Page 1
`
` IN THE UNITED STATES DISTRICT COURT
` FOR THE DISTRICT OF NEW JERSEY
` - - -
`HELSINN HEALTHCARE, : Civil Action
`S.A., and ROCHE PALO : DOCKET NO.
`ALTO, LLC, : 12-2867 (MLC)
` :
` Plaintiffs, :
` :
` v. :
` :
`DR. REDDY'S :
`LABORATORIES, LTD., et :
`al., :
` :
` Defendants. :
` - - -
` Friday, April 15, 2016
` - - -
`
` Videotaped deposition of
` DR. CHRISTOPHER A. FAUSEL, taken pursuant
` to notice, was held at the law offices of
` Lerner David Littenberg Krumholz &
` Mentlik, 600 South Avenue West,
` Westfield, New Jersey, beginning at 8:47
` a.m., on the above date, before Constance
` S. Kent, a Certified Court Reporter,
` Registered Professional Reporter,
` Certified LiveNote Reporter, and Notary
` Public in and for the State of New
` Jersey.
`
` * * *
` MAGNA LEGAL SERVICES
` (866) 624-6221
` www.MagnaLS.com
`
`Helsinn Healthcare Exhibit 2017
`Dr. Reddy's Laboratories, Ltd., et al. v. Helsinn Healthcare S.A.
`Trial PGR2016-00007
`
`Page 1 of 17
`
`

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`Page 2
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`Page 4
`
`A P P E A R A N C E S:
` PAUL HASTINGS, LLP
` BY: ISAAC S. ASHKENAZI, ESQUIRE
` SABRINA MAWANI, ESQUIRE
` 200 Park Avenue
` New York, New York 10166
` 212.318.6432
` issacashkenazi@paulhastings.com
` sabrinamawani@paulhastings.com
` Counsel for Helsinn
` LERNER DAVID
` BY: RUSSELL W. FAEGENBURG, ESQUIRE
` 600 South Avenue West
` Westfield, New Jersey 07090
` 908.654.5000
` rfaegenburg@lernerdavid.com
` Counsel for Dr. Reddy's
`
` - - -
` I N D E X
` - - -
` Testimony of: CHRISTOPHER A FAUSEL
` By Mr Ashkenazi 9
` By Mr Faegenburg 562
` By Mr Ashkenazi 568
`
` - - -
` E X H I B I T S
` - - -
`
`NO DESCRIPTION PAGE
`
`Exhibit 1 Expert Report of Dr 7
` Christopher A Fausel
`Exhibit 2 Reply Expert Report of 7
` Dr Christopher A
` Fausel
`Exhibit 3 Excerpts of a PDR, 55th 142
` edition, 2001
`
`Exhibit 4 US Patent No 5,202,333 226
`
`Exhibit 5 Pharmacology 226
` Characterization of R
` 25259-197, a Novel and
` Selective 5-HT3 Receptor
` Antagonist, in Vivo
`
`Exhibit 6 Article titled 267
` Recommendations For the
` Use of Antiemetics
` Evidence Based Clinical
` Practice Guidelines
`
`1
`2
`3
`4
`5
`6
`7
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`9
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`12
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`NO DESCRIPTION PAGE
`Exhibit 7 Article titled, Should 304
` 5-Hydroxytryptamine-3
` Receptor Antagonists Be
` Administered Beyond
` 24 Hours After
` Chemotherapy to Prevent
` Delayed CINV, Systemic
` Re-Evaluation of
` Clinical Evidence and
` Drug Cost Implications
`
`Exhibit 8 Guidance for Industry 316
` and Reviewers
`Exhibit 9 Article, Volunteer 336
` Models for Predicting
` Antiemetic Activity of
` 5-HT3 Receptor
` Antagonists
`Exhibit 10 US Patent Application 347
` No 60,444,351
`
`Exhibit 11 Frame PowerPoint Slides 364
`
`Exhibit 12 Grunberg Article 400
`
`Exhibit 13 Supplemental Opinion 406
`
`Exhibit 14 Abstracts of Scientific 427
` Papers, 1996 Annual
` Meeting
`
`Exhibit 15 Article titled, The 432
` Efficacy of RS 25259, a
` Long-Acting Selective
` 5-HT3 Receptor
` Antagonist, for
` Preventing Postoperative
` Nausea and Vomiting
` After Hysterectomy
` Procedures
`
`NO DESCRIPTION PAGE
`Exhibit 16 Notice of Allowability 455
`Exhibit 17 Memorandum Opinion 460
`Exhibit 18 5-Hydroxytrptamine 468
