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`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 10, 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
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`Helsinn Healthcare Exhibit 2008
`Dr. Reddy's Laboratories, Ltd., et al. v. Helsinn Healthcare S.A.
`Trial PGR2016-00007
`
`Page 1 of 18
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`

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`A P P E A R A N C E S:
`
`PAUL HASTINGS
`BY: JOSEPH O'MALLEY, ESQUIRE
` ERIC W. DITTMANN, 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
` MICHAEL H. IMBACUAN, ESQUIRE
` HUA HOWARD WANG, ESQUIRE
` CONSTANCE S. HUTTNER, ESQUIRE
` KENNETH E. CROWELL, 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
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`I N D E X
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`Candiotti - Direct
`
`(In open court. June 10, 2015, 9:30 a.m.)
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`THE COURT: Good morning.
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`ALL: Good morning, your Honor.
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`THE COURT: On we go.
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`MR. DITTMANN: For our next witness plaintiffs call
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`Dr. Keith Candiotti.
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`THE DEPUTY CLERK: Please state and spell your full
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`name for the record. Have a seat.
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` (Whereupon, KEITH CANDIOTTI, witness for the plaintiffs,
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`sworn.)
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`THE WITNESS: Thank you. My name is Dr. Keith Allen
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`Candiotti, K-E-I-T-H. Middle name, A-L-L-E-N. Last name
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`C-A-N-D-I-O-T-T-I.
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`VOIR DIRE EXAMINATION BY MR. DITTMANN:
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`Q.
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`Dr. Candiotti, I'm going to hand you some exhibits and
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`demonstratives that we'll use today.
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`A.
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`Q.
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`A.
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`Q.
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`Thank you.
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`Good morning, Dr. Candiotti.
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`Good morning.
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`Could you please bring up PTX-98, which you have in your
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`witness book. And can you tell us what you see here, Dr.
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`Candiotti?
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`A.
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`Q.
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`This is my current CV as of May 31st, 2015.
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`And would you please tell us your educational background,
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`starting with college?
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`United States District Court
`
`Trenton, New Jersey
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`Candiotti - Direct
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`5
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`A.
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`I attended Washington University in St. Louis, where I
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`majored in biology, psychology, and ancient history. I then
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`went on to medical school at the University of Miami.
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`Q.
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`A.
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`Q.
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`A.
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`And when did you graduate medical school?
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`1989.
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`And what did you do after receiving your medical degree?
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`I went on to train in internal medicine, where I
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`completed training for three years, became board certified,
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`and I also then went on to train in anesthesiology, which I
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`completed training and went on to be board certified.
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`Q.
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`A.
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`Where do you currently work?
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`I'm still currently at the University of Miami Miller
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`School of Medicine, and I practice at the hospitals within our
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`system, University of Miami Hospital, Jackson Memorial.
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`Q.
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`A.
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`What positions do you hold at Jackson Memorial Hospital?
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`I am the executive vice chair of the department of
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`anesthesiology, perioperative medicine and pain management.
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`I'm the -- I'm the vice chair for clinical research. I'm the
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`chief of perioperative medicine, and I hold the rank of a full
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`tenured professor in the department of anesthesia, internal
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`medicine, with secondary appointments in urology, obstetrics
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`and gynecology.
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`Q.
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`And when did you become chief of the perioperative
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`medicine?
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`A.
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`Some time in the 1990s, '95 or so.
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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
`KEITH CANDIOTTI
`By Mr. Dittman 4 14 266
`By Ms. Huttner 111 276
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`United States District Court
`Trenton, New Jersey
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`Page 2 of 18
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`

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`Candiotti - Direct
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`Candiotti - Direct
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`that were run, even looking at the data from other companies
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`that might be looking to buy each other's drugs or things
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`along those lines.
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`Q.
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`And have you served as a reviewer for any peer-reviewed
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`publications?
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`A.
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`Yes. I have been a peer reviewer for quite a few, but
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`New England Journal, Anesthesiology, Anesthesia-Analgesia,
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`those are probably our two top journals. Journal of Clinical
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`Anesthesia. I guess that would be the third, but...
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`Q.
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`A.
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`And do you serve on any journal editorial boards?
