Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 1 of 470 PageID #: 2206
`
`172
` - VOLUME 2 -
`IN THE UNITED STATES DISTRICT COURT
`IN AND FOR THE DISTRICT OF DELAWARE
`- - -
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`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-
`
`
`
`172
` - VOLUME 2 -
`IN THE UNITED STATES DISTRICT COURT
`IN AND FOR THE DISTRICT OF DELAWARE
`- - -
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`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-
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 2 of 470 PageID #: 2207
`173
`
`APPEARANCES (Continued):
`
`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
`
`-
`
`- -
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 3 of 470 PageID #: 2208
`174
`
`P R O C E E D I N G S
`
`(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.
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 4 of 470 PageID #: 2209
`Cho - cross
`175
`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
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 5 of 470 PageID #: 2210
`Cho - cross
`176
`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;
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`1 2 3 4 5 6 7 8 9
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 6 of 470 PageID #: 2211
`Cho - cross
`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
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 7 of 470 PageID #: 2212
`Cho - cross
`178
`immunotherapies that were in development for the
`treatment of advanced RCC, did you?
`So while I did not go into an
`A.
`in-depth description of the state of the art of
`the immunotherapy, the presentation format I
`chose was actually as a summary of my opinions,
`and my opinions were derived by --
`I'm not asking for different
`Q.
`opinions. I'm asking about what you did on your
`direct, Dr. Cho.
`And in your direct, you did not
`describe the state of the art as of
`February 2001 with respect to the
`immunotherapies that were in development for the
`treatment of advanced RCC; right?
`Yes. While I did not --
`A.
`Okay. Thank you, Dr. Cho.
`Q.
`So you didn't discuss
`immunotherapy with tumor infiltrating
`lymphocytes in the treatment of advanced RCC,
`did you?
`No, I did not discuss that in my
`A.
`direct examination.
`And you also didn't discuss
`Q.
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`1 2 3 4 5 6 7 8 9
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 8 of 470 PageID #: 2213
`Cho - cross
`179
`immunotherapy with lymphokine activated killer
`cells in your treatment, sorry. You did
`not discuss immunotherapy with lymphokine
`activated killer cells for the treatment of
`advanced RCC?
`Although I did not discuss that
`A.
`specifically and other mechanisms, that does
`not actually affect my opinion as to whether an
`mTOR path inhibitor would have been obvious for
`RCC.
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`And you also didn't discuss
`Q.
`immunotherapy with tumor cell vaccines in
`the treatment of advanced RCC, did you,
`Dr. Cho?
`No, I did not discuss
`A.
`immunotherapy vaccines.
`Okay. And you didn't compare what
`Q.
`was known about the immunotherapies that were in
`development to treat advanced RCC with what was
`known about everolimus as of February 2001, did
`you?
`
`No, a comparison such as that
`A.
`would not have affected my obviousness opinion.
`All right. But you didn't do that
`Q.
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 9 of 470 PageID #: 2214
`Cho - cross
`180
`comparison in your direct testimony?
`I did not do that in my direct
`A.
`testimony, particularly because I didn't think
`it was relevant.
`All right. So let's talk about
`Q.
`another approach in development for advanced
`RCC. Agents targeting growth factors and
`intracellular signaling pathways.
`And if we can have here, this is
`the slide from the Adjei 2000 reference. And
`you agree this is a schematic representation of
`some of the important intracellular signaling
`pathways involved in cancer cell proliferation;
`is that correct?
`Yes, I would agree with that
`A.
`description.
`And this does not show all of the
`Q.
`intracellular signaling pathways involved in
`cancer cell proliferation that were known as of
`February 2001, does it, Dr. Cho?
`No. It would be difficult to fit
`A.
`all of that into one figure.
`And this also doesn't depict all
`Q.
`of the components of each of the intracellular
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`1 2 3 4 5 6 7 8 9
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 10 of 470 PageID #: 2215
`Cho - cross
`181
`signaling pathways that were involved in cancer
`cell proliferation, does it?
`No, this figure does not depict
`A.
`every single element of every single pathway.
`So, Dr. Cho, hormones, growth
`Q.
`factors and cytokines are all molecules that
`regulate the proliferation of cells through
`intracellular signaling pathways; is that right?
`I think that's a little bit
`A.
`oversimplified, but in principle, I would agree
`with that.
`And as of February 2001, it was
`Q.
`known that there were many types of growth
`factors involved in cell proliferation; is that
`correct?
`Yes, there were many types of
`A.
`growth factors that were involved with cell
`proliferation.
`And the mTOR pathway was not the
`Q.
`only pathway involved in growth factor signaling
`at that time; right?
`While the mTOR pathway was not the
`A.
