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` THE UNITED STATES PATENT AND TRADEMARK OFFICE
` _____________________
` BEFORE THE PATENT TRIAL AND APPEAL BOARD
` _____________________
` COALITION FOR AFFORDABLE DRUGS VIII LLC
` Petitioner
` v.
` THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA
` Patent Owner
` _____________________
` Case IPR2015-01836
` U.S. Pat. No. 7,932,268
` Case IPR2015-01835
` U.S. Pat. No. 8,618,135 B2
` ________________________
`
` DEPOSITION OF RANDALL M. ZUSMAN, M.D.
` Boston Massachusetts
` Tuesday, October 4, 2016
`
`Reported by: Dana Welch, CSR, RPR, CRR, CRC
`Job No: 113300
`
`TSG Reporting - Worldwide 877-702-9580
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`PENN EX. 2306
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`IPR2015-01836
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` THE UNITED STATES PATENT AND TRADEMARK OFFICE
` _____________________
` BEFORE THE PATENT TRIAL AND APPEAL BOARD
` _____________________
` COALITION FOR AFFORDABLE DRUGS VIII LLC
` Petitioner
` v.
` THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA
` Patent Owner
` _____________________
` Case IPR2015-01836
` U.S. Pat. No. 7,932,268
` Case IPR2015-01835
` U.S. Pat. No. 8,618,135 B2
` ________________________
`
` DEPOSITION OF RANDALL M. ZUSMAN, M.D.
` Boston Massachusetts
` Tuesday, October 4, 2016
`
`Reported by: Dana Welch, CSR, RPR, CRR, CRC
`Job No: 113300
`
`TSG Reporting - Worldwide 877-702-9580
`
`PENN EX. 2306
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`IPR2015-01836
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`Page 2
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` October 4, 2016
` 9:01 a.m.
`
` Deposition of RANDALL M. ZUSMAN, M.D.,
`held at the offices of GOODWIN PROCTER, 100
`Northern Avenue, Boston, Massachusetts, pursuant to
`Notice, before Dana Welch, Certified Shorthand
`Reporter, Registered Professional Reporter,
`Certified Realtime Reporter, and Notary Public of
`the Commonwealth of Massachusetts.
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`A P P E A R A N C E S:
`McNEELY HARE & WAR
`Attorneys for Coalition for Affordable Drugs
`12 Roszel Road
`Princeton, NJ 08540
`BY: CHRISTOPHER CASIERI, ESQ.
`
`GOODWIN PROCTER
`Attorneys for Trustees of the University
`of Pennsylvania
`New York Times Bldg.
`620 Eighth Ave, New York, NY 10018
`BY: CYNTHIA LAMBERT HARDMAN, ESQ.
` - and -
`WILMERHALE
`60 State Street
`Boston, MA 02109
`BY: KEVIN PRUSSIA, ESQ.
`
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` ZUSMAN
` P R O C E E D I N G S
` RANDALL M. ZUSMAN, M.D., sworn
` EXAMINATION
`BY MS. HARDMAN:
` Q. Good morning.
` A. Good morning.
` Q. Will you please state your name for the
`record.
` A. Randall Mark Zusman.
` Q. I know you've had your deposition taken
`before, so I'll keep it short.
` If I ask any questions today that are
`unclear, will you please let me know and I'll try
`to rephrase them.
` A. Yes, I will.
` Q. Is there any reason today that you can't
`give accurate testimony?
` A. No, there's not.
` Q. Okay. I handed you what's been
`previously -- well, I've handed you your
`declarations from two IPRs, the IPR of 2015-01835
`and 2015-01836.
` Are these declarations you submitted in
`these IPRs?
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` A. Yes, they are.
` Q. Is there any substantive difference
`between the two declarations?
` A. No. I don't believe there is.
` Q. So just for clarity, if we could just
`primarily refer to the version from the 01835
`today.
` A. 35, okay.
` Q. So this is a supplemental declaration and
`it's directed to two separate papers. It's in
`support of the petition and in opposition to the
`motion to amend; is that correct?
` A. That's correct.
` Q. And how was this declaration prepared?
` A. Well, after I gave my -- or provided my
`original report, and after my deposition, I believe
`plaintiff's experts provided their reports, and
`this is a declaration in response to those reports.
`I conferred with counsel for CFAD and we went back
`and forth in terms of the content of the report,
`eventually resulting in the document that you see
`here.
` Q. And besides counsel, did anybody assist in
`the preparation of this declaration?
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` ZUSMAN
` A. No, they did not.
` Q. And which counsel did you work with?
` A. Mr. Gonsalves and Mr. Casieri.
` Q. Anyone else?
` A. No.
` Q. In terms of preparing for today's
`deposition, did you do anything specific to prepare
`for today?
` A. I reread many, many, many documents that
`had been circulated in this litigation.
`Mr. Casieri and I met for about three hours
`yesterday and talked about the deposition; that was
`the extent of my preparation.
` Q. All right. So now turning to the
`substance: So lomitapide was known as of 2004,
`correct?
` A. That's correct.
` Q. And given what was known about the drug,
`would a person of skill in the art have had a
`reasonable expectation that if a patient could
`tolerate a titration regimen where the dosage was
`tripled, that they could also tolerate a titration
`regimen where the dosage was doubled?
` A. Yes. I believe there was a reasonable
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` ZUSMAN
`expectation of success for what you've just
`described.