` (5-HT3) Receptors:
` Molecular Biology,
` Pharmacology and
` Therapeutic Importance
`Exhibit 20 Article titled 481
` Antiemetics for Cancer
` Chemotherapy-Induced
` Nausea and Vomiting
`
`Exhibit 19 Article titled 487
` Pharmacology Mechanism
` of 5-HT3 and Tachykinin
` NK1 Receptor Antagonisms
` to Prevent
` Chemotherapy-Induced
` Nausea and Vomiting
`
`Exhibit 21 Copy of January 16, 2002 506
` press release
`Exhibit 22 Article, Antiemetics in 513
` Development
`
`Exhibit 23 Article, Comparison of 514
` oral itasetron with oral
` ondansetron: Results of
` a double-blind,
` active-controlled phase
` II study in
` chemotherapy-naive
` patients receiving
` moderately emetogenic
` chemotherapy
`Exhibit 24 Product Monograph, Aloxi 537
`Exhibit 25 Transcript dated 6/8/15 539
`Exhibit 26 US Patent, 9,066,980 554
`
`Page 5
`
`
`
`2 (Pages 2 to 5)2 (Pages 2 to 5)
`
`Page 2 of 17
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`

`
`Page 274
`
`Page 276
`
`1
`that. So granisetron, I think was in the
`2
`neighborhood of maybe 70 or 80 bucks. So
`3
`it was a significant difference.
`4
` Q. Okay.
`5
` A. So for inpatient population
`6 where you're concerned with controlling
`7
`costs, we talked about this before, if
`8
`you had two drugs which were -- and these
`9
`from a toxicity standpoint there's no
`10
`difference between the IV and the oral
`11
`formulations of the 5-HT3 antagonist, and
`12
`if the efficacy was the same and you
`13
`could gain a little bit of cost benefit,
`14
`you would consider using the oral agents
`15
`preferentially in the inpatient setting
`16
`in the patient populations that it was
`17
`appropriate for.
`18
` Q. Okay. So I'm going to --
`19
`there was a lot in that answer.
`20
` A. Sorry.
`21
` Q. I'm going to try to ask some
`22
`focused questions.
`23
` A. Okay.
`24
` Q. Are there advantages to
`
`Page 275
`
`1
`oral -- to the use of oral antiemetics
`2
`over IV antiemetics? Yes or no?
`3
` A. Yes. At the time they were
`4
`cheaper.
`5
` Q. Okay.
`6
` A. That's not the case anymore,
`7 with these specific agents because
`8
`they're all now all generic and they're
`9
`all almost free. In some instances, it
`10 may be easier -- and from an insurance
`11
`standpoint, and we still run into this --
`12
`this problem today, there are some
`13
`insurance companies that won't cover oral
`14 medications well, and so patients have a
`15
`bigger copay out of pocket, so it may be
`16
`you can -- you can bill for the IV
`17
`formulation, get it covered under their
`18
`hospital benefits when they come into a
`19
`clinic and get IV therapy, so even today
`20
`there's -- there's reasons to use one
`21
`versus another.
`22
` Q. I'm going to put myself back
`23
`in 2002.
`24
` A. Okay.
`
`1
` Q. If a patient is in the
`2
`outpatient setting, he is being given a
`3
`setron, okay? Are they given that setron
`4
`on multiple -- are they given it only on
`5
`day one or are they given it afterwards?
`6
` MR. FAEGENBURG: Objection
`7
` to the form.
`8
` THE WITNESS: So in 2002, it
`9
` was -- it was an interesting time
`10
` and I had, you know, I was
`11
` involved with developing our own
`12
` institutional guidelines at the
`13
` time for this. The rule of thumb
`14
` was -- and it's -- it's
`15
` articulated in much better detail
`16
` in here in this document.
`17
`BY MR. ASHKENAZI:
`18
` Q. In the ASCO guidelines?
`19
` A. In the ASCO guidelines.