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`I'm an editor on the Journal of Perianesthesia Nursing
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`and the Journal of Anesthesia and Perioperative Medicine.
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`MR. DITTMANN: Your Honor, at this time, plaintiffs
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`proffer Dr. Candiotti as an expert in the clinical care of
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`surgical patients, including the management of PONV, and
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`clinical aspects of drug product research and development.
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`MS. HUTTNER: No objection, your Honor.
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`THE COURT: Thank you, counsel. Admitted as such.
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`DIRECT EXAMINATION BY MR. DITTMANN:
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`Q.
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`Now I'd like to turn to the opinions you are offering in
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`this case. Do you have a slide that summarizes what you're
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`prepared to discuss today?
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`A.
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`Yes, I do. Thank you.
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`MR. DITTMANN: Please bring up PDX-402.
`
`BY MR. DITTMANN:
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`United States District Court
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`BY MR. DITTMANN:
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`Q.
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`And we see reference on the slide a POSA, or a person of
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`ordinary skill in the art. Do you have a slide setting forth
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`the definition of a POSA you applied --
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`A.
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`Q.
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`A.
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`Yes, sir.
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`-- in reaching your opinions?
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`Yes.
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`MR. DITTMANN: Please bring up PDX-403.
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`BY MR. DITTMANN:
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`Q.
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`A.
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`Is this the definition you applied?
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`This is. I actually took this from Dr. Amidon, which I
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`thought was quite relevant. And, basically, I feel I fit into
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`this because I am very active in the development of
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`pharmaceutical products.
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`THE COURT: Whatever you are, you're not a person of
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`ordinary skill.
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`THE WITNESS: Oh.
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`THE COURT: You're a higher skill in your field.
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`THE WITNESS: Thank you, your Honor.
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`THE COURT: But anyway, we're looking for a
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`definition of what a person of ordinary skill in whatever the
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`art is that we're trying to focus on here.
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`Go right ahead.
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`THE WITNESS: I should continue with this slide?
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`THE COURT: Yes.
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`United States District Court
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`Trenton, New Jersey
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`Trenton, New Jersey
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`Candiotti - Direct
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`Q.
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`And if you wouldn't mind, Doctor, would you please
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`briefly walk us through what you are prepared to talk about
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`today?
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`A.
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`So, just briefly, the first point being that a person of
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`ordinary skill in the art would not have been motivated at
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`that time period of 2003 to pursue the development of another
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`, specifically palonosetron. They probably would have
`5-HT
`3
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`focused more in the area of NK-1 receptor antagonists.
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`Two, had palonosetron been pursued, a dose of not lower
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`than 2 milligrams for treating emesis would have been chosen
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`based on the prior art that was available.
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`And, finally, a POSA would have been inclined or would
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`have definitely pursued a volume of, really, 1 to
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`2 milliliters, but 1 to 5 milliliters and, given the milligram
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`dosing and the volume, would have subsequently pursued or
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`would not have pursued, a POSA at the time, simply because of
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`the milligrams and the volume, a concentration of
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`.05 milligrams per mL.
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`THE COURT: They would have had a higher
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`concentration?
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`THE WITNESS: Yes, just by the de facto of having
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`2 milligrams or more in 1 to 5 ccs. I have a slide later on
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`that. Just straight concentration would have come up much
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`higher than that.
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`THE COURT: Okay.
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`United States District Court
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`Trenton, New Jersey
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`Candiotti - Direct
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`THE WITNESS: Okay. I possess a degree in medicine,
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`and I have experience in designing, developing, evaluating,
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`and testing pharmaceutical formulations. I possess an M.D.
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`with many more years than one or two years of experience.
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`BY MR. DITTMANN:
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`Q.
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`Dr. Candiotti, did you review the patents-at-issue in
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`this case?
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`A.
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`I did.
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`MR. DITTMANN: Could you please bring up PDX-404.
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`BY MR. DITTMANN:
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`Q.
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`And can you explain what we see on the slide, Dr.
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`Candiotti?
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`A.
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`So, this is the '219 patent, and I'm referring to Claim 1
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`here. The part that would concern me for my background is
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`simply the topic that this is a pharmaceutical single-use
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`agent to reduce the likelihood of cancer chemotherapy-induced
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`nausea and vomiting. It would be in a 5-mL sterile solution
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`with an amount of .25 milligrams by weight.
