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`
`NO. 14-1043 (RGA)
`CIVIL ACTION
`
`- VOLUME 2 -
`
` IN THE UNITED STATES DISTRICT COURT
` IN AND FOR THE DISTRICT OF DELAWARE
`NOVARTIS PHARMACEUTICALS
`CIVIL ACTION
`CORPORATION and NOVARTIS
`AG,
` Plaintiffs,
` vs.
`BRECKENRIDGE
`PHARMACEUTICALS INC.,
` Defendant.
`------------------------
`NOVARTIS PHARMACEUTICALS
`CORPORATION and NOVARTIS
`AG,
` Plaintiffs,
` vs.
`ROXANE LABORATORIES,
`INC.,
` Defendant.
`------------------------
`NOVARTIS PHARMACEUTICALS
`CORPORATION and NOVARTIS
`AG,
` Plaintiffs,
` vs.
`PAR PHARMACEUTICAL,
`INC.,
`NO. 14-1289 (RGA)
` Defendant.
`
`
` Wilmington, Delaware
` Tuesday, August 30, 2016
` 8:30 o'clock, a.m.
` - - -
`BEFORE: HONORABLE RICHARD G. ANDREWS, U.S.D.C.J.
`
`
`
`NO. 14-1196 (RGA)
`CIVIL ACTION
`
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`453
`don't know that. There's nothing on that to
`indicate where it was published, or that it was,
`in fact, in the European Journal of Cancer.
`THE COURT: Mr. Brown, how do you
`know it was published in the European Journal of
`Cancer?
`
`MR. BROWN: Well, we provided the
`citation to them. It has been in the expert
`reports and everything throughout the case.
`The first we heard of the
`authenticity, other than there was some
`boilerplate objections across the board, but the
`first time we heard this articulated was last
`night.
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`We already the found the cover
`page of the document and I think we've got
`librarians looking for it.
`But --
`THE COURT: All right. Well, I'm
`not going to exclude it on the basis of this,
`so, Ms. Jacobsen, you might as well address it
`in your -- in the testimony.
`I assume Dr. Ratain -- Dr.
`Ratain's document, I assume he will say, yes, I
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`know it came from the cancer journal. The cover
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`page is not going to upset me.
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`All right. Can we give this back
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`to Ms. Jacobsen?
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`MS. JACOBSEN: Thank you.
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`So, your Honor, plaintiff's next
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`Dr. Burris will be providing
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`a safe and effectivetreatment for Afinitor's
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`renal cell carcinoma and breast cancer
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`indications and objective indicia of
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`nonobviousness. And Dr. Burris will also be
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`responding to issues the defendants' expert, Dr.
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`Ratain, raised in his expert report.
`17
`... DR. HOWARD A. BURRIS, III,
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` having been duly sworn as a witness, was
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` examined and testified as follows...
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`MS. JACOBSEN: Your Honor, may I
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`approach the witness?
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`THE COURT: Yes.
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`(Ms. Jacobsen handed binders to
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`the witness.)
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`Burris - direct
`DIRECT EXAMINATION
`BY MS. JACOBSEN:
`Q.
`Good morning.
`A.
`Good morning.
`Q.
`Please state your name for the
`record.
`A.
`
`My name is Dr. Howard A. Burris,
`
`III.
`
`What is your current position, Dr.
`
`Q.
`Burris?
`A.
`My current position is I am the
`president of clinical operations, the chief
`medical officer, and the executive director of
`drug development at the Sarah Cannon Research
`Institute in Nashville, Tennessee, and I'm also
`an associate with Tennessee Oncology.
`Q.
`What is the Sarah Cannon Research
`Institute?
`A.
`The Sarah Cannon Research
`Institute is a private clinical research
`organization. We conduct all phases of clinical
`trials for cancer patients, Phase I through
`Phase III.
`Q.
`Can you turn to PTX-520 in your
`Burris - direct
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`binder, Dr. Burris. It's also on the screen if
`that would help.
`A.
