` BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`- - - - - - - - - - - - - - - +
` |
`MYLAN PHARMACEUTICALS, INC., |
` |
` Petitioner, |
` |
` |
` vs. |
` |
`YEDA RESEARCH AND DEVLOPMENT |
`CO., LTD., |
` Patent Owner. |
` |
`- - - - - - - - - - - - - - - +
`
` Case IPR2015-00643 (8,232,250)
` Case IPR2015-00644 (8,399,413)
` Case IPR2015-00830 (8,969,302)
`
` Deposition of STEPHEN J. PEROUTKA, M.D.,
`Ph.D., taken on behalf of the Patent Owner Yeda, at
`901 New York Avenue, Washington, D.C., beginning at
`9:30 a.m. on October 29, 2015, before Michele E.
`Eddy, RPR, CRR, CLR, and Notary Public for the
`District of Columbia.
`
`The Little Reporting Company
` (646) 650-5055 | www.littlereporting.com
`
`IPR2015-00644
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`EXHIBIT NO. 1066 PAGE 1
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` A P P E A R A N C E S
`
`ON BEHALF OF THE PATENT OWNER YEDA:
` WILLIAM G. JAMES, ESQUIRE
` DANIEL P. MARGOLIS, Ph.D., ESQUIRE
` ELIZABETH J. HOLLAND, ESQUIRE
` Goodwin Procter LLP
` The New York Times Building
` 620 Eighth Avenue
` New York, New York 10018
` (212) 813-8800
` wjames@goodwinprocter.com
` dmargolis@goodwinprocter.com
` eholland@goodwinprocter.com
`
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` (646) 650-5055 | www.littlereporting.com
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`EXHIBIT NO. 1066 PAGE 2
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`ATTENDANCE, Continued
`
`ON BEHALF OF MYLAN AND THE WITNESS:
` DAVID L. ANSTAETT, ESQUIRE
` SHANNON M. BLOODWORTH, ESQUIRE
` EMILY J. GREB, ESQUIRE
` Perkins Coie
` 700 13th Street, Northwest
` Suite 600
` Washington, D.C. 20005
` (202) 654-6200
` danstaett@perkinscoie.com
` sbloodworth@perkinscoie.com
` egreb@perkinscoie.com
`
`ON BEHALF OF MYLAN:
` MATTHEW J. BRESNAHAN, ESQUIRE
` Wilson Sonsini Goodrich & Rosati
` 12235 El Camino Real, Suite 200
` San Diego, California 92130
` (858) 350-2226
` mbresnahan@wsgr.com
`
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` (646) 650-5055 | www.littlereporting.com
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`EXHIBIT NO. 1066 PAGE 3
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`ATTENDANCE, Continued
`
`ON BEHALF OF AMNEAL PHARMACEUTICALS:
` VINCENT L. CAPUANO, Ph.D., ESQUIRE
` Duane Morris, LLP
` 100 High Street, Suite 2400
` Boston, Massachusetts 02110
` (857) 488-4250
` vcapuano@duanemorris.com
`
`ALSO PRESENT:
` Lori Wolfe, Teva Pharmaceuticals
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`EXHIBIT NO. 1066 PAGE 4
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` EXAMINATION INDEX
` PAGE
`EXAMINATION BY MR. JAMES 8
`EXAMINATION BY MR. ANSTAETT 218
`FURTHER EXAMINATION BY MR. JAMES 226
`
` E X H I B I T S
` (Attached to the Transcript)
`DEPOSITION EXHIBIT PAGE
`Exhibit 1 Declaration in the '250 IPR 9
`Exhibit 2 Declaration in the '413 IPR 9
`Exhibit 3 Declaration in the '302 IPR 9
`Exhibit 4 Document titled 32
` "Multiple Sclerosis" from
` PRA website
`Exhibit 5 U.S. Patent 8,232,250 38
`Exhibit 6 Decision by United States 45
` District Judge in case titled
` Endo versus Mylan
`Exhibit 7 Some or all of the prescribing 52
` information for Copaxone from
` 2009; Mylan Exhibit number 1052
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` EXHIBIT INDEX CONTINUED
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`6
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`DEPOSITION EXHIBIT PAGE
`Exhibit 8 Summary Basis of Approval 60
` Document; '250 IPR Mylan Exhibit
` 1007; cover sheet: affidavit
` from Marlene S. Bobka
`Exhibit 9 Article entitled "A Single 122
` Amino Acid Difference Confers
` Major Pharmacological Variation
` Between Human and Rodent
` 5-HT1B receptors"
`Exhibit 10 Document entitled "Randomized 158
` Double-blind Dose Comparison