`20 And -- but the rule of thumb is if you
`21
`had somebody getting highly emetogenic
`22
`chemotherapy or moderately emetogenic
`23
`chemotherapy for acute chemotherapy-
`24
`induced nausea and vomiting, the either
`
`Page 277
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`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`granisetron, ondansetron, or dolasetron,
`any one of those three could be given
`either IV or orally for prophylaxis.
` Q. Okay. Let me just cut
`through all this.
` There are advantages to an
`oral route of administration for a setron
`in -- in 2002, correct?
` A. There are advantages for
`certain patient populations and there are
`advantages for other patient populations
`for IV.
` Q. Okay. And the cells, the --
`the 5-HT3 receptor antagonists that
`setrons are believed to work on, or were
`believed to work on in 2002, those are
`located in the gut, correct?
` A. Not entirely. So some of
`them are in the central nervous system.
`So there's something called the
`chemoreceptor trigger zone, pretty clear
`name. It is a group of neurons for which
`there are serotonin receptors and also
`neurokinin 1 receptors, that's why it's
`
`
`
`70 (Pages 274 to 277)70 (Pages 274 to 277)
`
`Page 3 of 17
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`

`
`Page 278
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`Page 280
`
`1
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`4
`5
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`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`believed the neurokinin 1 receptor
`antagonists work for chemotherapy-induced
`nausea and vomiting.
` If you give someone a dose
`of a cytotoxic chemotherapy drug, it's
`going to release serotonin from these
`enterochromaffin cells in the gut, which
`are -- these cells are just big vacuoles
`or big storage bags of serotonin. When
`the drug is -- when the chemotherapy drug
`is given systemically, a lot of the
`serotonin is released, so it's released
`locally, but a lot of it goes into the
`central nervous system and then starts
`hitting the chemoreceptor trigger zone.
`The chemoreceptor trigger zone then sends
`a signal to some -- another spot in the
`brain called the vomiting center. The
`vomiting center says, Oh, wait, I'm being
`exposed to some sort of toxic moiety, I
`need to start the process of getting rid
`of this compound.
` So that's what starts the
`process of first nausea, and then
`
`Page 279
`
`1
`retching, and them ultimately emesis.
`2
` Q. Okay. All right. Sir, a
`3
`couple of questions.
`4
` Do you prescribe
`5
`palonosetron? Do you work with doctors
`6
`to prescribe palonosetron?
`7
` A. Yes.
`8
` Q. And in what -- do you
`9
`prescribe palonosetron more than you do
`10
`ondansetron?
`11
` A. So I dispense it. I want to
`12
`clarify that.
`13
` Q. Okay.
`14
` A. So in my outpatient clinic
`15
`of -- so there are several outpatient --
`16
`I don't know if we get into this before,
`17
`but I managed pharmacies for several
`18
`outpatient cancer clinics in Indianapolis
`19
`that are a part of Indiana University
`20 Health.
`21
` Our workhorse 5-HT3 receptor
`22
`antagonist -- when I say workhorse, I
`23 mean the one that we use most of the time
`24
`in our outpatient clinics exclusively is
`
`1
`palonosetron, and we use that for
`2
`prophylaxis for highly emetogenic and
`3 moderately emetogenic chemotherapy.
`4
` We also stock ondansetron,
`5
`and the reason why we stock ondansetron
`6
`is there are some patients that get
`7
`either low emetogenic potential
`8
`chemotherapy or minimal emetogenic
`9
`chemotherapy, but, you know, you may be
`10
`giving them a drug that doesn't have a
`11
`highly likelihood of causing emesis, but
`12
`because they've gotten a lot of
`13
`chemotherapy with other regimens in the
`14
`past, and because of where the tumor may
`15
`be located in the GI tract, they may have
`16
`a lot of nausea to begin with.
`17
` Q. Okay.
`18
` A. So we'll give ondansetron
`19
`for those folks, and if someone has a
`20
`headache with palonosetron -- so there's
`21
`a class effect with palo -- with 5-HT3
`22
`receptor antagonists where they all cause
`23
`headache. And anywhere between 5 and
`24
`20-ish percent, depending on which
`
`Page 281
`
`1
`clinical trial you read, but it's
`2
`reproducible, it happens.
