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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 8, 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 2005
`Dr. Reddy's Laboratories, Ltd., et al. v. Helsinn Healthcare S.A.
`Trial PGR2016-00007
`
`Page 1 of 14
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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
` ISAAC S. ASHKENAZI, ESQUIRE
`SAUL EWING
`BY: CHARLES M. LIZZA, ESQUIRE
`Attorneys for the Plaintiffs
`
`BUDD LARNER
`BY: STUART D. SENDER, ESQUIRE
` MICHAEL H. IMBACUAN, ESQUIRE
` HUA HOWARD WANG, ESQUIRE
` CONSTANCE S. HUTTNER, ESQUIRE
` KENNETH E. CROWELL, 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
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`United States District Court
`Trenton, New Jersey
`
`Colloquy
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`I N D E X
`
`WITNESS VOIR DIRECT CROSS REDIRECT RECROSS
` DIRE
`David G. Frame
`By Mr. Imbacuan
`By Mr. Ashkenazi
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`United States District Court
`Trenton, New Jersey
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`Colloquy
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`4
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`(In open court. June 8, 2015, 9:30 a.m.)
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`THE COURT: Good morning, everybody.
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`ALL: Good morning, your Honor.
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`THE COURT: Okay. Mr. Lombardi, do you have a
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`witness?
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`MR. LOMBARDI: Yes. DRL is going to be presenting
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`our next witness.
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`THE COURT: I see. Mr. Imbacuan, good morning.
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`MR. IMBACUAN: Good morning, your Honor.
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`MR. DITTMANN: Your Honor, if I may?
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`THE COURT: Yes, sir. Mr. Dittmann.
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`MR. DITTMANN: Briefly, we wanted to address first an
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`issue that has come up, and we discussed it briefly
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`previously, but it's now been crystallized, and we'd like to
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`present it to your Honor, if I may, at this time with respect
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`to the deposition testimonies of Dr. Markman. Can I present
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`that to you briefly now?
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`THE COURT: Whatever. He is our witness this
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`morning, no?
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`MR. DITTMANN: He is someone that we intend to call
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`this week, at least through his deposition testimony.
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`If you recall shortly before trial, Dr. Markman, we
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`were told, was not going to come to trial. We attempted to
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`procure his testimony, his appearance in our case, but he's
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`not available, and that's fine. We, of course, have no issues
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`Colloquy
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`5
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`with that. And what we had was an agreement with defendants,
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`which this letter, if I can, hand up to your Honor.
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`THE COURT: Mr. Dittmann, I'm not sure we're going to
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`do this right now. We have a witness here. Is it necessary?
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`MR. DITTMANN: It is because we're about to begin our
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`case, and we need to know our order of proof, and part of that
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`is Dr. Markman. And we think that Dr. Markman's testimony is
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`particularly appropriate, considering Dr. Frame is about to
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`testify.
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`It's plaintiffs' position that some of the things
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`you're about to hear from Dr. Frame are directly contrary to
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`what Dr. Markman testified to in his deposition, and we've set
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`forth all these positions in this letter that you've asked
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`for, which we can hand up to your Honor.
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`THE COURT: Okay. Hand it to me, and I'll look at it
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`during the break.
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`MR. DITTMANN: Okay.
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`THE COURT: Then I'll know what you're talking about.
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`MR. DITTMANN: Thank you.
`
`THE COURT: Sure.
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`Anything else at the moment?
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`MR. SENDER: Judge, on the same topic, we had
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`objected, since Dr. Markman was our expert, and we can hand
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`you a letter, as well.
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`THE COURT: Do you have one?
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`Frame - Direct
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`A.
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`So, CINV, so chemotherapy-induced nausea and vomiting is
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`typically classified in a few different ways.
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`So, I give you chemotherapy, okay? Within the first
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`24 hours if you have nausea and vomiting, we call that acute
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`nausea and vomiting. If you have nausea and vomiting past
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`24 hours, we call that --
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`THE COURT: You mean onset past 24 hours, or enduring
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`past 24 hours?
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`THE WITNESS: Either way. So anything that happens
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`past 24 hours, we call delayed nausea and vomiting. And I'll
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`be honest with you, there's no magic to why that is 24 hours.
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`It was literally set as a tool to be able to have different
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`endpoints to be able to do research and evaluate your
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`antiemetics.
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`There's no necessarily special, absolute time frame
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`that everything changes at 24 hours. It's just used for
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`convention.