`only factor implicated in growth factor
`regulation, I'm sorry, growth regulation, it was
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`1 2 3 4 5 6 7 8 9
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 11 of 470 PageID #: 2216
`Cho - cross
`182
`the only pathway that was obvious based on the
`molecular biology of renal cell carcinoma.
`Well, Dr. Cho, you agree that
`Q.
`agents that targeted the ras map kinase pathway
`that we've highlighted here on the slide were
`being investigated in February of 2001 for the
`treatment of advanced RCC; is that correct?
`Yes. While those agents were
`A.
`being developed, they again, this pathway was
`not clearly linked to the fundamental biology of
`RCC, which we disclosed yesterday is the VHL
`mutation, which leads to HIF overexpression.
`But agents targeting that pathway
`Q.
`were in development for advanced RCC as of
`February 2001; is that correct?
`Yes, they were in development.
`A.
`And in connection with your
`Q.
`obviousness opinions, you did not discuss the
`state of the art with respect to the ras map
`kinase pathway; is that correct?
`As I just answered, this pathway
`A.
`was not central to the biology of RCC.
`Therefore, we didn't discuss this pathway.
`You didn't discuss any prior art
`Q.
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`1 2 3 4 5 6 7 8 9
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 12 of 470 PageID #: 2217
`Cho - cross
`183
`relating to this pathway; is that correct?
`No, we did not discuss any prior
`A.
`art relating specifically to this pathway,
`although it was encompassed within the prior art
`we reviewed.
`And you didn't compare what was
`Q.
`known about the mTOR pathway with what was known
`about the other intracellular signaling pathways
`as of February 2001. You didn't do that
`comparison, did you?
`I'm sorry. I don't know how you
`A.
`compare a pathway to each other.
`I'm asking you, you didn't do a
`Q.
`comparison about what was known in the art about
`the mTOR pathway with what was known in the art
`about other intracellular signaling pathways,
`did you, Dr. Cho?
`Well, to the extent that I
`A.
`identified the mTOR pathway as the most -- I'm
`sorry, the VHL/HIF/VEGF pathway as the most
`critical pathway to the molecular biology of
`RCC, hence leading me to the relevance of the
`mTOR pathway, I believe that's a comparison of
`the relevance of various signaling pathways.
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`1 2 3 4 5 6 7 8 9
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 13 of 470 PageID #: 2218
`Cho - cross
`184
`Dr. Cho, you didn't discuss what
`Q.
`was known about any of the other signaling
`pathways; is that correct?
`I did not discuss that in my
`A.
`direct, no.
`Now, if we have a look at Adjei
`Q.
`2000 and this time Figure 2, that's on page 368.
`The legend of Figure 2 shows that this is a
`simplified schematic of intracellular signaling
`pathways with an indication of the molecules to
`which clinical agents were targeted; right?
`Yes, this does note three separate
`A.
`signaling pathways and a few drugs that target
`those elements.
`And this figure depicts that there
`Q.
`were multiple places in the intracellular
`signaling pathways that different agents were
`targeted towards; is that right?
`Yes. This figure does illustrate
`A.
`that there are -- the drugs act at different
`points along the signaling pathway.
`And for instance, this figure
`Q.
`shows at the top RTK. That's a reference to
`receptor tyrosine kinase; right?
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`1 2 3 4 5 6 7 8 9
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 14 of 470 PageID #: 2219
`Cho - cross
`185
`That's correct.
`A.
`And number one at the bottom here
`Q.
`identified different agents that targeted the
`receptor tyrosine kinase.
`That's correct.
`A.
`And then number 6 here, that's
`Q.
`CCI-779, that's temsirolimus; right?
`Yes, that is temsirolimus.
`A.
`And this figure shows temsirolimus
`Q.
`targeting a downstream component of the
`PI3/AKT/mTOR pathway; is that correct?
`By downstream target, you mean
`A.
`mTOR, that's correct.
`And mTOR is downstream of the P13K
`Q.
`and Akt components of that pathway?
`That's correct.
`A.
`And downstream of the receptor
`Q.
`tyrosine kinase as well?
`Yes, it is.
`A.
`A POSA would have been aware of
`Q.
`the hypothesis that disrupting an upstream
`component in a pathway may be more effective or
`at least silence more intracellular signaling
`pathways than disrupting a downstream one; is
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`1 2 3 4 5 6 7 8 9
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 15 of 470 PageID #: 2220
`Cho - cross
`186
`
`that right?
`While a POSA would have been aware
`A.
`of that hypothesis, inasmuch as a POSA believes
`that the mTOR pathway is critical, the PI3, a
`POSA would also have been aware that there were
`not any drugs that inhibited PI3 or P13K.
`Moreover, none of the data with respect to
`tyrosine kinase inhibitors or growth factors has
`shown any ability to inhibit HIF expression
`which was shown directly shown by the mTOR
`inhibitors.
