`
`
`CIVIL ACTION NUMBER:
` 11-3962
`
` TRIAL
`
` UNITED STATES DISTRICT COURT
` FOR THE DISTRICT OF NEW JERSEY
`__________________________________
`HELSINN HEALTHCARE, S.A. and
`ROCHE PALO ALTO, LLC,
` Plaintiffs,
` -vs-
`DR. REDDY'S LABORATORIES, LTD.,
`DR. REDDY'S LABORATORIES, INC.,
`TEVA PHARMACEUTICALS USA, INC.,
`and TEVA PHARMACEUTICAL
`INDUSTRIES, LTD.
` Defendants.
`__________________________________
` Clarkson S. Fisher United States Courthouse
` 402 East State Street
` Trenton, New Jersey 08608
` June 4, 2015
`B E F O R E: THE HONORABLE MARY L. COOPER
`
`UNITED STATES DISTRICT JUDGE
`
`Certified as True and Correct as required by Title 28, U.S.C.,
`Section 753
`
`/S/ Regina A. Berenato-Tell, CCR, CRR, RMR, RPR
`/S/ Carol Farrell, CCR, CRR, RMR, CCP, RPR, RSA
`
`United States District Court
`Trenton, New Jersey
`
`1 2 3 4 5 6 7 8 9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`Helsinn Healthcare Exhibit 2003
`Dr. Reddy's Laboratories, Ltd., et al. v. Helsinn Healthcare S.A.
`Trial PGR2016-00008
`
`Page 1 of 4
`
`
`
`A P P E A R A N C E S:
`
`PAUL HASTINGS
`BY: JOSEPH O'MALLEY, ESQUIRE
` ISAAC S. ASHKENAZI, ESQUIRE
` ANGELA NI, ESQUIRE
`SAUL EWING
`BY: CHARLES M. LIZZA, ESQUIRE
`Attorneys for the Plaintiffs
`
`BUDD LARNER
`BY: STUART D. SENDER, ESQUIRE
` ANDREW ALLEN, ESQUIRE
`Attorneys for the Defendant, Dr. Reddy's Laboratories
`
`WINSTON & STRAWN
`BY: JOVIAL WONG, ESQUIRE
` GEORGE LOMBARDI, ESQUIRE
` JULIA MANO JOHNSON, ESQUIRE
` BRENDAN F. BARKER, ESQUIRE
`LITE DePALMA, GREENBERG, LLC
`BY: MAYRA V. TARANTINO, ESQUIRE
`Attorneys for the Defendant, Teva
`
`United States District Court
`Trenton, New Jersey
`
`I N D E X
`
`2
`
`3
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`Voir Dire - Fruehauf
`
`4
`
`(In open court. June 4, 2015, 9:30 a.m.)
`
`THE COURT: Good morning, everyone. Okay. Are we
`
`ready to go to work today? Would you like to call your next
`
`witness?
`
`MR. WONG: Yes. Good morning, Your Honor. My name
`
`is Jovial Wong. I represent the Teva defendants. Good to see
`
`you again.
`
`As our first witness defendants call Dr. John Freuhauf.
`
`He will be discussing more about the efficacy of palonosetron.
`
`(Whereupon, JOHN FRUEHAUF, witness for the
`
`defendants, sworn.)
`
`THE DEPUTY CLERK: Please state and spell your full
`
`name for the record.
`
`THE WITNESS: John P. Fruehauf, F-R-U-E-H-A-U-F.
`
`VOIR DIRE EXAMINATION BY MR. WONG:
`
`Q.
`
`A.
`
`Q.
`
`Good morning, Dr. Fruehauf.
`
`Good morning.
`
`Dr. Fruehauf, have you been asked to provide expert
`
`opinions in this case?
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`Yes, I have.
`
`And, in general, what do your opinions relate to?
`
`They relate to the clinical development of palonosetron.
`
`Okay. Let's do a little background first, Dr. Fruehauf.
`
`Where are you currently employed?
`
`University of California Irvine.
`
`United States District Court
`
`Trenton, New Jersey
`
`Voir Dire - Fruehauf
`
`5
`
`And what is your current position at the University of
`
`California Irvine?
`
`A.
`
`I'm a professor of clinical medicine and the director 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
`25
`
`1
`
`2 3 4
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`clinical pharmacology and developmental therapeutics.