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`BY MR. IMBACUAN:
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`Q.
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`Is the same delineation used for post-operative nausea
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`and vomiting?
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`A.
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`So, it is -- it is similar. It's not really been -- I
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`don't think it's been set in stone quite as much as what we
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`have in CINV, and people have a little bit different opinions
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`on when is your higher rate of post-op nausea and vomiting.
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`A lot of that occurs much earlier than what you see
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`inserts for all the drugs.
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`Frame - Direct
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`THE COURT: And this one happens to be dated 2001?
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`THE WITNESS: Yes, it is.
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`THE COURT: Okay.
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`BY MR. IMBACUAN:
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`Q.
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`A.
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`Is there another package insert included in DTX-1231?
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`Yes. So, the next one is granisetron. And the third one
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`is dolasetron.
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`Q.
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`So, based on the package inserts what forms of -- what
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`dosage forms were these prior 5-HT
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` antagonists available in?
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`3
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`A.
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`Q.
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`These were available both orally and intravenously.
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`Is there a benefit to having an intravenous form of a
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`5-HT
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` antagonist?
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`3
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`A.
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`So, yeah, there really is for a couple different reasons.
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`One, as you can imagine, if you are having emesis or even if
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`you're terribly nauseated, you really don't want to put
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`anything in your stomach, right? And, so, it is not uncommon
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`that if you're already sick and I give you an oral antiemetic
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`you actually throw it back up, and, so, that's not going to
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`help you. And, so, that's a main -- that's a big reason why
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`you would like to have an I.V. form available.
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`The other big reason is -- is especially in the
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`oncology setting, so a patient comes in for their
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`chemotherapy, right? We want to make sure that they have good
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`concentrations of that serotonin antagonist so that we can
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`Frame - Direct
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`Frame - Direct
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`39
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`41
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`with CINV, but a lot of the trials do use a 24-hour endpoint
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`for PONV, as well.
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`Q.
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` antagonists
`Before palonosetron, were there any 5-HT
`3
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`commercially available?
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`A.
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`Yes, there were. There were three before palonosetron.
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`One was ondansetron.
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`THE COURT: You don't have to give its chemical name.
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`That's all right. Ondansetron.
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`THE WITNESS: Ondansetron.
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`THE COURT: That will do.
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`THE WITNESS: Okay.
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`THE COURT: We're familiar with those names.
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`THE WITNESS: Okay. Great. Granisetron and
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`dolasetron.
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`BY MR. IMBACUAN:
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`Q.
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`A.
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`Q.
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`Did you review the labels for these 5-HT
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` antagonists?
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`3
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`I did.
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`And do you have a binder up there, Dr. Frame, with some
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`exhibits?
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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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`Can we look at DTX-1231? What is DTX-1231?
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`So, this is the package insert from ondansetron, or
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`Zofran®, and it actually comes from what we call the
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`Physician's Desk Reference. And, so, this is essentially a
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`publication that comes out that includes all of the package
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`help prevent that nausea and vomiting.
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`And, so, you really want to give -- we like to give
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`that as an I.V. drug so that we know it all gets in your
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`system, right? We don't have to worry how much gets absorbed.
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`And we can do it right before we give your chemotherapy so
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`your concentrations are very high as we start to give you your
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`chemotherapy.
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`And, so, the standard way that almost every oncology
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`clinic gives a serotonin antagonist is as an I.V. form.
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`Q.
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`Prior to the approval of palonosetron how were the 5-HT
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`3
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`antagonists used to treat CINV?
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`A.
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`So, they were actually used both for acute and delayed
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`nausea and vomiting. As I said, you don't get quite as much
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`benefit out of them usually for delayed nausea and vomiting
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`because, again, serotonin is not your biggest driver later in
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`the game, right?
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`And, so, when ondansetron -- so just, for example, when
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`ondansetron first came out, okay, we had to compare it to what
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`was our gold standard. And our gold standard at the time was
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`what we call high-dose metoclopramide. So, high-dose -- and
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`the reason we use high-dose metoclopramide is because
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`interestingly at very high doses it would block some 5-HT
`3
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`receptors. But the problem with high-dose metoclopramide is
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`it also causes other problems with the nerves and you become
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`very jittery and you'll just shake and shake and shake. We
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`

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`Frame - Direct
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`Frame - Direct
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`call it an extrapyramidal symptom. It also affects your GI
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`tract.