`3
` What is interesting is you
`4
`can actually give another one of the
`5
`5-HT3s. So if I'm given palo and get a
`6
`headache with palo, you can switch me
`7
`over to ondansetron, and about half the
`8
`time the headache doesn't come back.
`9
` Or you -- if I'm getting
`10
`ondansetron and then I get a headache and
`11
`then you switch me over to granisetron,
`12
`if you switch me to the granisetron after
`13
`I've had a headache with ondansetron, the
`14
`headache will go away.
`15
` Q. Okay.
`16
` A. So I think it's always wise
`17
`to have two of these drugs around because
`18
`of this side effect.
`19
` Q. All right. Let's -- let's
`20
`break this down, and I'm going to try to
`21 make it into specific questions --
`22
` A. Okay.
`23
` Q. -- that you can answer yes
`24
`or no, if you can't, you'll explain you
`
`
`
`71 (Pages 278 to 281)71 (Pages 278 to 281)
`
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`

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`Page 282
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`Page 284
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`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`can't, but I want to get you out of here
`for your flight and the question is
`getting a little long.
` A. Fair enough.
` Q. I understand. So let's just
`try to keep it -- I'll try to keep it
`focused.
` The workhorse antiemetic
`that you use, you've described as
`palonosetron, correct?
` MR. FAEGENBURG: Objection
` to the form.
` THE WITNESS: So the -- the
` main 5-HT3 receptor antagonist
` that we use at our clinics at
` Indiana University Health for our
` cancer centers is palonosetron for
` prophylaxis of highly emetogenic
` and moderately emetogenic
` chemotherapy.
`BY MR. ASHKENAZI:
` Q. Great.
` Now you use granisetron you
`said for certain -- ondansetron?
`
`Page 283
`
`1
` A. Yeah.
`2
` Q. Okay. So you use
`3
`ondansetron for certain patients, either
`4
`they're given minimally emetogenic
`5
`chemotherapy or the patient had a side
`6
`effect to palonosetron; is that correct?
`7
` A. Yes, that's fair.
`8
` Q. Okay. Now, the -- the side
`9
`effects that you discussed with the
`10
`headache, as long as you have two setrons
`11
`available, you're in -- you're in good
`12
`shape? Let me make -- let me clarify
`13
`that question.
`14
` For patients who had
`15
`headaches back in 2002 and they were on
`16
`granisetron, most of those patients would
`17
`not have the headache if you switched
`18
`them to the ondansetron?
`19
` A. I'd say about half.
`20
` Q. Okay. And then dolasetron
`21
`also?
`22
` A. Yeah, it's a class effect.
`23
`So whichever two of these drugs that you
`24 were stocking in your hospital, if a
`
`1
`patient had a headache to one, hopefully
`2 when you switched them over to the second
`3
`one, the headache would go away. In some
`4
`cases it still stuck around, that
`5
`headache, and you may even have to try
`6
`and order in special the third one.
`7
` Q. So there's really no
`8
`distinct advantage to having a fourth
`9
`setron with respect to that -- to
`10
`avoiding the headaches because you were
`11
`basically able to treat a patient by
`12
`using the other alternatives of the other
`13
`of the three setrons that were available,
`14
`correct?
`15
` A. You need -- you need at
`16
`least a second agent available, at least
`17
`that's always been my long-standing
`18
`clinical belief on formulary at a
`19
`hospital or in a clinic to manage the
`20
`headache situation.
`21
` Q. So to be clear, for setrons,
`22
`in order to manage any toxicity issues or
`23
`headache, side effect issues, having a
`24
`second setron available is all that you
`
`Page 285
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`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`needed to ensure the safety of your
`patients?
` MR. FAEGENBURG: Objection
` to form.
` THE WITNESS: From the
` hospital's standpoint, having two
` agents would be best. I mean, it
` would be great to have three but
` there's a cost associated with
` having too many drugs in stock.
` So most -- most hospitals would
` say, All right, let's just carry
` two, if we need a third one we'll
` order it in.
`BY MR. ASHKENAZI:
` Q. So back in 2002 with
`granisetron, ondansetron and dolasetron
`available, there would be no need for a
`fourth setron just for take -- treating
`patients who may have gotten a headache
`to the first use of a setron, correct?
` A. So long as you have two, you
`should be good to go for most patients.