`Yes.
`Q.
`Do you recognize that document?
`A.
`Yes, I do.
`Q.
`What do you recognize it to be?
`A.
`The document is my curriculum
`vitae, my CV.
`MS. JACOBSEN: Thank you, Dr.
`
`Burris.
`
`Plaintiffs move into evidence
`PTX-520, Dr. Burris' CV.
`THE COURT: All right. Admitted
`without objection.
`(PTX-520 was admitted into evidence.)
`MS. JACOBSEN: And, your Honor,
`plaintiffs offer Dr. Burris as an expert in
`medicinal oncology, including the past and
`current treatment of renal cell carcinoma and
`breast cancer, and in the clinical development
`of anticancer and antitumor agents.
`THE COURT: All right. You may
`
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`BY MS. JACOBSEN:
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`
`457
`Burris - direct
`Q.
`Dr. Burris, what is renal cell
`carcinoma?
`A.
`Renal cell carcinoma is the most
`common form of cancer arising from the kidney.
`Q.
`Can we abbreviate renal cell
`carcinoma to RCC?
`A.
`Yes, we can.
`Q.
`Thank you.
`Is everolimus FDA approved for the
`treatment of RCC?
`A.
`Yes, it is. Everolimus is
`approved for adults with advanced RCC after
`failure of treatment with either sunitinib or
`sorafenib.
`Q.
`And what is sunitinib and
`sorafenib?
`A.
`Those are two oral agents that
`work with different mechanisms of action than
`everolimus that are used for the treatment of
`RCC.
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`Q.
`Is everolimus also FDA approved
`for the treatment of breast cancer?
`A.
`Yes, it is. Everolimus is also
`approved for the treatment of breast cancer in
`Burris - direct
`458
`post-menopausal women. That's hormone receptor
`positive and HER2 negative. It's approved in
`combination with exemestane, and after these
`women have failed therapy with either
`Anastrazole or Letrozole.
`Q.
`And what are anastrozole,
`letrozole and exemestane?
`A.
`Those three drugs are each oral
`agents that work through blocking hormonal
`pathways that are used for the treatment of
`patients with hormone receptor positive HER2
`negative advanced breast cancer.
`Q.
`Are those therapies considered
`hormonal therapies?
`A.
`Yes, they are.
`MS. JACOBSEN: For the record, Dr.
`Burris referred to JTX-155 on PDX-5002. That's
`the Afinitor February 2006 label, and plaintiffs
`move to introduce this exhibit into evidence.
`MR. BROWN: No objection.
`THE COURT: All right. Admitted
`without objection.
`(JTX-155 was admitted into
`
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`Burris - direct
`MS. JACOBSEN: I'm sorry. I
`understand I misspoke and said 2006. It should
`be 2016.
`BY MS. JACOBSEN:
`Q.
`Dr. Burris, is it significant that
`everolimus is FDA approved in RCC and breast
`cancer after failure of other therapies?
`A.
`Yes, it is. Patients and their
`cancers who have been treated with other
`therapies have more resistant disease, more
`aggressive disease, and have a greater need for
`control of their disease, so this is a more
`difficult group of cancer patients to treat.
`Q.
`Dr. Burris, will you please
`summarize the conclusions on the validity of the
`'772 patent that you reached in this case?
`A.
`Yes. Based on the little evidence
`we had for rapamycin, that there was no
`reasonable expectation for the clinical efficacy
`seen with everolimus.
`With regard to evidence for
`nonobviousness, there was a long and unfelt
`need -- a long-felt and unmet need, I should
`say, for the treatment of both advanced RCC and
`Burris - direct
`460
`advanced breast cancer.
`There were also many others who
`had tried and failed, attempting to develop
`therapies for this disease, that there was,
`these results that we saw for everolimus with
`the demonstrated effectiveness in RCC and breast
`cancer was unexpected. That there was
`widespread industry praise for everolimus'
`efficacy in these settings, and that there's a
`clear connection between the clinical efficacy
`of everolimus and the commercial success that
`we've seen with Afinitor.