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`THE COURT: What's that?
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`THE WITNESS: Extrapyramidal?
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`THE COURT: Spell "pyramidal."
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`THE WITNESS: P-Y-A-R --
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`THE COURT: P-Y-R-A?
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`THE WITNESS: Yes.
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`THE COURT: Okay. So, it makes you shaky.
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`THE WITNESS: Yes. It makes you really, really
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`shake, so, literally I would have patients that literally
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`would be sitting there shaking, but it was better than
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`throwing up 20 times a day.
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`Sadly, though, once in a while that effect won't go
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`away. So, even though you take the drug away, once in a while
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`patients still wind up with that for a long period of time.
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`The metoclopramide also plays interactions with your GI
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`tract and actually will often cause you to have a lot of
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`diarrhea. So that's not very helpful either. But that was
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`our -- that was our main standard of care for patients that
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`were -- to prevent emesis in these patients, nausea and
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`vomiting in these patients.
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`THE COURT: So, that drug isn't regarded as a 5-HT
`3
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`antagonist?
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`THE WITNESS: It is not because you have to use very,
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`Q.
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`Dr. Frame, are you aware that plaintiffs' experts have
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`stated that the art had shifted its focus from setrons to NK-1
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`antagonists at the time palonosetron was being involved?
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`A.
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`Q.
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`A.
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`Yes, I do.
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`And do you agree with that statement?
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`So, I don't totally agree with that statement. NK-1
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`antagonists -- I'm sorry. Let me back up one second. Sorry.
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`THE COURT: Can we go back to your schematic, please?
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`THE WITNESS: Yes.
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`THE COURT: This is your Slide 6.
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`THE WITNESS: So, as I described a few minutes ago,
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`we know that there's not only one neurotransmitter, right, not
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`only one of these chemicals that are causing nausea and
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`vomiting.
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`And, so, at the time it had been discovered that these
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`NK-1 antagonists were also important in nausea and vomiting.
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`And interestingly in the animal models, one of the reasons for
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`the excitement of this is in the animal models it actually had
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`the broadest range as an antiemetic of virtually any drug we
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`had seen, and what I mean by that --
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`THE COURT: What did?
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`THE WITNESS: The NK-1 antagonists.
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`THE COURT: Plural?
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`THE WITNESS: Yes.
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`THE COURT: And these are approved drugs?
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`Frame - Direct
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`43
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`very high doses, and, so, now I would never, ever do that.
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`THE COURT: So, it is not considered to be in this
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`class?
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`THE WITNESS: It is not. No, that's correct.
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`THE COURT: So, ondansetron was the first 5-HT
`3
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`antagonist?
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`THE WITNESS: Yes. Exactly. So that was the very
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`first one that was approved, and, so, they did their trials to
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`compare ondansetron to metoclopramide. So even with having
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`all those side effects, the best results we saw was about
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`40 percent complete response with the metoclopramide. With
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`the ondansetron, that response went up to approximately 70,
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`75 percent.
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`THE COURT: For acute?
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`THE WITNESS: For acute.
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`They also looked at delayed in those initial trials
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`because that was also one of our standards for delayed nausea
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`and vomiting. And both ondansetron and metoclopramide had
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`about a 60 percent overall response rate for delayed nausea
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`and vomiting. So, it pretty much matched a lot of our
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`standard.
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`And, so, it became very commonplace, and, actually,
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`even in the Guidelines at the time, to be -- to use 5-HT
`3
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`antagonists for both acute and delayed nausea and vomiting.
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`BY MR. IMBACUAN:
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`Frame - Direct
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`THE WITNESS: They are now.
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`THE COURT: Okay. Counsel, I think we need a little
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`more foundation because Dr. Frame knows exactly what he is
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`talking about, but I don't.
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`NK-1 antagonists, if we're going to talk about them, we
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`need to know a name or names for them, and are they on, you
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`know, the market or are they just in lab work at a given point
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`in time. I don't know.
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`MR. IMBACUAN: We can move on, your Honor.
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`THE COURT: Okay.
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`BY MR. IMBACUAN:
`
`Q.
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`So, Dr. Frame, palonosetron is approved for treating
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`delayed emesis?
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`A.
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`Q.
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`It is.
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`And is it the only setron that's approved for treating
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`delayed emesis?
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`A.
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`Q.
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`It is.