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`Q.
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`And do you understand there are three other patents at
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`issue in this case?
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`A.
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`Q.
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`Yes, sir.
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`Can we bring up PDX-405?
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`THE COURT: Before we get there, I think, Mr.
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`Dittmann, I interrupted when Dr. Candiotti was saying what his
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`definition of person of ordinary skill in the art is, and we
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`United States District Court
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`Trenton, New Jersey
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`Page 3 of 18
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`saw the slide on the screen, but the slides are
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`demonstratives, and he didn't get a chance to say how he would
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`define the person of ordinary skill in the art for purposes of
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`these four patents.
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`So, I'd suggest you go back and get his testimony on
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`that, because the slide is just a demonstrative.
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`MR. DITTMANN: Sure.
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`BY MR. DITTMANN:
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`Q.
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`Dr. Candiotti, you discussed the definition of a POSA we
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`see on PDX-403, correct?
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`A.
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`Q.
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`Yes.
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`And you understand this is a definition that was offered
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`by Dr. Amidon in connection with his expert reports, correct?
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`A.
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`Q.
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`A.
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`I do.
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`And do you agree with this definition?
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`I do agree with it.
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`THE COURT: And what is, it for the record? Just
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`read it out from the slide.
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`MR. DITTMANN: Oh, for the record, the definition of
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`a person of ordinary skill in the art is "Someone who is
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`actively involved in the development of pharmaceutical
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`products which involves collaborative teamwork among persons
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`with relevant experience. This person would have a degree in
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`chemistry, pharmaceutical chemistry, pharmacy, medicine,
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`clinical pharmacology, or another pharmaceutical
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`opinion listed here on the slide, that a POSA would not have
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`been motivated in 2003 to pursue palonosetron.
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`Do you have a slide discussing the types of classes of
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`drugs that were used to treat PONV in the 2003 time period at
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`issue in this case?
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`A.
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`Yes, I do.
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`MR. DITTMANN: Can we please bring up PDX-406.
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`BY MR. DITTMANN:
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`Q.
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`A.
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`And can you please explain what we see here on the slide?
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`So, I believe something similar was presented to the
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`Court the other day. This is simply just showing the classes
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`of medications that we use to either prevent or treat:
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`Phenothiazines, butyrophenones, dopamine antagonists,
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`steroids, antihistamines, 5-HT
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` receptor antagonists, which of
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`relevance are the drugs ondansetron, granisetron and
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`dolasetron. These three drugs were on the market at that time
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`and available for use.
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`Q.
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`And we see here that ondansetron was introduced in 1991.
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`At this time when the first setron was introduced, how was
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`this class of drugs perceived by the medical community?
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`A.
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`They were quite welcome. Nausea and vomiting, emesis,
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`was a problem, both a significant problem for chemotherapy
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`patients and post-operative patients. Whether the drugs
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`were -- had superior efficacy or not depends on how you look
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`at it, but for sure they had better side effects.
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`United States District Court
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`Trenton, New Jersey
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`United States District Court
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`Trenton, New Jersey
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`Candiotti - Direct
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`science-related field and experience in designing, developing,
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`evaluating, and/or testing pharmaceutical formulations with a
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`B.S. or master's degree in, and two to three years experience,
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`or a Ph.D. or M.D. degree and one to two years of experience."
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`Thank you, your Honor.
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`THE COURT: Do you subscribe to that, sir?
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`THE WITNESS: I do.
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`THE COURT: Okay. Go on.
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`MR. DITTMANN: Thank you.
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`Can we go back to PDX-405, please.
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`BY MR. DITTMANN:
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`Q.
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`And can you explain what we see here with respect to the
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`other patents-in-suit besides the '219 patent, Doctor?
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`A.
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`So, the other three patents, basically, refer again to a
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`pharmaceutical agent for reducing emesis and reducing the
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`likelihood of emesis at a concentration of .05 milligrams per
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`mL of palonosetron.
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`Q.
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`And, again, these are the portions of the claims on which
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`you focus your testimony today, correct?
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`A.
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`Yes, sir. I'm clinically oriented, and that's what I
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`focused on.
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`MR. DITTMANN: Could we please bring up PDX-402
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`again?