`Q.
`So can I have PDX-5003.
`Dr. Burris, does this slide
`accurately reflect the areas that you'll be
`testifying on today?
`A.
`Yes, it does.
`Q.
`Thank you.
`Now, in reaching these
`conclusions, what definition of a POSA did you
`use?
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`I used the definition that a POSA
`23
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`Burris - direct
`with at least several years of experience in
`treating patients with malignant or benign
`tumors, or that that POSA, the medicinal chemist
`would also have access to someone with a Ph.D.
`in medical oncology or medicinal oncology who
`had knowledge and expertise in preclinical
`assays.
`Q.
`As of October 1992, were you a
`person who would have advised the POSA under
`this definition?
`A.
`Yes, I would have been.
`Q.
`And can we agree that when we
`refer to what a POSA would have understood in
`October 1992, we're including what the medicinal
`chemist would have learned from somebody who
`advised them such as yourself?
`A.
`Yes, we can.
`Q.
`Thank you.
`So, Dr. Burris, we'll take these
`opinions out of order and start with the
`long-felt, unmet medical need in advanced RCC.
`As of October 1992, were there any
`treatments available for advanced RCC?
`A.
`Yes, there were.
`462
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`And what treatments were
`
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`patients who actually benefited from IL-2, and
`unfortunately, about as many patients benefited
`from the therapy as actually passed away from
`complications of the therapy.
`An expert summarizes, as shown
`here, there were severe side effects and only
`marginal activity.
`Q.
`For the record, Dr. Burris, on
`PDX-5006 referred to PTX-597, the 1993 PDR for
`IL-2. PTX-607, Stahl 1992 at page 73. And
`PTX-618, Wersall 1992 at page 71.
`And plaintiffs move to introduce
`those exhibits into evidence.
`MR. BROWN: No objection.
`THE COURT: All right. Admitted
`without objection.
`(PDX-597, PDX-607 and PTX-618 were
`admitted into evidence.)
`BY MS. JACOBSEN:
`Q.
`You also mentioned interferon
`alpha. Were there any problems associated with
`therapy using that treatment?
`A.
`Yes. Although interferon alpha
`was not FDA approved, it was a drug that was
`Burris - direct
`464
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`known to stimulate the immune system. That was
`2
`thought to be one mechanism of trying to treat
`3
`patients with advanced RCC. Only a small set
`4
`of, subset of patients actually responded to
`5
`this treatment.
`6
`Again, we as clinicians that were
`7
`treating these patients at the time had
`8
`difficulty administering the therapy. Patients
`9
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`10
`different side effects than that of IL-2 but
`11
`were classified more as severe flu-like. These
`12
`patients had fever, fatigue, headache. And,
`13
`most importantly, these toxicities actually
`14
`limited our ability to give the drug at a
`15
`reasonable dosage.
`The IL-2 therapy was very toxic
`16
`As experts described at that time,
`and caused severe side effects in the majority
`17
`these flulike symptoms were substantial and yet
`of patients. Those side effects actually
`18
`we had an overall a minority of patients that
`resulted in a black box warning. That black box
`19
`actually benefit from the interferon alpha.
`warning largely centered on the capillary leak
`20
`MS. JACOBSEN: For the record, on
`syndrome or fluid overload that these patients
`21
`PDX-5007, Dr. Burris referred to PTX-551,
`would develop that often resulted in admissions
`22
`Belldegrun 1992, at page 23. PTX-596, the 1992
`to the Intensive Care Unit and frequently
`23
`PDR for Interferon Alpha, and PTX-607, Stahl
`resulted in death.
`24
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`1992, at page 71.
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`Q.
`available?
`A.
`The treatments that were available
`in October 1992 included the recently approved
`drug at that time, a drug known as interleukin-2
`or IL-2, and then there was also use of a drug
`known as interferon alpha.
`Q.
`We'll take those in turn.
`Were there any problems associated
`with IL-2?
