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`CIVIL ACTION NUMBER:
` 11-3962
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` 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
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`United States District Court
`Trenton, New Jersey
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`Helsinn Healthcare Exhibit 2003
`Dr. Reddy's Laboratories, Ltd., et al. v. Helsinn Healthcare S.A.
`Trial PGR2016-00008
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`Page 1 of 4
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`

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