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`BY MR. DITTMANN:
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`Q.
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`And I would like to start, Doctor, with your first
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`The other drugs were not well tolerated, and sometimes
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`patients were almost more miserable from the drugs than they
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`were from the nausea and vomiting. And these drugs were very
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`welcome. They were extensively used, and I think made a big
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`difference to patients.
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`Q.
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`So, that moving forward now about a decade later to the
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`2003 time period, how did the available setrons compare with
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`one another in terms of their efficacy and safety concerning
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`PONV?
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`A.
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`I would say that the vast majority of the literature that
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`I'm aware of felt that the drugs were, basically,
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`interchangeable. The three 5-HT
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`s, some minor differences in
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`dosing perhaps and cost at the time, but they really weren't
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`different from each other.
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`They were safe, as understood in 2003, and were used
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`almost interchangeably. You'd find different hospitals with
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`different 5-HT
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`s for no particular reason. They would just
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`have one or the other.
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`Q.
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`Now, in the 2003 time period, what was being done to try
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`to help improve the treatment of PONV?
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`A.
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`So, since we had -- so the key to treating a patient --
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`and this was even recognized many years before this -- is
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`multimodal therapy, and what that really means is attacking
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`the different receptors to get a combined effect to help treat
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`or prevent a patient from getting sick.
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`So, we already had drugs to address these related
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`different receptors, whether it be the histamine or the
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`serotonin receptors, and, as I said, these three drugs were
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`basically interchangeable.
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`So, around that time period, including myself, people
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`started looking towards new drugs and new targets, and the
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`most or the best candidate at that time was the NK-1 receptor,
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`which is a receptor for something called substance P. And we
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`were trying to develop NK-1 receptor antagonists as part of
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`the armamentarium to develop drugs to help protect patients as
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`well as treat them.
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`MR. DITTMANN: Can we please bring up PTX-100?
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`THE COURT: As part of your arsenal, right?
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`THE WITNESS: Yes, ma'am, if you will.
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`THE COURT: Is that what you mean? Okay.
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`BY MR. DITTMANN:
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`Q.
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`Doctor, can you please tell us if you recognize this
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`document?
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`A.
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`Q.
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`A.
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`I do.
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`What is it?
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`This is a paper by Dr. Geszetesi that was the first -- I
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`believe was the first trial for an NK-1 receptor antagonist
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`designated by its number CPP 122721.
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`This was -- this paper is from 2000, as I recall, and,
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`as I said, this was a major effort to try and develop the
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`limited efficacy and well known side effects associated with
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`the available antiemetic drugs, the search for more
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`efficacious compounds without side effects has continued."
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`Do you see that, Doctor?
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`Yes, sir.
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`What would a POSA understand this sentence to be saying?
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`So, they're really talking about two different things in
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`A.
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`Q.
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`A.
`
`this sentence.
`
`First of all, when they say given the limited efficacy
`
`and well known side effects, they're talking about two things.
`
`The efficacy of the 5-HT
`
` receptor antagonists, as I read it,
`
`3
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`who really didn't have a lot of side effects; but they're also
`
`describing the problem with the side effects of the more
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`classic agents, if you will, droperidol and things like that.
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`Furthermore, they make the point that while there
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`are -- there were a fair number of drugs available at the
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`time, people were still getting sick. So, we had -- we did
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`better, but we needed to do better. And the goal was to
`
`develop additional drugs to make a more comprehensive therapy
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`for patients by combining agents.
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`So, this being a whole new receptor, you could add it
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`to the list of receptors you were able to address.
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`THE COURT: And the NK-1 receptor had been identified
`
`as playing a role in nausea and vomiting of patients?
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`THE WITNESS: Yes, and approximately -- substance P
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`NK-1s and bring them into clinical use.
`
`Q.
`
`A.
`
`Q.
`
`A.
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`And do you recognize any of the authors of this article?
`
`I personally know three of them.
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`And can you explain who they are and how you know them?
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`I know Dr. Scuderi, Dr. White and Dr. D'Angelo. These
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`were all people doing research in the area of post-operative
`
`nausea and vomiting, and it became kind of a circle, if you
`
`will. You know the people who deal in the field that you deal
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`in.
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`Q.