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`And do you have a view on its approval for treating
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`delayed emesis?
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`A.
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`So, I do. So, one of the -- one of the advantages of
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`palonosetron -- and we're going to get to this in a little bit
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`I think -- but one of the advantages of palonosetron is it has
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`what we call a very long half-life.
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`THE COURT: It is eliminated slowly from the body?
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`THE WITNESS: Exactly. And, so, it has about a
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`Q.
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`So let's focus --
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`Frame - Direct
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`THE COURT: So that's three?
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`THE WITNESS: That's three.
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`BY MR. IMBACUAN:
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`Q.
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`A.
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`Q.
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`So there are three press releases in DTX-1022?
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`Yes.
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`So let's just focus on the October 3rd, 2001 press
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`release, if we could have that on the screen. That's
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`DTX-1022-0004.
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`You reviewed this press release, right, Dr. Frame?
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`A.
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`Q.
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`I did.
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`And what was reported just generally in this press
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`release?
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`A.
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`So, this press release, the main purpose of this press
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`release was to describe that they had gone on to Phase III
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`trials and that they were completing patient enrollment.
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`Q.
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`A.
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`Q.
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`And you said "they." Who are you referring to?
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`I'm sorry. Helsinn.
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`So let's just go through the press release. Does the
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`press release say anything about Phase I trials that Helsinn
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`conducted?
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`A.
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`Q.
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`A.
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`It does. So right here.
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`Can you read that into the record, please?
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`Yes. So, "Results of Phase I trials in healthy
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`volunteers to assess the pharmacokinetic properties and safety
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`as well as essentially the delayed, or Days 2 through 5.
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`Frame - Direct
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`THE COURT: This is in the Phase III now?
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`THE WITNESS: No, that was the Phase II.
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`THE COURT: Well, it says --
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`THE WITNESS: So --
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`THE COURT: -- "Based on the extended half-life of
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`palonosetron and the results of a Phase II trial, its efficacy
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`is being assessed over Day 2 through Day 5." How do you read
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`that?
`
`THE WITNESS: Yes. I'm sorry. So they were able --
`
`I apologize.
`
`So they were able to assess -- that's what I was saying
`
`-- is they were able to assess this in the Phase II trial,
`
`and, yes, it was also being assessed in the Phase III.
`
`BY MR. IMBACUAN:
`
`Q.
`
`So you anticipated my next question.
`
`Does this press release say anything about Phase III
`
`trials that were being conducted?
`
`A.
`
`Yes. And, so, it says that the double-blind randomized
`
`Phase III trial compares I.V. palonosetron to currently
`
` antagonists.
`marketed 5-HT
`3
`
`Q.
`
`So, based on the press release, Dr. Frame, what can you
`
`conclude about how Helsinn was conducting its clinical trials
`
`for palonosetron?
`
`A.
`
`So, again, this is the very standard way that all
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`Frame - Direct
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`59
`
`of palonosetron were presented at the American Society of
`
`Clinical Oncology meeting in May of 2001."
`
`It also goes on to say that the elimination half-life
`
`that they found was 37 hours.
`
`Q.
`
`And how did this compare to the then marketed 5-HT
`3
`
`antagonist?
`
`A.
`
`So the marketed agents at the time had between
`
`approximately four- and nine­hour half-life, and so this was
`
`significantly longer.
`
`Q.
`
`A.
`
`And was this reflected in the press release?
`
`It was. It says that it was at least three times longer
`
`than marketed agents.
`
`Q.
`
`So, what about Phase II trial, did the press release say
`
`-- did this press release say anything about Phase II trials
`
`that Helsinn had conducted?
`
`A.
`
`It does. So just the next line, it actually says that
`
`Phase II trials assessing the efficacy beyond 24 hours were
`
`done. And, again, due to the long half-life of the drug, you
`
`were able to study it for a longer period of time.
`
`Q.
`
`And what does that mean when you say you were able to
`
`study it for a longer period of time?
`
`A.
`
`Right. So I apologize.
`
`If you look just up a little bit further in the press
`
`release, right up here, it says that the efficacy in the Phase
`
`II trial was to look at both acute, so the 24-hour duration,
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`61
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`these -- that the majority of these clinical trials are done.
`
`Q.
`
`So, Dr. Frame, this is a -- the information about
`
`palonosetron is being disclosed in a press release. Does the
`
`fact that it's -- the information is contained in a press
`
`release make it any less relevant to you?
