JACOBSEN:
`-- in your deposition?
`Q.
`MR. COTTLER: Objection, your
`
`Honor.
`
`This is not the same question that
`counsel has asked the witness.
`THE COURT: All right.
`Well, overruled.
`THE WITNESS: This is what I said.
`BY MS. JACOBSEN:
`Okay.
`Q.
`You can put your deposition away,
`
`Dr. Cho.
`
`And yesterday you pointed the
`Court to Column 2, Lines 56 to 62 of the '772
`patent. I just want to look at what this says.
`Line 35 says, "The novel compound
`for an immunosuppressive use are preferably
`everolimus," correct?
`Yes, that is what it says here.
`A.
`And you didn't note that it said
`Q.
`immunosuppressive use, did you, yesterday, Dr.
`Cho?
`
`A.
`
`No, I did not.
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`Cho - cross
`That's correct.
`A.
`And it was not formally peer
`Q.
`reviewed, right?
`This was not peered review in this
`A.
`instance, no.
`Q.
`
`Okay.
`And this half-page article
`summarizes preliminary results from two Phase I
`dose escalation studies for temsirolimus, right?
`Inasmuch as they were not fully
`A.
`published, then, yes, that would be true.
`And the primary objective of a
`Q.
`Phase I clinical study was most typically to
`assess safety and determine the dose of
`experimental therapies, right?
`Well, that is the most common and
`A.
`frequently the primary end point. Efficacy end
`points are always included. And their signal of
`efficacy can be determined. Otherwise, they
`would never be included in the conclusions of
`abstracts and manuscripts.
`Right.
`Q.
`But you agree, Dr. Cho, that the
`Phase I studies were not powered to demonstrate
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`Cho - cross
`
`198
`
`efficacy, right?
`No, not Phase I studies. They
`A.
`were powered to demonstrate efficacy.
`You're saying it is powered to
`Q.
`demonstrate?
`It is -- Phase I trials are
`A.
`typically not powered to demonstrate efficacy.
`And that's true of the Phase I
`Q.
`temsirolimus studies as well, correct?
`I'm actually not familiar with how
`A.
`they were powered, but I would agree in general
`that Phase I trials are not powered to determine
`efficacy.
`Now, the first of the Phase I
`Q.
`temsirolimus dose escalation studies discussed
`in Hutchinson 2000, took place in France, and it
`was done by the investigator Raymond, right?
`Yes, that is true.
`A.
`And this half-page article does
`Q.
`not tell a POSA the total number of RCC patients
`enrolled on the French Phase I study, correct?
`This does not instruct a POSA
`A.
`about the total number of RCC patients in this
`study.
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`Cho - cross
`That is correct.
`A.
`There was no data available as of
`Q.
`February 2001, for that temsirolimus phase II
`RCC trial, right?
`There was no data available as of
`A.
`
`2001.
`
`And a POSA would not assume, on
`Q.
`the basis of a drug entering phase II testing,
`that it would have a reasonable expectation of
`success, right, Dr. Cho?
`A POSA would not make a
`A.
`determination or reasonable suggestion simply
`based in isolation upon whether a drug enters
`phase II. A POSA would consider many other
`factors.
`Q.
`
`All right.
`And you have not disputed that
`between 1990 and 2000, more than 70 percent of
`oncology drugs failed at phase II, correct?
`No, I have not disputed that fact.
`A.
`So let's discuss Hutchinson 2000
`Q.
`
`next.
`
`That's JTX-14.
`Sorry, Hidalgo 2000 does not
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`Cho - cross
`mention everolimus at all, does it?
`Everolimus is not mentioned in
`A.
`this manuscript.
`And in your direct you noted that
`Q.
`Hidalgo 2000, discussed preclinical testing of
`rapamycin and temsirolimus in cancer models,
`right?
`
`Yes, I do -- I did discuss that
`
`A.
`yesterday.
`And with respect to rapamycin,
`Q.
`Hidalgo 2000 does not suggest that rapamycin had
`shown any preclinical activity in any RCC
`models, right?
`No, that suggestion is not made in
`A.
`this manuscript.
`And just because a compound showed
`Q.
`tumor regression in a model of one type of
`cancer, does not mean that it would show tumor
`regression in a model of a different type of
`cancer, right?
`No, a POSA would not make that
`A.
`assumption.
`And with respect to temsirolimus
`Q.
`now, Hidalgo 2000 does not mention RCC, among
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`Cho - cross
`the types of tumor cell lines that were most
`sensitive to temsirolimus, correct?