`A.
`Yes, there were. The problems
`with IL-2 could best be described as the
`difficulties with the toxicity profile of
`IL-2.
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`465
`Burris - direct
`And plaintiffs move to introduce
`PTX-551 and 596 into evidence.
`MR. BROWN: No objection.
`THE COURT: All right. Admitted
`without objection.
`(PTX-551 and PTX-596 were admitted
`into evidence.)
`BY MS. JACOBSEN:
`Q.
`Dr. Burris, as of October 1992,
`was there a recognized need for a safe and
`effective treatment for patients with advanced
`RCC?
`
`A.
`Yes, there was. It was clear at
`that time that none of the therapies we were
`delivering offered substantial efficacy for
`patients, and the toxicity profiles were a
`problem.
`
`This slide demonstrates some of
`the conclusions that authors and experts in the
`field described for the state of treatment of
`RCC.
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`Dr. Stahl commented it was
`unquestionable that none of the available
`systemic approaches could be recommended as a
`Burris - direct
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`standard treatment. There was an urgent need
`2
`for an effective treatment, and actually, sadly,
`3
`over the prior 20 years, the prognosis for RCC
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`5
`MS. JACOBSEN: For the record, on
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`7
`1992, at pages 75 to 76 PTX-618, Wersall 1992,
`8
`at page 71.
`9
`BY MS. JACOBSEN:
`Q.
`10
`Was the need that existed limited
`11
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`12
`therapies?
`A.
`13
`No. As I've stated, some of the
`14
`patients were treated, many with both IL-2 and
`15
`interferon alpha. For those that were able to
`16
`go on and receive subsequent lines of therapy,
`17
`there was a large, unmet need. These patients
`18
`also had growing tumors and more aggressive
`19
`tumors, so that was clearly an area where we
`20
`needed new therapies.
`Q.
`21
`So moving on then to your opinions
`22
`regarding the failure of others, but still in
`23
`RCC, prior to October 1992, had anyone tried to
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`find a new treatment for advanced RCC?
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`A.
`Yes. Numerous investigators and
`developers had attempted to find new therapies
`for advanced RCC. With a little bit of success
`seen with both IL-2 and interferon alpha, much
`of the research focused on the immune system.
`It was felt that the immune system played a
`critical role in these patients in regulating
`tumor growth, so we saw a number of
`immunotherapies in the clinic.
`This slide lists several of those.
`LAK, which stands for lymphocyte activated
`killers cells; TIL, tumor infiltrating
`lymphocytes; and TNF, a drug known as tumor
`necrosis factor were all studied.
` As is described here in summary
`publications, the side effects were severe and
`life-threatening. There was no evidence for
`superiority. And we had low response rates with
`each of these therapies.
`MS. JACOBSEN: For the record, on
`PDX-5010, Dr. Burris referred to PTX-551, the
`Belldegrun 1992. PTX-605, Skillings 1992 at
`page 70. PTX-607, Stahl 1992, page 74. And
`PTX-619, Whiteside 1991.
`468
`Burris - direct
`Plaintiffs move to introduce
`PTX-605 and 619 into evidence.
`MR. BROWN: No objection.
`THE COURT: Admitted without
`
`objection.
`(PTX-605 and PTX-619 were admitted into
`
`evidence.)
`BY MS. JACOBSEN:
`Q.
`Dr. Burris, had any other
`therapies been tested by October 1992?
`A.
`Yes. During this time period a
`number of chemotherapies and hormonal therapies
`had entered the clinic and been tested in
`patients.
`
`Dr. Yagoda summarized in a later
`publication that over 75 chemotherapy and
`hormonal therapies had been utilized. In
`summarizing the data for those patients, results
`were classified as dismal. Only six percent of
`patients benefiting by having a response or
`objective tumor shrinkage, and it was clear that
`advanced RCC showed continued resistance to the
`available therapies.
`Also, investigators at that time
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`Burris - direct
`concluded that hormonal therapies were of no
`value for the treatment of advanced RCC.