`
`A.
`
`No. So, you know, to me purposes of press releases are
`
`to be able to inform you where drugs are at in development.
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`And I'll be quite honest with you. We often have to prepare
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`for drugs coming to market, and so I'm actually even on a
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`Listserv for oncology drugs so that I get press releases so
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`that I can follow where drugs are at so that I can get ready
`
`for them to come to clinic.
`
`Q.
`
`So it's part of --
`
`THE COURT: We also see sometimes that a drug maker
`
`will say, ah, you know, we thought we were going to get this
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`drug to the public, but we had to shut it down in Phase III.
`
`THE WITNESS: That's actually a very good point. You
`
`know, press releases don't always just say all the good stuff
`
`that they find. You're absolutely right. The press releases
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`will tell you that, what you exactly said, was that, oop, it
`
`didn't work. Yeah.
`
`I guess the other thing I will say from this press
`
`release is the FDA would not have let you go to a Phase III
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`trial if you did not show an efficacious dose in Phase II.
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`BY MR. IMBACUAN:
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`

`
`Q.
`
`Let's move on to the '333 patent, Dr. Frame. Can I have
`
`Q.
`
`Does the -- the '333 patent also talks about
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`Frame - Direct
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`Frame - Direct
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`the slides back, please.
`
`concentrations, right?
`
`62
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`64
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`Did you review the '333 patent as part of your work in
`
`the case, Dr. Frame?
`
`A.
`
`Q.
`
`It does.
`
`And what does it say with respect to concentrations of
`
`the compounds?
`
`A.
`
`So, in Column 12, Lines 60 through 68, it states that the
`
`final composition will comprise 0.000001 percent to 10
`
`I did.
`
`And that's DTX-0343.
`
`Okay.
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`When did the '333 patent issue, Dr. Frame?
`
`percent, with, again, preferably a little bit lower range
`
`April 13th of 1993.
`
`of .00001 percent to 1 percent.
`
`In general, what is the subject matter of the '333
`
`Q.
`
`So does the '333 patent teach -- say anything about the
`
`patent?
`
`difficulty of finding a therapeutically effective amount of
`
`A.
`
`So, this is -- this is actually a sort of broad patent
`
`the compounds that include palonosetron?
`
`that looks at structures of several different potential HT
`
`3
`
`A.
`
`It states that, without undue experimentation -- I'm
`
`antagonists.
`
`sorry.
`
`Q.
`
`A.
`
`Q.
`
`And does the '333 patent cover palonosetron?
`
`In Column 12, Lines 19 through 24, it states that,
`
`It does.
`
`without undue experimentation, and in reliance upon personal
`
`And I believe you prepared some demonstratives that
`
`knowledge, it would -- you'd be able to ascertain a
`
`highlight relevant disclosures in the '333 patent, Dr. Frame?
`
`therapeutically effective dose.
`
`A.
`
`Q.
`
`I did.
`
`So let's go to the first slide.
`
`So, what uses for the compounds that included
`
`Q.
`
`A.
`
`Q.
`
`And do you agree with this statement in the '333 patent?
`
`Yes.
`
`Now, does the '333 patent disclose a representative --
`
`palonosetron did the '333 patent teach?
`
`THE COURT: Just a second. Before we leave that
`
`A.
`
`So, it talked about it would be used for emesis and,
`
`slide, I will always struggle with moving the decimal point
`
`again, for a little bit broad range of emesis, including
`
`when you've got a percentage --
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`radiation therapy, chemotherapy, and post-surgical nausea and
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`63
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`vomiting.
`
`Frame - Direct
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`Q.
`
`And, just so the record is clear, Dr. Frame, citing
`
`excerpts at Column 10, Line 69, Column 9, Lines 56 to 58 of
`
`the '333 patent, DTX-0343.
`
`So, what does the '333 patent teach about how the
`
`compounds that include palonosetron can be administered?
`
`A.
`
`So, it says that these actually can also be given in a
`
`variety of ways. Column 12, Lines 25 through 29, show
`
`that these can -- state that these can be given orally,
`
`systemic, by different routes including transdermal,
`
`internasal, even suppository, or parenteral, including an
`
`I.V., intramuscular or subcutaneous injection.
`
`Q.
`
`And does the '333 patent include any teachings regarding
`
`the potentially therapeutic dosages of these -- of the
`
`compounds that include palonosetron?
`
`A.