` Q. Okay. Next, with respect to
`
`
`
`72 (Pages 282 to 285)72 (Pages 282 to 285)
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`

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`Page 358
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`Page 360
`
`1
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`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
` that I don't know understand what
` it means, it's just that when I
` think of parameters for assessing
` the efficacy of chemotherapy-
` induced nausea and vomiting, I
` think of complete response, I
` think of complete control.
` Complete response being no
` episodes of emesis, no use of
` rescue medications; complete
` control, no episodes of emesis, no
` rescue medications, no more than
` minimal to moderate nausea.
`BY MR. ASHKENAZI:
` Q. Okay. But we've already
`determined that there's not a single drug
`that completely prevents chemotherapy-
`induced nausea and vomiting, correct?
` A. Correct, yeah.
` Q. So there's no drug that's
`going to prevent in every instance
`chemotherapy-induced nausea and vomiting,
`correct?
` A. No, there's not.
`
`Page 359
`
`1 Unfortunately, I wish there was.
`2
` Q. Okay. So every drug that's
`3
`being given, is being given to reduce the
`4
`likelihood that a patient will suffer
`5
`from chemotherapy-induced nausea and
`6
`vomiting, correct?
`7
` A. That -- that's the intent,
`8
`but that's not a measurable, deliverable
`9
`on that therapy.
`10
` Q. All right.
`11
` Now, you'll also agree with
`12 me that all the setrons that were on the
`13 market had shown at least some complete
`14
`response for acute CINV?
`15
` MR. FAEGENBURG: 2002 you're
`16
` saying?
`17
`BY MR. ASHKENAZI:
`18
` Q. Let's go to the 2002 time
`19
`period, sir.
`20
` The setrons that were
`21
`available on the market. Those setrons
`22
`had shown some substantial elimination of
`23
`acute CINV, correct?
`24
` A. So in 2002, the use of
`
`1
`5-HT3s, and we'll just say all of them
`2
`are tied for first and tied for last in
`3
`terms of efficacy and toxicity, although
`4
`dolasetron has a unique toxicity we can
`5
`talk about if you want to, that when you
`6
`use them for prophylaxis for highly
`7
`emetogenic chemotherapy, are you talking
`8
`as single agents or in combination with
`9
`other drugs?
`10
` Q. We're going way afield. Let
`11 me withdraw the question since that
`12 was -- we're going in a completely
`13
`different way.
`14
` What I'm trying to figure
`15
`out is: The setrons that were available
`16
`on the market, they just didn't increase
`17
`the patient's -- decrease the patient's
`18
`likelihood of suffering from -- of CINV
`19
`by 2 percent, correct?
`20
` A. Correct.
`21
` Q. There was a -- of all the
`22
`setrons available in 2003, showed a
`23
`significant ability to decrease a
`24
`patient's nausea and vomiting,
`
`Page 361
`1
`chemotherapy-induced nausea and vomiting,
`2
`correct?
`3
` A. For prophylaxis in the acute
`4
`setting, unequivocally they showed that.
`5
` Q. Okay.
`6
` A. And we talked about the
`7
`delayed setting where my opinion was in
`8 moderately emetogenic chemotherapy there
`9 was a small but real difference relative
`10
`to no therapy.
`11
` Q. So if you're going to move
`12
`forward in a drug development program in
`13
`2002 with a dose of a setron for -- to be
`14
`used with patients who suffer from CINV
`15
`as prophylaxis, you would want a dose
`16
`that showed a significant reduction in
`17
`emetic responses, correct?
`18
` A. With respect to what?
`19
`Placebo or other 5-HT3s?
`20
` Q. To at least placebo?
`21
` A. Placebo goes without saying.
`22 You would want to see -- so I would want
`23
`to see a drug that worked at least as
`24 well as the existing 5-HT3 receptor
`
`
`
`91 (Pages 358 to 361)91 (Pages 358 to 361)
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`Page 6 of 17
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`

`
`Page 362
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`Page 364
`
`antagonists in order for it to be
`considered something worth pursuing.
` Q. Okay. So let's go to
`placebo because I want to start with
`placebo.
` So if a drug did not show a
`significant -- if you're looking at a
`dose of a setron in 2002, if that setron
`did not show a significant reduction
`compared to placebo of emesis, you would
`not move forward with that drug in
`development, correct?