` Study of Glatiramer Acetate in
` Relapsing Remitting MS"
`Exhibit 11 Forte Press Release 164
`Exhibit 12 Abstract 650 entitled 175
` "Copolymer-1 - Copaxone
` Induces a Non-immunologic
` Activation of Connective Tissue
` Type Mass Cells"
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`DEPOSITION EXHIBIT PAGE
`Exhibit 13 Document entitled "Copolymer-1 184
` Glatiramer Acetate in Relapsing
` Forms of Multiple Sclerosis,
` Open Multicenter Study of
` Alternate Day Administration"
`Exhibit 14 Paper entitled "Copolymer-1 in 207
` Relapsing Remitting Multiple
` Sclerosis, a Multicenter Trial";
` Mylan Exhibit 1009
`Exhibit 15 Judge's ruling 219
`Exhibit 16 Patent Application 209
` WO 2007/081975; Inventor Irit
` Pinchasi
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` P R O C E E D I N G S
` October 29, 2015
` Washington, D.C.
` - - -
` STEPHEN J. PEROUTKA, M.D., Ph.D.,
`having been duly sworn, testified as follows:
` EXAMINATION BY COUNSEL FOR THE PATENT OWNER
`BY MR. JAMES:
` Q Good morning, Dr. Peroutka.
` A Good morning.
` Q I haven't had a chance to introduce myself
`on the record. My name is Bill James. I work at
`Goodwin Procter. I represent Yeda in this IPR
`matter.
` So a couple of things. I know you've
`been deposed in the past so I won't go through all
`the details about being deposed, but you submitted a
`lot of papers, they're very complicated, and I'll do
`my best to ask you questions that you'll understand
`if you'll agree to tell me when you don't understand
`my question. Is that fair?
` A Yes.
` Q The other thing is, in your declarations,
`there's talk about a three-times-a-week regimen and
`an alternate-day regimen. So today can we agree
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`that when I say a three-times-a-week regimen or a
`three-times-weekly regimen, you'll understand that
`to mean a regimen where it's just three times a
`week?
` A Yes.
` Q And when I say alternate day or every
`other day, you'll understand that to mean a regimen
`where on one week you would give three
`administrations and on the next week you would give
`four.
` Is that fair?
` A Yes.
` (Exhibit 1, Exhibit 2, and Exhibit 3 were
`marked for identification and attached to the
`deposition transcript.)
`BY MR. JAMES:
` Q Maybe I'll just start off by marking your
`declarations that you submitted. We've marked as
`Peroutka 1 the declaration in the '250 IPR; Peroutka
`2, the declaration in the '413 IPR; and Peroutka 3,
`the declaration in the '302 IPR.
` A Thank you.
` Q And today I'm going to focus on the '250
`IPR, but if there's any time that you feel like you
`need to refer to any of the other papers, feel free
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`to do so.
` A Thank you.
` Q Dr. Peroutka, I understand that you
`graduated with an M.D. degree from Johns Hopkins in
`1979?
` A Yes.
` Q And you got a Ph.D. from the same
`institution in 1980?
` A Yes.
` Q What was your thesis topic?
` A Multiple serotonin receptors.
` Q What is serotonin?
` A Serotonin is a neurotransmitter that is in
`the brain but also in the rest of the body. It acts
`as a neurotransmitter.
` Q And you studied serotonin receptors where,
`in the brain, the vagal nerve, or where?
` A Predominantly in the brain.
` Q Does serotonin or serotonin receptors,
`does that have any relationship to multiple
`sclerosis?
` MR. ANSTAETT: Objection, form.
` Q To the best of your knowledge.
` A To the best of my knowledge, no.
` Q After you graduated with your M.D. from
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`Johns Hopkins and your Ph.D. in 1980, you did an
`internship at Stanford University, correct?
` A Correct.
` Q How long was that?
` A One year.
` Q After you finished your internship, then
`you did a fellowship back at Johns Hopkins; is that
`correct?