`
`Q.
`
`Yes, it does.
`
`And what does it say with respect to therapeutically
`
`effective amounts?
`
`A.
`
`Yes. So in Column 12, Line 16 through 18, it states that
`
`for a 70­kilogram human, the range may be from 70 nanograms
`
`per day to 70 milligrams per day, and then it states,
`
`preferably, 700 nanograms per day to 7 milligrams per day.
`
`Q.
`
`And these are doses of the drug that could be
`
`administered, the compounds that could be administered?
`
`A.
`
`That's correct.
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`THE WITNESS: Right.
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`65
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`THE COURT: -- expressed. And so if we look at the
`
`patents that call for .05 milligram per milliliter, they don't
`
`have a percentage in there.
`
`THE WITNESS: Right.
`
`THE COURT: And so I'm not sure what these
`
`percentages in the Column 12 lines that you've quoted tell me
`
`in terms of concentration.
`
`THE WITNESS: Right. So, essentially, it's the dose
`
`divided by a hundred. So, in this case it would be 5
`
`multiplied by a hundred so it would be 5 percent.
`
`MR. IMBACUAN: .5 percent?
`
`THE WITNESS: Yes.
`
`THE COURT: I don't know --
`
`THE WITNESS: Right. So it would be --
`
`THE COURT: Well, there's a range there. The
`
`preferable range is stated to be a decimal point with four
`
`zeros after it and then a 1 and then a percentage sign --
`
`THE WITNESS: Right.
`
`THE COURT: -- to -- at the low end, and 1.0 percent
`
`at the high end, right?
`
`THE WITNESS: Right.
`
`THE COURT: So how does that give -- if at all,
`
`compare with a milligram per milliliter --
`
`THE WITNESS: Right.
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`THE COURT: -- volume concentration?
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`talking about the Tang reference.
`
`Frame - Direct
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`A.
`
`Q.
`
`A.
`
`Yes.
`
`And you had prepared some demonstratives regarding Tang?
`
`Yes.
`
`MR. IMBACUAN: Can we have Demonstrative 29?
`
`BY MR. IMBACUAN:
`
`Q.
`
`So just to recap, Dr. Frame, what was studied in the Tang
`
`reference?
`
`A.
`
`Yes. So, Tang was a preliminary Phase II trial where,
`
`again, they studied an increasing dose of palonosetron, this
`
`time given I.V., for post-op nausea and vomiting in women
`
`receiving hysterectomies.
`
`Q.
`
`A.
`
`And what doses were studied in the Tang reference?
`
`So, they studied 0.1, 0.3, 1, 3, and
`
`30-micrograms-per-kilogram.
`
`Q.
`
`And what did Tang conclude regarding the efficacy of
`
`palonosetron to treat PONV in this patient population?
`
`THE COURT: Was this micrograms of drug per kilogram
`
`a person or --
`
`THE WITNESS: Yes. So I do have the conversion there
`
`of what a 70-kilogram person would be. That's on the bottom
`
`line of that graph.
`
`THE COURT: Thank you.
`
`THE WITNESS: So, Tang concluded that the
`
`30-microgram-per-kilogram dose was the significant --
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`the Tang reference, concluded that based on the teachings in
`
`Tang only 30 -- only the 30-microgram-per-kilogram dose was
`
`effective for PONV?
`
`A.
`
`Q.
`
`Yes.
`
`And he further concluded that a person of ordinary skill
`
`in the art interested in an I.V. formulation of palonosetron
`
`would have only considered doses higher than 2.1 milligrams.
`
`Do you recall that?
`
`Yes.
`
`Do you agree with Dr. Candiotti's conclusion?
`
`I do not.
`
`A.
`
`Q.
`
`A.
`
`THE COURT: Just a second. He concluded -- I'm not
`
`sure that your statement was complete. I don't know what he
`
`concluded, of course, yet, but --
`
`MR. IMBACUAN: Maybe I can rephrase, your Honor.
`
`THE COURT: In an I.V. formulation of palonosetron
`
`for CINV?
`
`MR. IMBACUAN: I didn't specify. Well, let me ask
`
`the question again.
`
`BY MR. IMBACUAN:
`
`Q.
`
`Dr. Frame, do you recall that Dr. Candiotti concluded
`
`that if a POSA was interested in developing a palonosetron
`
`I.V. formulation for PONV, they would only consider doses of
`
`2.1 milligrams or higher --
`
`A.