`
`Do you know what their reputation was in the PONV field
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`in this time period of 2000 to 2003?
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`A.
`
`Yeah, they were viewed as good researchers, good
`
`clinicians, Well known.
`
`Q.
`
`And could you briefly summarize what this article
`
`generally discusses?
`
`A.
`
`It shows the efficacy of this particular NK-1 receptor
`
`antagonist. As I recall, this drug didn't happen to make it
`
`to market, but -- for other reasons; but it showed good
`
`efficacy in, I believe, the 200-milligram range or so, as I
`
`recall. Basically, showed promise for these types of drugs in
`
`this class.
`
`Q.
`
`If we can look over on the right column around midway
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`down, yes, there's a sentence that starts, "Given the
`
`limited." Do you see that?
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`I'll read it for the record. It states, "Given the
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`is quite old, it was known, I mean, for a long time, and we
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`knew what was involved probably in the 1990s.
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`BY MR. DITTMANN:
`
`Q.
`
`And approximately --
`
`THE COURT: Now, just a second.
`
`There's a sentence right before what you have
`
`highlighted there and -- from 2000, this article, it says,
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`well, even ondansetron has recently been reported with side
`
`effects.
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`THE WITNESS: Every drug has side effects, but it was
`
`unusual. As a matter of fact, that's why they even mentioned
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`it. You know, nobody mentioned that droperidol causes side
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`effects because it was so common. This was less common.
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`Ondansetron can cause allergic reactions, it can cause
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`EKG changes, as can the other drugs of the class; but,
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`generally, speaking it is extremely well tolerated. If you
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`compare it to what we had, way better, but no drug is
`
`flawless. There's no question.
`
`THE COURT: Okay. So, that's how you interpret that
`
`sentence.
`
`THE WITNESS: Yes, ma'am.
`
`BY MR. DITTMANN:
`
`Q.
`
`And turning to your Honor's question about NK-1s, if we
`
`can look at the next paragraph and blow that up, please. You
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`see here the second sentence states, "It has been suggested
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`the 5-HT
`
` receptor antagonists for chemotherapy-induced nausea
`
`3
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`and vomiting appears to be similar, this author believes a
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`similar conclusion may be drawn for PONV. At the present
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`time, the main differences in 5-HT
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` receptor antagonists for
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`3
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`PONV appear to be related to drug acquisition costs and
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`administration schedules."
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`Do you see that?
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`Yes, sir.
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`Can you explain how a POSA would understand these
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`A.
`
`Q.
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`statements in the 2003 time period?
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`A.
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`It's basically conveying what was my belief and still is
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`that the 5-HT
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` receptor drugs that were available at the time,
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`3
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`the three of them were basically interchangeable.
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`Different hospitals had different drugs, different
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`people liked different drugs just because they did, but there
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`was really no significant clinical difference between them.
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`And, as I said, the real slight differences in dosing,
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`differences in prices, but other than that, the drugs were
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`basically interchangeable.
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`MR. DITTMANN: Please bring up next PTX-092.
`
`BY MR. DITTMANN:
`
`Q.
`
`A.
`
`Q.
`
`A.
`
`And do you recognize this document, Doctor?
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`I do. It's an editorial out of JAMA.
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`And do you know the author of this article?
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`I do. It's T. J. Gan, Dr. Gan.
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`in the peripheral nervous system. A recent study suggests
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`that NK-1 receptor antagonists may effectively prevent PONV."
`
`And do you see that, Doctor?
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`THE COURT: Keep going one more sentence.
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`MR. DITTMANN: Sure.
`
`BY MR. DITTMANN:
`
`Q.
`
`Sure. "Combining this new class of antiemetics with a
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`serotonin antagonist may eliminate PONV. Use of the
`
`combination of an NK-1 receptor antagonist and ondansetron
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`significantly prolonged the time to administration of rescue
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`antiemetics compared with the use of either drug alone and
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`almost completely abolished emesis."
`
`Do you see that, Doctor?
`
`Yes, I do.
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`Can you explain what this passage would have been stating
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`A.
`
`Q.
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`to a POSA in the 2003 time period?
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`A.