` A Residency and fellowship.
` Q Okay. And when did you finish that?
` A 1984.
` Q What did you do after that?
` A I became a faculty member at Stanford
`University in the departments of neurology and
`pharmacology.
` Q And what were your duties in the Stanford
`department of neurology?
` A The three main duties were to be a
`clinical neurologist and either -- and weekly see
`patients in the clinic and then multiple times a
`year for a month stretch be the attending physician
`in the neurology service in the hospital. Second
`was to teach the medical students, and the residents
`and the third was to run a laboratory.
` Q And your Ph.D. was a pharmacology Ph.D.,
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`correct?
` A Technically, pharmacology and experimental
`therapeutics.
` Q But at Stanford you were working in the
`department of neurology.
` A I had a joint appointment also in
`pharmacology. I taught some pharmacology courses.
` Q What percentage of your time did you spend
`seeing patients during that time at Stanford?
` A Approximately a third.
` Q What percentage of that one third of your
`time did you see multiple sclerosis patients?
` A I would have to check and see the
`incidence of MS, whatever it is, but without going
`back and getting specifics, I would say in the 10 to
`20 percent range. It's a reasonably common
`disorder.
` Q Now, during that same period of time, you
`also worked at the VA, correct?
` A Correct, as part of it.
` Q Were the patients that you saw at the VA,
`were they predominantly men or women?
` A Men.
` Q Amongst those men, how many people had
`multiple sclerosis, roughly?
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` A I honestly can't estimate at the VA
`system, in the VA system, how many showed up in
`clinic. Can you clarify specifically?
` Q The people that you were treating during
`your time treating patients at the VA, how many of
`those patients, roughly, would you say had MS?
` MR. ANSTAETT: Objection to form.
` A I honestly can't go back and estimate the
`exact number. I can give an estimate, a very rough
`estimate. It's about 10 percent.
` Q And is that roughly how the percentage --
`I'll strike that.
` In 1990, you went to work for
`Genentech, correct?
` A Correct.
` Q And in 1990, did you cease the practice of
`medicine?
` A I kept my license, I maintain my
`continuing medical education, my CME credit. So I
`still have an active license in the State of
`California.
` Q You have an active license today?
` A Correct.
` Q When was the last time you treated
`patients?
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` A Treated patients for money, for
`compensation, was in 1990.
` Q 1990.
` What's the distinction between
`treating them for money and not treating them for
`money?
` A I occasionally get asked to do consults on
`patients, colleagues, friends, family members,
`individuals that want consulting services.
` Q But you last practiced medicine on a
`full-time basis in 1990.
` A Correct.
` Q And in 1990, what treatments were
`available for multiple sclerosis?
` A Not too many. Basically, we would use
`steroids acutely when there were exacerbations, and
`some people tried more immunosuppressive agents,
`but -- for the severe cases. I did see a number of
`severe cases. Some, vividly, I can still remember
`the name of the person, what he looked like, and how
`severely ill he was at the very end stage of MS.
` Q So steroids and immunosuppressants; is
`that correct?
` A Were the only available agents at that
`time.
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` Q There were no disease-modifying agents
`available at that time, correct?
` A Not on the market. I was aware of
`Dr. Bornstein and his work, but they were not -- it
`was a compassionate IND, perhaps, but they were not
`usually available.
` Q Have you ever treated a patient with
`glatiramer acetate?
` A No.
` Q You understand that glatiramer acetate is
`sometimes referred to as copolymer-1?
` A Yes.
` Q So if I use those terms today, you'll
`understand them to be interchangeable, at least for
`our purposes today?
` A I would prefer glatiramer acetate because
`that's how I refer to it.
` Q I understand, but, for example,
`Dr. Bornstein doesn't refer to the drug he was using
`as glatiramer acetate.
` A Correct.
` Q Since 1990, you've been employed in the
`pharmaceutical industry and as a consultant,
`correct?
` A Correct.
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` Q And you recently changed jobs, correct?
` A Correct.
` Q What's your new position?
` A I'm consulting at present.
` Q What's the name of the company that you
`work for?
` A I --
` Q Oh, you're just working -- okay.
` A I'm an independent consultant.
` Q I saw a reference on the Internet to
`Alkahest. What's that?