`MS. JACOBSEN: For the record, on
`PDX-5011, Dr. Burris referred to PTX-618,
`Wersall 1992, at page 71. PTX-620, Yagoda 1995,
`at pages 44 to 50 and 54.
`And plaintiffs move to introduce
`PTX-620 into evidence.
`MR. BROWN: No objection.
`THE COURT: Admitted without
`
`objection.
`(PTX-620 was admitted into evidence.)
`BY MS. JACOBSEN:
`Q.
`Dr. Burris, had anyone studied
`drugs for use after failure of prior therapy
`before October 1992?
`A.
`Yes. Investigators had. As was
`shown here, Dr. Merimsky reported on one such
`publication, interferon alpha, as previously
`described, was difficult to give, difficult to
`maintain dosages. So one thought was to add
`drugs on in patients who had progressed on
`interferon alpha to see if we could obtain
`activity.
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`MS. JACOBSEN: For the record, Dr.
`Burris referred to PTX-582, Merimsky 1992 on
`page 133, on PTX-5012.
`And plaintiffs move to introduce
`PTX-582 into evidence.
`THE COURT: Admitted without
`
`470
`Burris - direct
`Vinblastine, a commercially
`approved drug at that time, was one such study,
`but, in fact, that clinical study was negative,
`and the authors concluded there was little, if
`any, effect of adding Vinblastine to interferon
`alpha.
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`(PTX-582 was admitted into evidence.)
`15
`BY MS. JACOBSEN:
`Q.
`16
`Has the long-felt need in advanced
`17
`RCC been satisfied?
`A.
`18
`Yes, it has been.
`Q.
`19
`And what has satisfied that need?
`A.
`20
`That need has been satisfied by
`21
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`22
`the clinical trials conducted in RCC.
`Q.
`23
`And what was the design of those
`24
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`A.
`As is shown here, the RECORD-1 is
`the Phase III clinical trial that led to the
`approval of everolimus.
`As described, it's a double blind,
`randomized, placebo controlled, multi-center
`Phase III trial. Over 400 patients were
`enrolled after failure of receiving Sunitinib,
`Sorafenib, or both of the drugs. As can be seen
`here, the randomization was two to one, twice as
`many patients receiving Afinitor everolimus as
`received placebo.
`We see that the patients who
`received placebo were, in fact, allowed to cross
`over to everolimus upon disease progression and
`both arms of the trial received best supportive
`care for their cancer.
`Q.
`What does the crossover mean?
`A.
`The crossover means in an effort
`to be fair, those patients receiving placebo,
`the primary endpoint was to document progression
`free survival.
`So when those patients receiving
`the placebo, in fact, were documented to have
`progression of their disease, they were allowed
`Burris - direct
`472
`to begin receiving everolimus as part of the
`clinical trial.
`MS. JACOBSEN: For the record, on
`PDX-5013, Dr. Burris referred to PTX-583, Motzer
`2008, and plaintiffs move to introduce this
`exhibit into evidence.
`MR. BROWN: No objection.
`THE COURT: Admitted without
`
`objection.
`(PTX-583 was admitted into evidence.)
`BY MS. JACOBSEN:
`Q.
`Dr. Burris, what were the results
`of the RECORD-1 trial?
`A.
`The results are shown here in this
`standard Kaplan Meier graph that describes the
`results of the RECORD-1 trial.
`If a pointer was available, that
`might be helpful.
`Q.
`Yes.
`A.
`As is shown on this slide, we see
`here the comparison between those patients
`receiving the placebo and those patients
`receiving everolimus.
`(A pointer was handed to the
`10/14/2016 12:08:50 PM
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`Ex. 1071-0006
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`

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`Burris - direct
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`473
`
`witness.)
`
`THE WITNESS: Thank you very much.
`On the Y axis, we see the
`percentages. This is the progression-free
`probability, so the percent of patients whose
`tumor had not progressed while receiving the
`therapy.