`
`Yes.
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`statistically significant dose that worked in this trial.
`
`BY MR. IMBACUAN:
`
`Q.
`
`And just so the record is clear, can we go back?
`
`Dr. Frame, in the table that you have in the
`
`demonstrative, you have also have a row labeled "administered
`
`concentration."
`
`Do you see that?
`
`Yes.
`
`Can you explain how you arrived at the figures that are
`
`A.
`
`Q.
`
`listed there?
`
`A.
`
`Yes. So, again, each one of these doses was put into 15
`
`mLs of solution. And, so, if you take the dose and divide it
`
`by 15, you get your concentration.
`
`Q.
`
`A.
`
`Q.
`
`And that assumes a 70-kilogram patient?
`
`Yes.
`
`Okay. So, again, what was the dose that Tang concluded
`
`was -- had efficacy to treat palonosetron in PONV for these
`
`patients?
`
`A.
`
`Q.
`
`30 micrograms per kilogram.
`
`Now, Dr. Frame, do you recall reading Dr. Candiotti's
`
`expert report in this case?
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`Yes.
`
`And he's one of plaintiffs' experts, right?
`
`Yes.
`
`And do you recall that Dr. Candiotti, when he reviewed
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`A.
`
`Q.
`
`A.
`
`Q.
`
`A.
`
`-- based on the teachings in Tang?
`
`Correct.
`
`Do you agree with that?
`
`I do not.
`
`And why not?
`
`So, when we read studies, the very first thing we usually
`
`do is actually read the whole study and evaluate the data.
`
`And then we go back and read the author's conclusions because,
`
`believe it or not, it's not unusual that you may not conclude
`
`exactly what the author concluded.
`
`And, so, this was a -- Tang called this and this was a
`
`preliminary Phase II trial. And, so, what that means -- and
`
`we do this a lot, actually -- is that in order to
`
`statistically evaluate the trial, you have to have enough
`
`patients in each arm of the trial.
`
`And, so, a lot of times what you'll do is you'll
`
`actually do a smaller number so that we can get an idea of
`
`where the efficacy is, and then you can start adding more
`
`patients to the arms. Okay?
`
`And that's essentially what was done here. And, so, to
`
`me, the easiest way to look at this -- so, actually -- so in
`
`Table 2 --
`
`BY MR. IMBACUAN:
`
`Q.
`
`A.
`
`You prepared a demonstrative on that?
`
`Yes. Yes. I'm not going to bog you down with all these
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`118
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`120
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`numbers. I'll make it a little bit more simple in just a
`
`minute.
`
`But what this shows is increasing doses of
`
`palonosetron. And, again, this is the actual dose for a
`
`70-kilogram person, just to make it a little easier. And then
`
`these are the -- so the results for each one of these doses is
`
`a variety of different results here. So this was vomiting,
`
`say 0 to 2 hours, 0 to 12 hours.
`
`THE COURT: I see that.
`
`THE WITNESS: Okay. The next one is rescue
`
`antiemetics.
`
`The next one is time to first emesis, time to rescue
`
`antiemetics, and treatment failures.
`
`And, so, treatment failures here are, again, having
`
`emesis or getting a rescue antiemetic. So, same as what we
`
`saw in Chelly.
`
`Okay. So, you'll see throughout the columns, so where
`
`there's an asterisk means that there was statistical
`
`significance, okay, and you'll see that they're kind of spread
`
`out through the columns. And the reason for that is, again,
`
`because there's very small numbers of patients in each arm.
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`So, the smaller number of patients, it only takes one
`
`or two patients to change that number pretty dramatically and
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`so your statistical significance will go up and down, up and
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`down.
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`exactly where the inflection point was with Chelly. And what
`
`you see is as you, again, you go higher and higher and higher
`
`in your doses, you really don't see much more efficacy.
`
`THE COURT: So, the first point at which you got some
`
`real efficacy was the 1 --
`
`THE WITNESS: The 1 microgram per kilogram. So, what
`
`you would really do, or what I would do, I guess I should say,
`
`what most people would do with this, right, is you really want
`
`to concentrate in this area.
`
`THE COURT: Namely, the 1 or the 3.
`
`THE WITNESS: You really want to make sure --
`
`THE COURT: I'm just trying to have the record
`
`reflect what you're pointing to.
`
`THE WITNESS: Yes. So, I'm sorry. So, really
`
`between