` A That was a company I was helping with for
`a few months to start up.
` Q That was this summer?
` A Yes.
` Q Now, over the course of your career as a
`consultant and working in the pharmaceutical
`industry, have you worked on projects having to do
`with MS?
` A Yes.
` Q What were those?
` A I was employed 2008 to 2011 at a company
`called PRA, the letters P-R-A, at the time
`International. They've since changed their name PRA
`Health Sciences. I was the vice president of
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`neurosciences in what was called the therapeutic
`expertise group.
` So PRA at that point in time was the
`leading MS research organization at the CRO level.
`So what I mean by that is, at the time there were
`roughly -- I'm estimating again, but I think it's
`close -- 25,000 subjects around the world being
`studied for multiple sclerosis.
` Multiple sclerosis in 2008 was the
`most active area of clinical neuroscience research.
`There were many drugs being studied, the pipeline of
`pharmaceutical agents was very full, and PRA at the
`time did roughly one third of the global work. We
`had a preferred partner, who was a major company in
`the field of multiple sclerosis.
` So we would go -- over my three years
`there, I think, in the range of 30 different
`proposals for multiple sclerosis came in. It was my
`job to, number one, review the proposals to assess
`various aspects of the proposals. The entry
`criteria, the clinical end points for MS, the
`expected enrollment rates, where were the best
`places to go in terms of investigator sites. I
`would help and write for the companies, for the
`clients.
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` Secondly, I had to teach the internal
`people, who were not already up to speed on MS, what
`the current issues were in terms of various factors
`in the field, for example, placebos in MS, by that
`point in time, were becoming, in a sense,
`controversial. The Germans started and then the
`Europeans agreed that around that point in time it
`was becoming unethical, in many people's opinion, to
`treat an MS patient with a placebo because of the
`fact that there were so many agents available that
`were therapeutically beneficial, and it wasn't
`ethical to allow someone to be two years without
`treatment for the sake of a placebo study.
` Q So, during your time at PRA, you studied
`up on MS to educate your colleagues, right?
` MR. ANSTAETT: Object to form.
` Q Is that correct?
` A In part.
` Q In part.
` And you -- well, let's look at
`paragraph 6 of your declaration, if we could.
` MR. ANSTAETT: Bill, you're referring to
` Exhibit 1 here?
` MR. JAMES: I am, yes.
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`BY MR. JAMES:
` Q You have that, Doctor?
` A Yes.
` Q And in the middle of that paragraph, you
`say -- well, this is -- let me back up. This is a
`paragraph in which you talk about your work at PRA
`International, right?
` A Yes.
` Q And in the middle of that paragraph, you
`say you were "responsible for providing therapeutic
`expert advice on the design and development of human
`clinical trials for numerous neuropharmacological
`therapies," sorry, "neuropharmacological treatment
`therapies, including over 30 clinical trials for
`multiple sclerosis."
` Do you see that?
` A Yes.
` Q Now, a moment ago you referred to 30
`proposals.
` A Right.
` Q Do you recall that?
` Is that different than 30 clinical
`trials?
` A No. The proposals were for PRA to perform
`the work on the trials.
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` Q Where did that number 30 come from?
` A Reviewing my own records of just what I
`saw back in those days.
` Q So you have records from PRA from that
`time period?
` A General records.
` Q How many of those clinical trials that you
`consulted on related to glatiramer acetate?
` A I don't recall, and it's also
`confidential. I'm not really at liberty to
`disclose.
` Q Did any of them relate to glatiramer
`acetate?
` A To answer your question, which I would be
`happy to do if the confidentiality agreement that I
`have with PRA would allow it, and I'm not sure of
`that fact.
` Q I'm not asking you about details. I'm not
`asking you about who sponsored the clinical trial.
`I'm just asking you whether, sitting here today, you
`recall whether any of the clinical trials related to
`glatiramer acetate.
` A You are asking me to disclose the client.
` Q No, I'm not.
` MR. ANSTAETT: Wait a second, why don't
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` we -- maybe we can take a break to just get
` Dr. Peroutka comfortable with what he can
` disclose.
` MR. JAMES: Why don't we do that during
` the next break, our first break, he can talk to
` you about that. I'll move on for now.
` MR. ANSTAETT: Okay.