`
`Q.
`
`And is there a particular cancer center that you work at
`
`at UC, Irvine?
`
`A.
`
`Q.
`
`A.
`
`I work at the Chao Family Comprehensive Cancer Center.
`
`And what is a comprehensive cancer center?
`
`It is a cancer center -- there are 43 comprehensive
`
`cancer centers in the United States, and this is one of those.
`
`They're designated by the National Cancer Institute, and they
`
`have to have the complete array of services from basic
`
`research to clinical trials development to qualify.
`
`Q.
`
`A.
`
`Q.
`
`A.
`
`How long have you been at UC, Irvine?
`
`Since 1993.
`
`Can you briefly describe your educational history?
`
`I went to college at UC Santa Barbara where I got a
`
`bachelor's degree in psychology and a bachelor's degree in
`
`cellular and organismal biology. And then I proceeded to
`
`medical school and did an M.D./Ph.D. program at Rush
`
`University in Chicago, and my Ph.D. was in pharmacology.
`
`Q.
`
`A.
`
`Q.
`
`What is pharmacology?
`
`Pharmacology is the study of how drugs work.
`
`Okay. After you got your medical degree in 1985 what did
`
`you do?
`
`United States District Court
`
`Trenton, New Jersey
`
`WITNESS VOIR DIRECT CROSS REDIRECT RECROSS
` DIRE
`
`JOHN P. FRUEHAUF
`By Mr. Wong 4 14 183
`By Mr. O'Malley 107 204
`
`United States District Court
`Trenton, New Jersey
`
`5
`
`6
`
`7
`
`8 9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`23
`24
`25
`
`Page 2 of 4
`
`
`
`34
`
`36
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`Direct - Fruehauf
`
`effective at a certain time.
`
`MR. WONG: Okay. Let's go right to the first
`
`document. Can we have the Syntex Phase II trials, DTX-0227.
`
`Let's go to Page 5 of the study.
`
`BY MR. WONG:
`
`Q.
`
`A.
`
`Dr. Fruehauf, do you recognize this document, DTX-0227?
`
`Yes, sir. So, this is the final report on the 2330
`
`clinical trial, which is the dose ranging, efficacy, safety,
`
`and pharmacokinetic study of single-intravenous doses of
`
`RS-25259, which is palonosetron, for prevention of nausea and
`
`vomiting in chemotherapy-naive cancer patients receiving
`
`highly emetogenic chemotherapy.
`
`Q.
`
`Dr. Fruehauf, were you in court on Tuesday to hear Dr.
`
`Calderari's testimony on this document?
`
`A.
`
`Yes, I was.
`
`MR. O'MALLEY: And I'll just object until they lay
`
`the foundation that your Honor requested as to whether or not
`
`the POSA would have had this, since the overarching opinion is
`
`that a POSA would have known X.
`
`THE COURT: Okay. Mr. Wong, can you -- is this
`
`available to a POSA?
`
`BY MR. WONG:
`
`Q.
`
`Would this document have been available to a POSA? Was
`
`this document publicly available as of 1995?
`
`A.
`
`I don't believe so.
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`Direct - Fruehauf
`
`Right below.
`
`BY MR. WONG:
`
`Q.
`
`Dr. Fruehauf, how would you characterize this Phase II
`
`Study 2330?
`
`A.
`
`This is a very strong Phase II study because it was
`
`randomized and double-blinded in multicenter, so in
`
`multicenter trials, you have a variety of people
`
`participating, which decreases bias.
`
`And then it was this dose-ranging efficacy study, so
`
`they wanted to know what dose is working to suppress nausea.
`
`So it was a very strong design for a Phase II trial.
`
`THE COURT: You said not all Phase II trials are even
`
`blinded at all.
`
`THE WITNESS: Correct.
`
`THE COURT: This was?
`
`THE WITNESS: Yes.
`
`MR. WONG: Okay. Let's go to the next section, the
`
`number of subjects section.
`
`BY MR. WONG:
`
`Q.
`
`Dr. Fruehauf, how many patients in total were involved in
`
`this Phase II Study, 2330?
`
`A.