`While Hidalgo 2000 does not
`A.
`specifically mention data with RCC, it also does
`not disclose that was even studied in this
`study, nor did we rely on that data for an
`obviousness argument.
`And you agree that there were
`Q.
`examples in the prior art where preclinical
`activity did not predict activity in RCC in
`tumors, right?
`No, I have not made that argument.
`A.
`And it's also your opinion that
`Q.
`preclinical testing was not a good predictor of
`clinical success in humans, right, Dr. Cho?
`That is not something I argued.
`A.
`Our opinion was that preclinical testing can be
`beneficial in showing certain biologic
`principles. And it's generally something that
`needs to be positive to proceed under clinical
`development.
`But with respect as a predictor,
`it is not a good model.
`Okay.
`Q.
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`Cho - cross
`Hidalgo II 2000 abstract, as we did at your
`deposition, okay, Dr. Cho?
`Yes.
`A.
`This relates to the Hidalgo Phase
`Q.
`I study that was conducted in the U.S., right?
`Yes, it does.
`A.
`And this was also a Phase I dose
`Q.
`escalation study, right?
`That's correct.
`A.
`And this Phase I study was
`Q.
`conducted in patients with a variety of solid
`tumors, right?
`Yes, it was.
`A.
`It was not limited to advanced RCC
`Q.
`patients, right?
`No, this study was not limited to
`A.
`patients with advanced RCC.
`And the Hidalgo II 2000 abstract
`Q.
`does not report how many RCC patients in total
`were enrolled in the U.S. study?
`No, this study does not report
`A.
`
`that.
`
`Q.
`
`Okay.
`And the Hidalgo II 2000 abstract
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`Cho - cross
`does not the report whether any other RCC
`patients had tumor growth during the U.S. study,
`right?
`
`210
`
`No, it does not report whether
`A.
`other RCC patients had tumor growth.
`Okay.
`Q.
`And this abstract also -- sorry --
`you also -- you didn't point to anything in this
`abstract either that says that only patients
`with progressive disease or growing tumors were
`enrolled in the Phase I study, right?
`Again, while I did not point to
`A.
`anything specifically, it is highlighted that
`the patients who benefitted were drug
`refractory, which is consistent with what a POSA
`would understand is the standard eligibility
`criteria for Phase I trials.
`That's not -- it's not -- the
`Q.
`eligibility criteria of progressive disease or
`growing tumors is not stated in this abstract,
`correct?
`No, it is not exclusively stated
`A.
`in this abstract.
`And then turning back to Hidalgo
`Q.
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`Cho - cross
`Right. And we just discussed that
`Q.
`that didn't mention RCC in that discussion.
`No, it was not mentioned in that
`A.
`discussion.
`All right. In your direct you
`Q.
`only mentioned VEGF. You didn't mention the
`other growth factors; is that correct?
`Well, we actually reviewed that
`A.
`very manuscript with those three -- where those
`three factors were discussed. We focused on
`VEGF mainly because it is the is the most
`important factor for angiogenesis and because it
`is the factor that's induced by the relevant
`biology in RCC.
`Finally, you testified that a POSA
`Q.
`would have understood that mTOR inhibition would
`lead to lower HIF-1 levels which would result in
`decreased VEGF and inhibit angiogenesis and
`ultimately inhibit tumor growth. But you agree
`that a POSA would understand that you can have
`mTOR inhibition and still see tumor growth;
`right?
`
`A POSA would have been aware that
`A.
`that is possible.
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`
`Cho - cross
`And, Dr. Cho, a biomarker is
`Q.
`something that can predict whether or not a
`patient will respond to treatment; is that
`correct?
`A biomarker, that is actually not
`A.
`true. You have to specify that it is a
`predictive biomarker. There are prognostic
`biomarkers that don't do that. Biomarker is
`just a term that means a marker.
`If you are asking me if a
`predictive biomarker can do that, then, yes,
`that is a potential role for that.
`All right. As of February 2001,
`Q.
`no predictive marker had been shown to
`reasonably predict efficacy of an mTOR inhibitor
`against RCC; is that right?
`No, there was no predictive
`A.
`biomarker even in development.
`All right. As of February 2001,
`Q.
`VHL gene mutations had not been shown to
`reasonably predict efficacy of an mTOR inhibitor
`against RCC; is that correct?
`No, and as of that time, no one
`A.
`had even studied that.
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`NOVARTIS EXHIBIT 2093
`Breckenridge v. Novartis, IPR 2017-01592
`Page 20 of 20
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