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`It's, basically, the same comment that I have been
`
`addressing. Combination, multimodal therapy to eliminate a
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`post-operative nausea and vomiting, and reporting on the
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`combination of an NK-1 with ondansetron where they had very
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`good results in reduction in PONV. Very good efficacy by
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`combining the drugs.
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`THE COURT: Understood. Counsel, would you just make
`
`a note that I'm going to have a legal question for you
`
`regarding this time frame?
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`Q.
`
`And does Dr. Gan -- was he known to have a good
`
`reputation in the PONV field in the 2003 time period?
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`A.
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`Yes. He had a very good reputation. He was the first
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`author on the consensus guidelines by SAMBA for all the years
`
`it was published.
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`THE COURT: What's his degree there?
`
`THE WITNESS: It is an English degree. He's actually
`
`from Indonesia, and it's a British-based degree. He's now a
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`chairman of a department of anesthesia. He's a very good
`
`researcher.
`
`THE COURT: So, he's a doctor?
`
`THE WITNESS: Oh, yes, he's medical doctor.
`
`THE COURT: Okay.
`
`BY MR. DITTMANN:
`
`Q.
`
`A.
`
`Q.
`
`A.
`
`And what year was this article by Dr. Gan published?
`
`I believe --
`
`If you look at the bottom?
`
`Thank you. 2002.
`
`MR. DITTMANN: If we can please turn to Page 3. If
`
`we can look under the heading Future Development. Yes. Thank
`
`you.
`
`BY MR. DITTMANN:
`
`Q.
`
`Do you see it states, "The natural ligand of the
`
`neurokinin-1 (NK-1) receptor, substance P, is found in the
`
`nucleus tractus solitarius and the area postrema, as well as
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`MR. DITTMANN: Of course. Yes, your Honor.
`
`THE COURT: Go right ahead, though.
`
`BY MR. DITTMANN:
`
`Q.
`
`Doctor, in your opinion in the 2003 time period, how
`
`would a POSA go about trying to develop an improved antiemetic
`
`drug product for preventing PONV?
`
`A.
`
`Well, as I said, many of the other receptors had been
`
`addressed by different types of chemistry, including the
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`serotonin antagonists, and we still weren't winning.
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`30 percent of patients were still getting sick in that time
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`period. That's lot of people.
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`So, we were look to go improve our outcomes, and we
`
`started to lack for other receptors and other drugs. So,
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`that's why the development focused on the most promising
`
`target at the time, which was the NK-1 receptor and Substance
`
`P.
`
`Q.
`
`Is your opinion consistent with your own personal
`
`research experience in this time period?
`
`A.
`
`Yes. I was actually conducting trials in this time
`
`period and a little afterwards with the NK-1 receptor
`
`antagonists, and they're still looking at them, actually.
`
`Q.
`
`And --
`
`THE COURT: And some of them have come out on the
`
`market, right.
`
`THE WITNESS: Right. The first one was aprepitant,
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`and I worked on the first trial for the Phase III studies for
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`aprepitant for Merck to bring it to market.
`
`MR. DITTMANN: Your Honor anticipated my next
`
`question, so I'll continue.
`
`BY MR. DITTMANN:
`
`Q.
`
`Do you know when this first NK-1 was approved for use in
`
`PONV?
`
`A.
`
`In PONV I think was 2005 or so, a little earlier for
`
`CINV.
`
`Q.
`
`Can we please bring up PDX-402 again?
`
`So, I want to move on -- unless your Honor has any
`
`questions -- to the next opinion; that is, if palonosetron
`
`would have been pursued, a POSA would not have pursued a dose
`
`lower than 2 milligrams for treating emesis based on the prior
`
`art.
`
`Did you hear Dr. Frame testify on Monday that in his
`
`opinion a POSA would have been motivated to pursue a dose as
`
`low as 0.25 milligrams?
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`I did.
`
`And do you agree with Dr. Frame?
`
`I do not.
`
`Now, of the prior art that you have considered in this
`
`case, what prior art would have been considered the most
`
`important in your view to a POSA focusing on developing a
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`palonosetron drug product?
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`in, received by a section editor. The section editor sends it
`
`out to a series of experts, peers, if you will, three to four
`
`peer reviewers, and the articles are reviewed for methodology,
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`results, conclusions, bias inherent in the article, defects in
`
`conclusions, and discussion sections. And then
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`recommendations by the peers is sent back to the section
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`editor. It could be reject, accept, or accept with revision,
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`or rewrite and we'll reconsider it.