`
`There were 161 patients, more males than females, and
`
`then there were 13 patients who were excluded from the
`
`efficacy analysis for various reasons, which, you know, we
`
`won't go into, but -- and, so, it was 161 patients with 13
`
`United States District Court
`
`Trenton, New Jersey
`
`United States District Court
`
`Trenton, New Jersey
`
`37
`
`Direct - Fruehauf
`
`Direct - Fruehauf
`
`35
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`Q.
`
`If you saw this document in 1995, would you understand
`
`that, and reviewing the data, would you understand that
`
`palonosetron was effective to reduce CINV?
`
`MR. O'MALLEY: Objection. Calls for speculation.
`
`THE COURT: Sustained.
`
`You can ask him what this document tells him now.
`
`That's fine.
`
`MR. WONG: That's fine.
`
`So let's go to Page 14. Let's go right to results or
`
`the study synopsis, and let's go to objections down low. The
`
`objectives below.
`
`BY MR. WONG:
`
`Q.
`
`Dr. Fruehauf, what was a primary -- what was a primary
`
`objective of this Phase II study? Looking at this document
`
`today, what was the primary objective of the Phase II study?
`
`A.
`
`It was, basically, to determine whether palonosetron,
`
`over a dose range of 1-90 micrograms per kilogram, given to
`
`patients who were treated with highly emetogenic chemotherapy
`
`would reduce the likelihood of chemotherapy-related nausea.
`
`Q.
`
`Okay. In carrying out the primary objective of this
`
`study, would it include a determination of whether
`
`palonosetron reduces the likelihood of CINV when administered
`
`to humans?
`
`A.
`
`Yes.
`
`MR. WONG: Let's go to the methodology section.
`
`United States District Court
`
`Trenton, New Jersey
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`excluded.
`
`Q.
`
`And how many patients actually got the 0.25 milligram
`
`dose of palonosetron?
`
`A.
`
`There were -- which is the equivalent of
`
`3-micrograms-per-kilogram dose. Of 3 micrograms per
`
`kilogram, .25 was the equivalent to 3 micrograms per kilogram,
`
`and there were 24 patients who received that dose.
`
`Q.
`
`So, did the study design of this Phase II study allow the
`
`determination of whether palonosetron administered at
`
`0.25 milligrams reduces the likelihood of CINV when it was
`
`administered to a human?
`
`A.
`
`Yes.
`
`MR. WONG: Let's go to summary and conclusion section
`
`on Page 15.
`
`BY MR. WONG:
`
`Q.
`
`Right here in the first sentence, what was Syntex's
`
`conclusion on this Study 2330?
`
`A.
`
`They concluded that all four doses, and they're talking
`
`about 3, 10, 30 and 90, they didn't -- .3 to 1 was a low dose
`
`that wasn't expected to have the full effect, but it did have
`
`some effect because no drug would have lead to, you know, zero
`
`control of nausea and vomiting.
`
`So, they found that 3, 10, 30 and 90, let's take the
`
`percent complete control going across, those were equivalent
`
`and effective. All four doses were approximately equally
`
`United States District Court
`
`Trenton, New Jersey
`
`Page 3 of 4
`
`
`
`Direct - Fruehauf
`
`Direct - Fruehauf
`
`38
`
`40
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`effective as compared with the combined results from a cohort
`
`of the .3 to 1 micrograms per kilogram.
`
`Q.
`
`A.
`
`And what do they state in the first sentence?
`
`They state that palonosetron was administered as a single
`
`bolus intravenous injection of these doses 30 minutes prior to
`
`chemotherapy.
`
`Q.
`
`So, let's focus in on the --
`
`THE COURT: And that they were looking at suppressing
`
`CINV for 24 hours after the chemotherapy.
`
`THE WITNESS: Yes, ma'am. So, the endpoints here
`
`were complete control at 24 hours, which means, by definition
`
`in the study, that they didn't throw up and they didn't feel
`
`nauseated. They didn't need a medicine to help them after
`
`they got the first medicine.
`
`And then this is a second endpoint, complete response,
`
`where the numbers were a little lower because that would be
`
`those patients might have needed some rescue medicine, and
`
`then the median time --
`
`THE COURT: What's the difference between complete
`
`control at 24 hours and complete response at 24 hours, can you
`
`tell us?