` MR. FAEGENBURG: Objection,
` vague.
` THE WITNESS: In treatment
` of what?
`BY MR. ASHKENAZI:
` Q. Let's start with PONV.
` A. In PONV. PONV is not CINV,
`so I wouldn't necessarily extrapolate
`those results to chemotherapy-induced
`nausea and vomiting.
` And with the currently
`available -- or I'm sorry, with the
`
`Page 363
`
`1
` A. Yes.
`2
` Q. Okay. And you're aware that
`3 Dr. Frame testified that the dose for
`4
`PON -- the dose for CINV is usually eight
`5
`to ten times higher than the dose for
`6
`PONV?
`7
` A. I don't recall that specific
`8
`testimony. I'll accept that -- that
`9
`your -- what you said is true.
`10
` Q. Okay. Do you have any
`11
`reason to disagree with that statement?
`12
` MR. FAEGENBURG: Objection,
`13
` vague.
`14
` THE WITNESS: Can you read
`15
` exactly what he said again,
`16
` please?
`17
`BY MR. ASHKENAZI:
`18
` Q. Well, why don't I -- why
`19
`don't I provide you with something while
`20 we're waiting to get it.
`21
` (Fausel Exhibit No. 11,
`22
` Frame PowerPoint Slides, was
`23
` marked for identification.)
`24
`BY MR. ASHKENAZI:
`
`Page 365
`
`available agents in 2002, there -- as we
`had talked about, they're available for
`postoperative nausea and vomiting, the
`success rates of the chemotherapy-induced
`nausea and vomiting application of
`granisetron, ondansetron, dolasetron, for
`prophylaxis of emesis was, in my opinion,
`better than the benefit of using those
`drugs for postoperative nausea and
`vomiting.
` So I don't -- I don't think
`there's a one-on-one or a parallel as far
`as efficacy in PONV versus CINV. I think
`you have to study it in CINV.
` Q. Okay. Not whether -- all
`right, let me ask -- let me take a step
`back.
` You're aware that Dr. Frame
`testified at trial in this case related
`to palonosetron?
` MR. FAEGENBURG: In the ANDA
` case.
`BY MR. ASHKENAZI:
` Q. In the ANDA case, correct?
`
`1
` Q. I'm handing you what's been
`2 marked as Fausel Exhibit 11. It's a copy
`3
`of the slides that Dr. Frame used to
`4
`testify under oath at trial in the ANDA
`5
`case related to palonosetron.
`6
` A. Okay.
`7
` Q. Are you there?
`8
` A. Yeah. What page would you
`9
`like me to go to?
`10
` Q. Could you go to the Summary
`11
`slide. It's the second-to-last slide?
`12
` A. This one right here?
`13
` Q. Yes.
`14
` A. Okay.
`15
` Q. Do you see where it says,
`16
`"CINV dose equals to eight to ten times
`17
`PONV dose" in the bottom in the legend?
`18
` A. Yes.
`19
` Q. Okay. Are you saying
`20
`that -- was Dr. Frame correct when he
`21
`testified under oath at trial --
`22
` MR. FAEGENBURG: Objection.
`23
`BY MR. ASHKENAZI:
`24
` Q. -- that the PONV dose is
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`
`
`92 (Pages 362 to 365)92 (Pages 362 to 365)
`
`Page 7 of 17
`
`

`
`Page 426
`
`Page 428
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
` Q. Are you done?
` MR. FAEGENBURG: Are you
` done or not?
` THE WITNESS: So what I was
` going to say is, look, when you're
` looking at clinical trials and
` you're looking at protocols, it's
` very explicit in the trial
` protocols of what a dose is.
` There shouldn't be any sort of
` wiggle room as to whether you're
` using one vial, two vials or three
` vials. So I would have hoped that
` this would have been a little bit
` more specific in disclosing that.
` That's -- so that's...
`BY MR. ASHKENAZI:
` Q. So again, the standard --
`the viewpoint you looked at this was from
`needing to know with 100 percent
`certainty --
` A. Yes.
` MR. FAEGENBURG: Objection
` to form.
`
`Page 427
`
`1
`BY MR. ASHKENAZI:
`2
` Q. -- that the dose was 0.25
`3 milligrams, correct?