`
`On the X axis is the time on
`study. One can see two months on out to
`14 months. The curves demonstrate those
`patients developing progression and dropping off
`of the clinical trial. This is the progression
`free survival, so the crossover patients are not
`included.
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`Q.
`What was the first rapamycin
`derivative to be approved?
`A.
`The first rapamycin derivative to
`be approved for advanced RCC was temsirolimus.
`Q.
`What was the basis for the
`temsirolimus RCC approval?
`A.
`The basis for the temsirolimus
`approval was a clinical trial that was conducted
`in first line patients, so these were newly
`relapsed patients not exposed to prior therapies
`in the advanced setting.
`The results were statistically
`positive for a group of patients that had poor
`prognostic features by a standard classification
`and that led to the approval of temsirolimus.
`Q.
`Was everolimus the first rapamycin
`derivative to demonstrate clinical efficacy
`after failure of a prior therapy?
`A.
`Yes, it was.
`Q.
`Dr. Burris, was Sunitinib and
`Sorafenib available in October of 1992?
`A.
`No, they were not.
`Q.
`Given that everolimus is approved
`for use after failure of Sunitinib and
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`Burris - direct
`Sorafenib, how is it that everolimus satisfied a
`need that existed in October 1992?
`A.
`The need in October 1992, much as
`the need that existed at the time of the
`everolimus RECORD-1 trial was a therapy that was
`effective in patients whose tumors had
`progressed or grown after first line treatment
`after receiving the prior therapy. So that
`first line therapy has simply changed with time,
`but the need to treat patients with resistant
`disease has remained.
`Q.
`Now, Dr. Ratain in his expert
`report opined that everolimus failed to satisfy
`a long-felt need because rapamycin was invented
`before everolimus.
`Do you agree?
`A.
`No, I do not.
`Q.
`Why not?
`A.
`Repeat the question for me again.
`Q.
`Yes. So Dr. Ratain opined that
`everolimus failed to satisfy a long-felt need
`because rapamycin was invented first.
`Do you agree?
`No, I do not. And the reasons are
`26 of 151 sheets
`
`A.
`
`The median progression free
`survival improved from 1.9 to 4.9 months. The
`statistical analysis showed a log rank T value
`of less than .001, and the hazard ratio of .33
`means there was a 67 percent reduction in the
`risk of progression or death for the patient by
`receiving everolimus versus placebo.
`Medical oncologists like to
`describe specific time points to compare results
`in trial. Here, the descriptor that at six
`Burris - direct
`474
`months, nearly 26 percent of the patients had
`not progressed on everolimus versus only two
`percent of the placebo group.
`BY MS. JACOBSEN:
`Q.
`Were the results of this trial
`clinically significant?
`A.
`Yes, they were. They were
`clinically significant, statistically
`significant, and they led to the approval of
`everolimus for this group of patients.
`MS. JACOBSEN: For the record, Dr.
`Burris, on PDX-5014 referred to PTX-583, Motzer
`2008, and PTX-591, NPC02181740 to 745.
`And plaintiffs move to introduce
`PTX-591 into evidence.
`MR. BROWN: No objection.
`THE COURT: Admitted without
`
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`objection.
`19
`(PTX-591 was admitted into evidence.)
`20
`BY MS. JACOBSEN:
`Q.
`21
`Was everolimus the first rapamycin
`22
`derivative to be approved for the treatment of
`23
`advanced RCC?
`A.
`24
`No, it was not.
`10/14/2016 12:08:50 PM
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`Ex. 1071-0007
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`

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`477
`Burris - direct
`that rapamycin had certainly not been FDA
`approved. Rapamycin had not been studied
`pre-clinically or clinically in patients with
`RCC, and rapamycin had not been tested in any
`clinical trials for RCC.
`Q.
`And was that as of October 1992?
`A.
`Yes. That was as of October 1992.
`Q.
`Now, Dr. Ratain also opined that
`everolimus failed to satisfy a long-felt need
`because Sorafenib was approved before
`everolimus.