`You didn't discuss in your direct
`Q.
`any prior art relating to PI3K or Akt or
`inhibitors?
`I did not as they were not in
`A.
`clinical development.
`You agree the targeting of an
`Q.
`upstream component like the receptor tyrosine
`kinase, targeting an upstream component of a
`pathway would include inhibiting the receptor or
`the receptor tyrosine kinase?
`That concept would include that.
`A.
`That, however, would be limited by the fact that
`many different receptor tyrosine kinases can
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 16 of 470 PageID #: 2221
`Cho - cross
`187
`signal to the same pathway, so it is known that
`if you inhibit one receptor tyrosine kinase, you
`may not actually inhibit the entire
`intracellular pathway.
`All right. But in connection with
`Q.
`your obviousness opinions, you didn't discuss
`the state of the art as of February 2001 with
`respect to receptor tyrosine kinase inhibitors,
`did you, Dr. Cho?
`No, we did not.
`A.
`You didn't compare what was known
`Q.
`about receptor tyrosine inhibitors in
`development to treat advanced RCC with what was
`known about everolimus as of February 2001; is
`that correct?
`Again, it's difficult for me to
`A.
`understand what you mean by compare the pathway.
`You didn't compare what was known
`Q.
`about the receptor tyrosine kinase inhibitors in
`development to treat advanced RCC with what was
`known about everolimus as of February 2001. You
`didn't do that comparison, did you, Dr. Cho?
`Well, I actually don't know how
`A.
`you can do a comparison like that. We were led
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`1 2 3 4 5 6 7 8 9
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 17 of 470 PageID #: 2222
`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
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 18 of 470 PageID #: 2223
`Cho - cross
`189
`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.
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`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.
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 19 of 470 PageID #: 2224
`Cho - cross
`190
`of February 2001, there was also no clinical
`data on the antitumor activity of rapamycin;
`right?
`
`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.
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 20 of 470 PageID #: 2225
`Cho - cross
`191
`"If this hypothesis proves correct."
`Do you see that?
`I do not see that on this -- oh,
`
`A.
`
`yes.
`
`We've added the highlighting, so
`Q.
`it says, "If this hypothesis proves correct."
`Yes, I do see that.
`A.
`All right. So this paper states
`Q.
`that whether deregulation of the PI3K, Akt, mTOR
`pathway leads to rapamycin sensitivity in human
`cancer cells was a hypothesis; right, Dr. Cho?
`While that is the hypothesis
`A.
`they're discussing, I would notice several
`points here. One is that is not a hypothesis we
`used to actually make our obviousness argument.
`What they are expressing in this paper in the
`context of this overall manuscript is a study
`showing whether or not molecular alterations
`which caused constitutive PI3 kinase, and by
`constitutive I mean baseline PI3, or mTOR
`pathway hyperactivation can predict whether or
`not those tumors would be sensitive to drugs
`targeting that pathway.
`In renal cell carcinoma, we've
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 21 of 470 PageID #: 2226
`Cho - cross
`192
`never made the argument that this pathway is
`hyperactive. We have only made the argument
`that the VHL pathway is hyperactive. Therefore,
`our obviousness argument does not depend upon
`this pathway being hyperactive.
`So this really is an entirely
`separate hypothesis scientifically.
`But you agree that this was a
`Q.
`hypothesis as of February 2001?
`Yes, and this is, as we discussed
`A.
`in my direct, which is actually the basis upon
`which we believe Hidalgo, I'm sorry, I believe
`that Hidalgo makes the statement that this is a
`developmental challenge, because they're trying
`to develop predictive biomarkers.
`Now, Dr. Cho, you contend that
`Q.
`claims 1 to 3 of the '131 patent are obvious
`over the '772 patent in view of Hidalgo,
`Hutchison -- sorry, Hidalgo 2000, Hutchinson
`2000, and the '973 patent, and the '772 patent.
`MS. JACOBSEN: You can take this
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`down.
`BY MS. JACOBSEN:
`Okay. So let's take those
`Q.
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 22 of 470 PageID #: 2227
`Cho - cross
`193
`references in turn, starting with the '772
`patent. Okay.
`You agree that the '772 patent
`does not contain any preclinical or clinical
`data demonstrating an antitumor effect of
`everolimus; is that correct?
`Yes, I would agree that this shows
`A.
`no preclinical or clinical data.
`Okay. And you do not contend that
`Q.
`the '772 patent contains any suggestion that
`everolimus would be effective for the treatment
`of RCC, do you?
`Inasmuch as RCC is a tumor, this
`A.
`patent does state that everolimus and other
`related compounds would be, it could be, will be
`useful for the treatment of tumors.
`You do not contend that the '772
`Q.