`4
` A. Yes.
`5
` Q. So if there's even a small
`6
`percentage -- small percentage of
`7
`uncertainty, you feel that the patent did
`8
`not properly disclose the invention,
`9
`correct?
`10
` A. I feel that the patent
`11
`should have been more clear about that.
`12
` Q. Okay. Let's move on, if we
`13
`can.
`14
` (Fausel Exhibit No. 14,
`15
` Abstracts of Scientific Papers,
`16
` 1996 Annual Meeting, was marked
`17
` for identification.)
`18
`BY MR. ASHKENAZI:
`19
` Q. Do you have the -- I'm going
`20
`to hand to you what's been marked as
`21
`Fausel Exhibit 14.
`22
` A. Are we done with these other
`23
`two?
`24
` Q. Yes, we're done with these.
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
` A. And the Frame as well?
` Q. Yes.
` A. I'm going to organize this
`here.
` MR. ASHKENAZI: I marked
` that at the top. I apologize.
` MR. FAEGENBURG: Since
` you're switching gears, we have
` been going for an hour and
` 20 minutes.
` MR. ASHKENAZI: Sure, why
` don't we take a break.
` THE VIDEOGRAPHER: Going off
` the record. The time is 3:47 PM.
` (Recess.)
` THE VIDEOGRAPHER: Back on
` the record. The time is now
` 4:07 PM. This begins DVD No. 6.
`BY MR. ASHKENAZI:
` Q. Dr. Fausel, can you turn to
`the Chelly abstract you have in front of
`you, Exhibit 14?
` A. Yes.
` Q. Okay. Now, this is an
`
`Page 429
`
`1
`abstract, correct?
`2
` A. Correct.
`3
` Q. It's not a pub -- a peer
`4
`reviewed publication?
`5
` A. Correct.
`6
` Q. The Chelly abstract
`7
`discusses the use of oral form of
`8
`palonosetron, correct?
`9
` A. Correct.
`10
` Q. And it's the endpoint that
`11
`it's using is a 24 hours -- withdrawn.
`12
` The endpoint that's being
`13
`evaluated is whether palonosetron reduced
`14
`the likelihood of emesis over a 24-hour
`15
`period?
`16
` A. So what it -- what I have
`17
`here is the endpoint --
`18
` "The primary efficacy
`19
`variable was defined as the proportion of
`20
`patients who did not develop an emetic
`21
`episode and did not require antiemetic
`22 medication for 24 hours after recovery
`23
`from anesthesia and surgery."
`24
` Complete responders. So
`
`
`
`108 (Pages 426 to 429)108 (Pages 426 to 429)
`
`Page 8 of 17
`
`

`
`Page 430
`
`Page 432
`
`1 we've talked about that endpoint I think.
`2
` Q. Okay. So the endpoint is a
`3
`24-hour endpoint that's the focus of the
`4
`authors of the Chelly article, correct?
`5
` A. Correct.
`6
` Q. And that's the same thing
`7
`for the other setrons, dolasetron,
`8
`granisetron and ondansetron, that they
`9 were being prescribed to treat emesis
`10
`over a 24-hour period, correct?
`11
` MR. FAEGENBURG: Objection
`12
` to the form.
`13
` THE WITNESS: There may be
`14
` other trials where they looked
`15
` farther out than 24 hours, but as
`16
` a rule of thumb, I believe
`17
` 24 hours is -- is -- is a standard
`18
` approach to evaluating
`19
` postoperative nausea and vomiting.
`20
`BY MR. ASHKENAZI:
`21
` Q. Okay. Now, let's move onto
`22
`the next -- to the next one.
`23
` Sorry, this was published in
`24
`the -- the -- withdrawn?
`
`Page 431
`
`1
` The Chelly abstract was
`2
`published in the -- Anesthesiology was
`3
`the name of the journal?
`4
` A. Yes.
`5
` Q. Okay. You haven't done
`6
`any -- you haven't been a reviewer for
`7 Anesthesiology, correct?
`8
` A. I have not, no.
`9
` Q. Okay.
`10
` A. I don't think -- it's mostly
`11
`anesthesiologists that review for that
`12
`journal.
`13
` Q. So you're not really
`14
`familiar with this journal?