`Do you agree?
`A.
`No, I do not.
`Q.
`Why not?
`A.
`Sorafenib was not available in
`October 1992. The available therapies in 1992,
`as we discussed, were Interferon-2 and the use
`of interferon alpha.
`The need to treat patients that
`existed in 1992 was after failure of such first
`line therapies. The need was simply different
`in terms of first line therapy by the time we
`got to the RECORD-1 trial time period.
`Q.
`And did Sorafenib satisfy the need
`Burris - direct
`478
`for a drug that was effective after failure of
`prior therapy?
`A.
`No, it did not. Sorafenib was
`studied in the first line setting. It was --
`it was studied in its clinical trials in
`patients with newly diagnosed metastatic
`advanced RCC.
`Q.
`And then Dr. Ratain also opined
`that everolimus failed to satisfy a long-felt
`need because two new agents called cabozantinib
`and nivolumab have allegedly shown some superior
`results to everolimus and advanced RCC.
`Do you agree?
`A.
`No, I do not. Both cabozantinib
`and nivolumab were not available in
`October 1992. They have only entered into
`clinical trials in the past few years and only
`received FDA approval during this past year.
`Q.
`Dr. Burris, I'd like to change
`topics and discuss your opinion that there was a
`long-felt, unmet medical need, this time in
`advanced breast cancer?
`A.
`Okay.
`Q.
`Were there any treatments
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`objection.
`12
`(PTX-569, PTX-579 and PTX-598 were
`13
`admitted into evidence.)
`14
`BY MS. JACOBSEN:
`Q.
`15
`Dr. Burris, why was resistance to
`16
`hormonal therapy a problem in October 1992?
`A.
`17
`Resistance to hormonal therapy was
`18
`a problem in 1992 for several reasons. These
`19
`patients had, of course, developed more
`20
`resistant disease having been exposed to prior
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`hormonal therapy. The options that were
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`available at that time were limited and the
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`patients were forced to choose to move on to
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`chemotherapy.
`Page 477 to 480 of 769
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`Burris - direct
`available for advanced breast cancer in
`October 1992?
`A.
`Yes, there were. There were a
`number of hormonal therapies and chemotherapies
`available in October 1992 for patients with
`hormone receptor positive, HER2 negative
`advanced breast cancer. The most commonly used
`therapy was a drug known as Tamoxifen.
`Q.
`Were there any problems associated
`with Tamoxifen?
`A.
`Yes. Tamoxifen, a hormonal pill
`that was used for the treatment of advanced
`hormone receptor positive breast cancer, had
`some side effect issues, but the primary issue
`associated with Tamoxifen is that the majority,
`if not all patients, failed to respond to
`therapy. Upon exhausting their response to that
`hormonal therapy, most patients were left with
`the option of moving on to chemotherapy.
`Q.
`And is that reflected on this
`
`slide?
`
`A.
`Yes, it is. Dr. Greenberg in his
`publication summarizing the success and the use
`of hormonal therapies in breast cancer made this
`Burris - direct
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`
`declaration.
`MS. JACOBSEN: For the record, on
`PDX-5016, Dr. Burris referred to PTX-569,
`Greenberg 1991, at pages 245 and 247. PTX-579,
`Macheledt, 1991. And PTX-598, Nolvadex PDR.
`And plaintiffs move to introduce
`those exhibits into evidence.
`MR. BROWN: No objection, your
`
`Honor.
`
`THE COURT: Admitted without
`
`10/14/2016 12:08:50 PM
`
`Ex. 1071-0008
`
`

`
`481
`Burris - direct
`This slide describes some of the
`chemotherapy agents commonly utilized at the
`time, like Cyclophosphamide and Methotrexate
`doxorubicin. All of these drugs had substantial
`toxicities.