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`So, basically, they can be submitted multiple times
`
`over and over again being revised, enhanced, clarified.
`
`Finally the section editor and the editor make the decision on
`
`whether the article will be accepted for final publication.
`
`THE COURT: And I suppose they have to have some kind
`
`of data in them, too. The person can't just be theorizing.
`
`They're going to be reporting on the results of some kind of
`
`work they're doing?
`
`THE WITNESS: Right. There are journals of pure
`
`theoretical writing and pure theory, but these are research
`
`articles, and this is a clinical trial, and you'll see animal
`
`trials. There can be thought pieces in these journals, but
`
`those are not considered peer-review articles.
`
`BY MR. DITTMANN:
`
`Q.
`
`Other than the Tang reference, are you aware of any other
`
`peer-reviewed publications in 2003 or available in 2003
`
`containing palonosetron clinical data?
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`Of the prior art that's available -- that was available
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`at the time, there was an article -- the only peer-reviewed
`
`article that I was aware of at the time was written by Dr.
`
`Tang, and that would have been the best source for information
`
`to a POSA at that time period.
`
`Q.
`
`Can we please bring up DTX-0276?
`
`And, Doctor, is this the Tang reference that you just
`
`mentioned?
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`It is.
`
`And in what journal was Tang published?
`
`Anesthesia & Analgesia.
`
`Is the commonly referred to as A & A in your field?
`
`It is. It is easier to say.
`
`Is this one of the journals you mentioned earlier that
`
`you have been a reviewer on for the past ten years or so?
`
`A.
`
`I am a reviewer for it, and my work has been published in
`
`it, as well.
`
`Q.
`
`A.
`
`What is the reputation of this journal?
`
`It has a very good reputation in the world of
`
`anesthesiology. I would say personally as good as
`
`Anesthesiology. That's the bigger journal. And this has a
`
`decent impact factor, similar actually, so quite good.
`
`Q.
`
`A?
`
`A.
`
`What is the process for submission of an article to A &
`
`A & A is a peer-reviewed journal, so articles are sent
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`I am not.
`
`Q.
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`A.
`
`What was the Tang study designed to show?
`
`The Tang study was a Phase II trial to determine a
`
`preliminary efficacy and to select doses for further study in
`
`more advanced trials, Phase III-type studies. So it was a
`
`dose-ranging study, kind of to pick doses, if you will.
`
`Q.
`
`In interpreting a clinical study such as Tang what does a
`
`clinical researcher typically focus on?
`
`A.
`
`So, the most important section is methodology, how the
`
`study was conducted, what was evaluated. Then the results are
`
`interpreted in light of the methodology. Analysis of the
`
`results usually can lead you to your own conclusions. You, of
`
`course, look at how the authors process the data, as well.
`
`And in light of the methodology and the study design you
`
`interpret the results.
`
`Q.
`
`And how --
`
`THE COURT: Interesting. So, you are kind of
`
`critically evaluating -- you said the most important thing to
`
`evaluate is the method?
`
`THE WITNESS: Yes.
`
`THE COURT: Which is when we lawyers read through
`
`these articles we skip that part, unless we have to focus on
`
`it, but it is interesting to know that the peers reviewing it
`
`look very carefully at what the setup was for the study.
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`THE WITNESS: Well, you can design a study to come
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`out a particular way if you wanted to.
`
`THE COURT: Oh.
`
`BY MR. DITTMANN:
`
`Q.
`
`A.
`
`And can you tell us how the Tang study was designed?
`
`The Tang study was what we would consider the highest
`
`level of scientific research. It was a double-blind
`
`randomized placebo-controlled trial.
`
`Q.
`
`And can you tell us the importance -- or whether it is
`
`important to include a placebo arm?
`
`A.
`
`Yes. Placebo arms are -- sometimes they're hard to
`
`include for clinical reasons, but they're extremely important
`
`because it demonstrates if there's a placebo effect. Simply
`
`giving someone a syringe of saline can have an effect on
`
`people, and that's been shown in multiple trials.
`
`So, it is very, very important to have it to determ