` MR. JAMES: We'll just come back to that
` to see whether or not you can just tell me, yes
` or no, some of them related to glatiramer
` acetate.
`BY MR. JAMES:
` Q So other than your work at PRA, did you do
`any other work on multiple sclerosis between 1990
`and beginning work on this case?
` A Just keeping up with continuing medical
`education and the literature, reading the journal,
`routinely keeping up to speed with the new drug
`approvals, just general education.
` Q So you were aware when Copaxone was
`approved initially?
` A Yes.
` Q Do you remember what year that was?
` A I believe 1996.
` Q That's correct. And -- let me strike
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`that.
` Do you consider yourself an expert in
`the mechanism of action of glatiramer acetate?
` MR. ANSTAETT: Objection, relevance.
` A I consider myself a person of ordinary
`skill in the art in terms of glatiramer acetate
`mechanisms.
` Q Do you consider yourself an expert in the
`mechanism of action of glatiramer acetate?
` MR. ANSTAETT: Objection, relevance, form.
` A Can you define "expert" for me, please.
` Q Just do you consider yourself to have
`expertise in your field. Would you hold yourself
`out to your colleagues as an expert in the mechanism
`of glatiramer acetate?
` MR. ANSTAETT: Objection, relevance.
` A I would consider myself of average
`expertise for a neurologist.
` Q Have you ever given a presentation on the
`mechanism of action of glatiramer acetate?
` A No.
` Q Now, you've been admitted as an expert in
`district court litigations in the past, correct?
` A Correct.
` Q What were the -- what was the subject
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`matter of those litigations?
` A Pharmaceutical patents.
` Q Do you recall what the drugs were?
` A One was ondansetron, a 5-HT3 antagonist,
`Glaxo product.
` Q The other?
` A Frovatriptan, a migraine product.
`F-R-O-V-A-T-R-I-P-T-A-N.
` Q So you've never been submitted in a
`district court litigation as an expert in glatiramer
`acetate, correct?
` MR. ANSTAETT: Objection. Objection,
` relevance.
` A Can you clarify when you mean submitted,
`appeared in court, is that what you're --
` Q Yes.
` A No, I have not appeared in court.
` Q In those district court litigations, you
`held yourself out as an expert in 5-HT matters,
`correct?
` MR. ANSTAETT: Objection, form, relevance.
` A One was 5-HT3, which is actually a GI
`nausea drug, and the second was a migraine --
`migraine therapeutic.
` Q Which also has to do with serotonin,
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`correct?
` MR. ANSTAETT: Objection, form.
` A Yes.
` Q In both cases you were submitted --
` MR. ANSTAETT: Bill, you have to give me a
` chance to get my objections on the record.
` Objection to form, and relevance.
` Q In both cases you were submitted, I'm
`sorry, strike that.
` In both cases you held yourself out
`to the district court as an expert in
`serotonin-receptor-related issues, correct?
` MR. ANSTAETT: Objection to form,
` relevance.
` A In those two instances, yes.
` Q Would you hold yourself out as an expert
`in the mechanism of action in glatiramer acetate in
`the same way?
` MR. ANSTAETT: Objection, form, relevance.
` A In terms of mechanism of action, which in
`my opinion has not been fully elucidated, I would
`consider myself as knowledgeable as a person of
`ordinary skill of the art.
` Q And your expertise arises from your study
`of the literature, keeping up with the literature
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`over the last 25 years, correct?
` MR. ANSTAETT: Objection to form,
` relevance.
` A No, I would disagree, and I would say my
`expertise is also as a pharmacologist in
`understanding various aspects of drug development,
`how drugs are given to patients, assessing efficacy,
`safety, and tolerability.
` Q Have you ever performed a clinical trial
`studying glatiramer acetate?
` A It depends on the definition of "have I
`performed." I have been involved at PRA with
`performing trials where we looked at the trial. We
`recruited the investigators. I was helping in part
`of that. I helped with endpoint selection. So in
`that sense, as many investigators in the field, I
`was actively involved in studies of multiple
`sclerosis.
` Q My question was directed to glatiramer
`acetate specifically.
` A No.
` Q Have you ever designed a dosing regimen
`for a multiple sclerosis drug?