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`As Dr. Greenberg in a publication
`summarizing the problems with chemotherapy,
`there was toxicity, bone marrow depression,
`which is lowering of blood counts, nausea,
`vomiting, diarrhea, hair loss and other organ
`toxicities. And, in fact, the side effects of
`chemotherapy limit the total dose of the drug
`that could be administered.
`MS. JACOBSEN: For the record, Dr.
`Burris referred to PTX-569, Greenberg 1991 at
`pages 249 and 251, and that was on PDX-5017.
`BY MS. JACOBSEN:
`Q.
`Dr. Burris, was there a recognized
`long-felt need for new breast cancer therapy in
`October 1992?
`A.
`Yes, there was. There was a
`desperate need for new therapy from this very
`common malignancy as we discussed, patients were
`progressing on frontline therapies, particularly
`Burris - direct
`482
`those with hormone receptor positive, failing
`with Tamoxifen and having to decide on
`chemotherapy.
`Doctor George Sledge from Indiana
`University and Harvard published a review
`article in 1992, which summarized the facts
`listed here. In the prior decade, no new
`chemotherapeutic agents had been approved by the
`FDA for the treatment of metastatic breast
`cancer. Sadly, the median survival of women
`with this had not changed in the 50 years prior
`to the publication.
`Q.
`That was prior to 1992?
`A.
`Yes.
`MS. JACOBSEN: So for the record,
`Dr. Burris referred to PTX-506, Sledge 1992 at
`page 317. And I'm told I said 506. I meant
`606, so I will try that again.
`On PDX-5018, Dr. Burris referred
`to PTX-606, Sledge 1992, at page 317, and
`plaintiffs move to introduce this exhibits into
`evidence.
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`Honor.
`10/14/2016 12:08:50 PM
`
`MR. BROWN: No objection, your
`
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`Burris - direct
`THE COURT: Admitted without
`
`objection.
`(PTX-606 was admitted into evidence.)
`BY MS. JACOBSEN:
`Q.
`Dr. Burris, was the need limited
`to drugs that could be used for first line
`therapy?
`A.
`No. The need existed strongly for
`patients who had relapsed or recurrent
`progressive disease after receiving first line
`therapy.
`Q.
`And what was the most common first
`line therapy in those days?
`A.
`The most common first line therapy
`in those days was Tamoxifen.
`Q.
`And what type of therapy is
`Tamoxifen?
`A.
`Tamoxifen is a hormonal treatment.
`Q.
`So moving on to your opinions
`regarding the failure of others still in breast
`cancer, prior to October 1992, had any drugs
`been tested for their ability to overcome
`resistance to hormonal therapy?
`A.
`Yes. There had been much work in
`Burris - direct
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`this area. Shown here is a representative
`publication from Dr. Macheledt. She was at MD
`Anderson at the time.
`There was data there that was
`there to support that interferon alpha could
`work through the hormonal pathways, work through
`the estrogen pathway to help overcome Tamoxifen
`resistance. This was studied in clinical
`trials.
`
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`MS. JACOBSEN: For the record, Dr.
`20
`Burris on PDX-5020 referred to PTX-579,
`21
`Macheledt 1991 at pages 165 and 168.
`22
`BY MS. JACOBSEN:
`Q.
`23
`Has the long-felt need in advanced
`24
`breast cancer been satisfied?
`Page 481 to 484 of 769
`
`The results of that Phase II
`evaluation simply showed that there was
`additional toxicity. There was little activity,
`and interferon alpha was concluded to not be
`able to overcome Tamoxifen resistance. In fact,
`of the 21 patients treated, 16 required dose
`reductions of their interferon alpha and eight
`actually had to stop the therapy due to
`toxicity.
`
`Ex. 1071-0009
`
`

`
`485
`
`Burris - direct
`Yes, it has been.
`What has satisfied that need?
`Everolimus has satisfied that
`
`A.
`Q.
`A.
`
`need.
`
`And what is the basis for that
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`Q.
`A.
`
`trial.
`
`Q.
`opinion?
`A.
`The basis for the opinion of
`everolimus satisfying this need in advanced
`breast cancer is based