`
`THE WITNESS: Yeah, this is really the difference
`
`between who needed a rescue medication, and the percentage of
`
`people -- like this is a lower number for complete response
`
`because they might have felt nauseated. They didn't throw up,
`
`United States District Court
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`palonosetron is it was very potent. And, you know, you're
`
`binding to a receptor, and if you -- if you have enough drug
`
`to bind to all the receptors and they're all blocked at a
`
`certain dose, giving more drug won't have any more benefit.
`
`THE COURT: Doctor, we're talking about this H --
`
`THE WITNESS: 5-HT.
`
`THE COURT: -- 5-HT
`
` receptor. That's not the only
`
`3
`
`receptor that sends signals of nausea to the brain, is it?
`
`THE WITNESS: No. As I was explaining earlier from
`
`my practice, I will combine drugs that will work on different
`
`receptors because here there's only a 50 percent control.
`
`THE COURT: Even at best --
`
`THE WITNESS: Even at best.
`
`THE COURT: -- with palonosetron.
`
`THE WITNESS: With one drug. So, if you give a
`
`second drug and a third drug, now you're going to improve your
`
`control rate to some degree; but, of course, as you add more
`
`drugs, you're getting into more side effects.
`
`THE COURT: But the other drugs would target other
`
`receptors theoretically.
`
`THE WITNESS: Correct.
`
`THE COURT: Thank you.
`
`THE WITNESS: So, here we have a saturation of the
`
`receptors, and as you go higher, you don't really see any
`
`change after that.
`
`United States District Court
`
`Trenton, New Jersey
`
`Trenton, New Jersey
`
`Direct - Fruehauf
`
`39
`
`41
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`but they might have felt nauseated. They filled out a
`
`questionnaire --
`
`THE COURT: Yes.
`
`THE WITNESS: -- about how they felt over the 24-hour
`
`period --
`
`THE COURT: Yes.
`
`THE WITNESS: -- and they used that questionnaire to
`
`assess the benefit of the drug for its intended effect.
`
`THE COURT: And that last row says, "median time in
`
`hours to failure defined as first emetic episode or rescue
`
`drug."
`
`THE WITNESS: Yes. So that is, you know, basically,
`
`they got the medicine, they got the chemotherapy, and how long
`
`did the medicine work for? When did it wear off?
`
`So when it wore off, that means you're starting to feel
`
`sick. And that's the delayed emesis. And, so, let's say for
`
`the .25 or the 3-micrograms-per-kilogram, that time to failure
`
`was 22.7 hours, compared to, let's say, 19 for 10, greater
`
`than 24 for 30, and 21.8 for 90. We can see these numbers are
`
`all pretty consistent, but these numbers are lower, so there's
`
`sort of a --
`
`THE COURT: In other words, the dosage beginning with
`
`3 and going up was pretty consistent. It's just the dosage
`
`below 3 that fell off.
`
`THE WITNESS: So, you know, what we understand about
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`Direct - Fruehauf
`
`BY MR. WONG:
`
`Q.
`
`Let's just focus on the 0.25 milligram data that's under
`
`3-microgram-per-kilogram. What do the data, 46 percent,
`
`39 percent and 22.7 hours, based on those data what can you
`
`conclude about whether 0.25 milligrams of palonosetron reduced
`
`the likelihood of CINV in patients who got this dose?
`
`A.
`
`It's very clear that it effectively reduced the risk. I
`
`mean, if there was zero here, from my clinical experience if
`
`you don't give any premedication to someone who's getting
`
`highly emetogenic chemotherapy, 90 percent of them are going
`
`to throw up.
`
`THE COURT: Because that's nature's way --
`
`THE WITNESS: That's nature's way.
`
`THE COURT: -- is that right?
`
`THE WITNESS: They get a poison, they want to throw
`
`up. So, you have to have something in there to suppress that
`
`natural reaction to the poison that we're putting in their
`
`veins.
`
`And, so, this was partially effective, and then this
`
`was the maximal effect, I think, in this Phase II trial.
`
`THE COURT: You're referring to the Column 3.
`
`THE WITNESS: Yes.
`
`THE COURT: The column under the Dosage 3.
`
`THE WITNESS: Right. So this is -- these percentages
`
`of control are similar as they stated, all four doses were
`
`United States District Court
`
`Trenton, New Jersey
`
`United States District Court
`
`Trenton, New Jersey
`
`Page 4 of 4