`patent contains any suggestion that everolimus
`would be effective for the treatment of RCC, do
`you, Dr. Cho?
`Well, I mean, in terms -- if you
`A.
`are using the word suggestion, and a POSA knows
`that this is an orally available mTOR inhibitor
`and believes that mTOR inhibitors will be
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`1 2 3 4 5 6 7 8 9
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 23 of 470 PageID #: 2228
`Cho - cross
`194
`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.
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`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.
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 24 of 470 PageID #: 2229
`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.
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 25 of 470 PageID #: 2230
`Cho - cross
`196
`Okay.
`Now, I would like to discuss the
`'973 patent.
`You agree that the '973 patent
`does not contain any preclinical or clinical
`data demonstrating any antitumor effect of
`everolimus, right?
`Yes, I would agree with that.
`A.
`And you do not contend that the
`Q.
`'772 -- sorry -- the '973 patent contains any
`suggestion that everolimus would be effective
`for the treatment of RCC, right?
`No, I did not make that
`A.
`contention.
`Q.
`
`So let's discuss Hutchinson 2000
`
`next.
`
`Now, Hutchinson 2000 does not
`mention everolimus at all, does it?
`No, everolimus is not mentioned in
`A.
`
`this.
`
`Q.
`
`Okay.
`So this is a half-page article
`from the Lancet under the heading News Desk,
`right?
`
`Q.
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 26 of 470 PageID #: 2231
`Cho - cross
`197
`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
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 27 of 470 PageID #: 2232
`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.
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 28 of 470 PageID #: 2233
`Cho - cross
`199
`Okay. And Hutchinson 2000, does
`Q.
`not tell a POSA whether there were any RCC
`patients with tumor growth during the study,
`does it?
`
`No, it does not say that.
`A.
`Now, the second of the Phase I
`Q.
`temsirolimus dose escalation studies discussed
`in the Hutchinson 2000 references to a study in
`the U.S., and it was done by the investigator
`Hidalgo, correct?
`That's correct.
`A.
`Okay.
`Q.
`And Hutchinson 2000, also doesn't
`tell a POSA the total number of RCC patients
`enrolled in the U.S. study, right?
`While -- while this does not say
`A.
`the total number, a POSA would actually know
`that renal cell carcinoma, would expect that
`renal cell carcinoma would actually be a
`minority of the patient population, because in
`the overall population, renal cell cancer is
`actually a rare tumor.
`That is not discussed in this
`Q.
`reference, though, is it, Dr. Cho?
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 29 of 470 PageID #: 2234
`Cho - cross
`200
`It is not discussed in this
`
`A.
`reference.
`And weren't an expert in the field
`Q.
`of RCC in 2001, were you, Dr. Cho?
`I was not an expert in 2001. I'm
`A.
`an expert now. And I'm familiar with the
`prevalence of RCC in the advanced tumor
`population.
`And this reference does not tell a
`Q.
`POSA in Hutchinson 2000, does not tell a POSA
`whether RCC patients had tumor growth during the
`U.S study, correct?
`This does not discuss tumor growth
`A.
`in this study.
`Okay.
`Q.
`And you have not disputed that by
`February of 2001, that literature also reported
`the spontaneous regressions were known to occur
`in RCC tumors even without treatment, correct?
`While I have not disputed that, I
`A.
`discussed in my direct yesterday that was in a
`very specific clinical scenario.
`Dr. Cho, you did not cite any
`Q.
`prior art relating to your opinions regarding
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 30 of 470 PageID #: 2235
`Cho - cross
`201
`spontaneous regression that you gave yesterday,
`correct?
`While I did not cite that, I also
`A.
`noticed that this was never a concern raised in
`the prior art regarding these studies.
`You weren't practicing in the
`Q.
`field of RCC in February of February 2001, were
`you?
`
`While I was not practicing in that
`A.
`field, I'm very familiar with conduct of
`spontaneous regression. I've treated over a
`thousand patients with RCC, and it's an
`extremely rare phenomenon, limited to a very
`specific clinical scenario, which is not
`relevant to patients treated in this trial.
`That's not in Hutchinson, it's not
`Q.
`mentioned in Hutchinson, correct?
`This is not mentioned in
`A.
`Hutchinson.
`Q.
`
`Okay.
`Now, in your direct you noted that
`Hutchinson 2000 says that temsirolimus had
`entered a phase II clinical trial for advanced
`RCC, right?
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 31 of 470 PageID #: 2236
`Cho - cross
`202
`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
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 32 of 470 PageID #: 2237
`Cho - cross
`203
`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
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`Case 1:15-cv-00474-RGA Document 98 Filed 12/04/17 Page 33 of 470 PageID #: 2238
`Cho - cross
`204
`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 preclinic
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