`15
` A. I'm -- I'm familiar with it.
`16
`I mean, I've looked up articles from it
`17
`before, but I'm not an -- I'm not an
`18
`anesthesiologist and I haven't
`19
`participated in any reviews with journal
`20
`articles that are submitted.
`21
` Q. Or abstracts. Abstracts are
`22
`not --
`23
` A. Either -- either way.
`24
` Q. Withdrawn. Okay.
`
`1
` Abstracts -- you have no
`2
`information that the abstract, the Chelly
`3
`abstract, was reviewed in the peer review
`4
`process, correct?
`5
` A. Whether it was or it wasn't,
`6
`I -- I have no way of knowing especially
`7
`from this time period.
`8
` Q. All right.
`9
` (Fausel Exhibit No. 15,
`10
` Article titled, The Efficacy of RS
`11
` 25259, a Long-Acting Selective
`12
` 5-HT3 Receptor Antagonist, for
`13
` Preventing Postoperative Nausea
`14
` and Vomiting After Hysterectomy
`15
` Procedures, was marked for
`16
` identification.)
`17
`BY MR. ASHKENAZI:
`18
` Q. I'm going to hand you what's
`19
`been marked as Fausel Exhibit 15. It's a
`20
`copy of the Tang reference.
`21
` Do you see that, sir?
`22
` A. Yes.
`23
` Q. This is the Tang reference
`24 we've been referring to?
`
`Page 433
`
`1
` A. Correct.
`2
` Q. Okay. Let me get a couple
`3
`of things just to -- to set the stage.
`4
`Is it true that the Tang reference is the
`5
`only peer review journal article with
`6
`human data for palonosetron prior to
`7
`January 30th, 2002?
`8
` A. That may or may not be true
`9
`depending on whether Chelly was indeed
`10
`peer reviewed, and perhaps it was.
`11
` Q. As far as you're concerned,
`12
`you're not aware of -- withdrawn.
`13
` You're not aware of the fact
`14
`that Chelly was peer reviewed, correct?
`15
` A. I don't know if it was or it
`16 wasn't. Tang, since it was a full
`17
`publication, presumably would have been.
`18
` Q. Okay. Now, are you aware of
`19
`any instance where a -- well, withdrawn.
`20
` Let's move on.
`21
` Tang was designed as a
`22
`randomized double -- double blind placebo
`23
`controlled dose-ranging study; is that
`24
`correct?
`
`
`
`109 (Pages 430 to 433)109 (Pages 430 to 433)
`
`Page 9 of 17
`
`

`
`1
` A. Uh-huh.
`2
` Q. Sorry, sir, you have to say
`3
`yes or no.
`4
` A. Oh, I'm sorry, yes.
`5
` Q. Okay. And as a dose-ranging
`6
`study it was identified -- it was being
`7
`used to identify which dose of
`8
`palonosetron to move forward in
`9
`development with for a PONV, correct?
`10
` A. Yes.
`11
` Q. Okay. Now, there were 218
`12
`patients that were included in the Tang
`13
`article, correct?
`14
` A. Correct.
`15
` Q. Sorry, withdrawn. Not
`16 withdrawn, but let me -- let me rephrase
`17
`that.
`18
` There were 218 patients that
`19 were part of the Tang study, correct?
`20
` A. That were enrolled --
`21
` Q. That were enrolled in the
`22
`Tang study?
`23
` A. -- how's that?
`24
` That's fine, sure.
`
`Page 434
`
`Page 436
`
`1
`requirement for rescue antiemetics."
`2
` Do you see that?
`3
` A. Yes, I do.
`4
` Q. And do you disagree with
`5
`that conclusion?
`6
` A. From a statistical
`7
`significant standpoint, that is true.
`8
` Q. Okay. Now, again, we've --
`9 we've said a little earlier today that
`10
`the purpose of statistics is to identify
`11 whether the effect that's being observed
`12
`in a clinical trial is actually
`13
`occurring, correct?
`14
` A. Correct.
`15
` Q. Okay. So if a specific dose
`16
`is showing some effect compared to
`17
`placebo, but that effect does not show
`18
`statistical significance, then a person
`19
`of ordinary skill in the art can't
`20
`conclude that that effect is actually due
`21
`to the --