` A I would have to go back and review my --
`what I have available, which is actually very
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`limited now; but I believe I provided consultative
`services as part of my job at PRA to certain
`companies on possible dosing regimens, but I cannot
`specifically cite at this point because I no longer
`have the information available; but I do recall a
`couple of small companies with MS drugs that we did
`discuss that issue.
` Q Have you ever designed a dosing regimen
`for a drug that exerts its effect without passing
`through the systemic circulation?
` MR. ANSTAETT: Objection to form.
` A I would have to give that some thought
`before answering.
` Q Sitting here right now, you can't think of
`one, correct? I'm not saying you can't go think of
`one later, but right now you can't think of one.
` A Well, give me a few minutes, let me just
`think.
` Q Well, why don't you think about it and
`we'll come back to it.
` MR. ANSTAETT: Wait. You can't -- you
` can't just ask him a question and then --
` MR. JAMES: I'll strike the question.
` A The answer is yes.
` Q Yes, okay, what drug was that?
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` A Capsaicin, in my job at NeurogesX. It's a
`topically applied drug that acts by destroying the
`tips of the pain fibers in your skin. My job there,
`part of my job was -- we have a marketed product
`called Qutenza, Q-U-E-T-E-N-Z-A [sic]. It was a
`patch or is a patch. And we were designing a second
`generation lipid formulation. We had to determine
`at a local level how much of the liquid we could use
`compared to what was in the patch.
` Q Capsaicin, that's like a derivative of
`chili pepper, something like --
` A Yes, it's the active hot sauce component.
` Q That causes some inflammatory sort of
`reaction on the skin; is that right?
` A It can, yes.
` Q Does it cause the body to create
`antibodies to the capsaicin?
` A Not that I'm aware of.
` Q Are you aware of any topical inflammatory
`agents that will raise systemic antibodies?
` MR. ANSTAETT: Objection, relevance.
` A Topical inflammatory agents.
` Q Correct. Something that causes
`inflammation on the skin that raises systemic
`antibodies.
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` MR. ANSTAETT: Objection, relevance.
` A This isn't part of my report, and I would
`have to do more due diligence. I can think of at
`least one but --
` Q What's that?
` A Poison oak.
` Q Poison ivy has an agent in it that will --
` A I believe you create antibodies because
`then you react more, but I would have to
`double-check.
` Q So it's not necessary for a component or a
`composition or a drug to reach the systemic
`circulation in order for the body to form
`circulating antibodies, correct?
` MR. ANSTAETT: Objection, form, relevance.
` A Could you repeat the question, please.
` Q It's not necessary for an agent to reach
`the systemic circulation in order for the body to
`create circulating systemic antibodies, correct?
` MR. ANSTAETT: Same objections.
` A I'm not sure that that's correct.
` Q Well, with respect to poison ivy, it
`raises IgE antibodies throughout the body, correct?
` MR. ANSTAETT: Objection to form,
` foundation, relevance.
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` A You're outside the scope of my report, and
`you're asking me questions that are answerable with
`some due diligence of looking into the database,
`but --
` Q In your report, you said that the presence
`of circulating antibodies reflects that the drug is
`in the systemic circulation, correct?
` A Could you point that out specifically?
` Q We'll come back to that. So you don't
`recall saying that?
` MR. ANSTAETT: Objection to form.
` Doctor, you've got to pause after
` Mr. James asks his question so I can insert my
` objections, and you also have to let Mr. James
` finish his questions before you start your
` answer.
` Objection to form.
` Q Would you like to have the question read
`back?
` A Yes, please.
` (Record read.)
` A I do recall that statement, but I would
`like to see it in context so I could interpret it
`properly.
` Q We'll come back to that.
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` So since 1990, Doctor, how many MS
`patients have you treated?
` A None, as a physician, practicing
`physician, but in terms of clinical trials, I was
`the therapeutic expert on multiple MS trials.
` Q Are you an immunologist?
` A No.
` Q If you could look at paragraph 1 of your
`report. The second sentence of that paragraph says
`"Throughout my career, I have practiced as a
`clinician in the field of neurology, conducted
`research in multiple neurological disorders
`including multiple sclerosis, and held a number of
`relevant positions in the biotechnology and
`pharmaceutical industry."
` Do you see that?
` A Yes.
` Q So it's not true that you've been
`practicing as a clinician in the field of neurology
`throughout your career, is it?