` Q. And let's look at Dr. Rader's declaration,
`if we could, please.
` Did you -- have you reviewed this
`document?
` A. Yes, I have.
` Q. And if you could turn to paragraph 37,
`please, which is on page 16. And just for the
`record, this is the declaration of Daniel J. Rader,
`M.D., PENN Exhibit 2026 in IPR 1835.
` Do you see the last sentence of paragraph
`37 where he says, "He selected a dose of
`0.03 milligrams per kilogram for the initial dose"?
` A. I see that, yes.
` Q. As of 2004, would a person of ordinary
`skill in the art have thought that that starting
`dose was a subtherapeutic dose for lomitapide?
` A. Yes, I believe they would.
` Q. Now, in your declaration you address the
`substitute claims submitted by patent owner,
`correct?
` A. I have, yes.
` Q. Okay. And in those substitute claims
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`there are different levels: First, second, and
`third levels of dosing, correct?
` A. That is correct, I believe.
` Q. And in paragraph 16 of your declaration,
`please --
` A. Oh, paragraph 16, I'm sorry.
` Q. Yeah. And it's on page 5. Well, it spans
`pages 4 to 5.
` A. Yes. I have the paragraph.
` Q. You state in that paragraph that the first
`dosage level -- this is referring to the substitute
`claims -- is from about 0. -- I'm sorry -- is from
`about .05 to about .1745 milligrams per kilograms
`per day, correct?
` A. Would you mind if I read the paragraph?
` MR. CASIERI: Object to form.
` Q. Yeah. Go ahead, please.
` A. Yes, okay.
` I'm sorry. Your question was...
` Q. So do you understand that the first dosing
`level in the substitute claims encompasses from
`about .05 to about .1475 milligrams per kilogram
`per day?
` A. That's correct. Calculating back from the
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` ZUSMAN
`third dosage level and assuming the doubling of the
`dose each time, that is the calculation that
`appears in this paragraph.
` Q. Okay. And as of 2004, would a person of
`skill in the art have understood that that dosage
`range encompassed subtherapeutic doses of
`lomitapide?
` MR. CASIERI: Object to form.
` A. So we're talking about a dosage of
`0.05 milligrams per kilogram, which for a person of
`70 kilograms would have been about 3 or
`4 milligrams, if I'm not mistaken, and that would
`possibly be a subtherapeutic dose, depending upon
`the patient's response to the medication and the
`initial level of their lipid abnormality.
` Q. And how about on the upper end of that
`range, 0.1475 milligrams per kilogram for a
`70-kilogram patient, would that have been expected
`to be a subtherapeutic dose?
` A. So that, if I'm doing the math correctly,
`would be about a 10-milligram dose for a
`70-kilogram person. A 10-milligram dose would have
`been a therapeutic dose based on previously
`acquired information in some patients and certainly
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` ZUSMAN
`might not be a subtherapeutic dose at that level.
` Q. And in this section of your declaration
`beginning on about page 3, you give the opinion
`that Dr. Rader's clinical trial is not a reduction
`to practice of the claimed regimen in the
`substitute claims, correct?
` A. I'm sorry. Where are you?
` Q. I'm looking at page 3 of your declaration.
` A. Yes.
` Q. Heading A.
` A. Oh, I see, okay. Yes, I see where you
`are.
` Q. And so that section is you give the
`opinion that Dr. Rader's clinical trial is not a
`reduction to practice of the regimen claimed in the
`substitute claims, correct?
` A. That's correct.
` Q. Now, your declaration does not include the
`legal standard for determining when an invention is
`reduced to practice, right?
` A. I don't believe I included that
`specifically as part of my declaration.
` Q. So in doing the analysis, did you simply
`look to see whether Dr. Rader's doses fell within
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` ZUSMAN
`the substitute claims?
` MR. CASIERI: Object to form.
` A. I believe that there's a, if you will,
`disconnect between Dr. Rader's protocol, the patent
`claims, the substitute claims as provided by the
`patent owners, and finally, the patient
`information, prescribing information for lomitapide
`or Juxtapid. So that appears to me that there was
`not a reduction to practice based upon the material
`available in the patent or provided by Dr. Rader.
` Q. When you say there's a disconnect between
`Dr. Rader's protocol and the substitute claims, is
`that because the doses in Dr. Rader's protocol
`don't fall within the doses in the substitute
`claims?
` A. That's correct. There are doses that fall
`outside of the substitute claims or fall outside of
`the protocol, depending upon, of course, the
`calculation of the size of the patient.
` Q. Do you know what the legal standard is for
`evaluating reduction to practice?
` A. My understanding is that the patent owner
`would have demonstrated in a clear fashion the
`means by which the invention would be used, and
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` ZUSMAN
`that the information available would allow one
`reading the patent to practice the alleged
`invention without the need to look for further
`information? That's my understanding.
` Q. And how did you use the prescribing
`information for Juxtapid in this analysis?
` A. Well, I looked at all of the information
`that's available. So we have the clinical
`protocol, we have the subsequent publication, we
`have the prescribing information, we have the
`patent, and we have the declarations of what the
`intent were of the patent owner as well as the
`prior work that were done by Bristol-Myers Squibb.
`And it appears to me in looking at that information
`that there is a disconnect, if you will,
`discordance between how the drug is actually
`prescribed and how Dr. Rader developed or suggested
`he developed the product, which ultimately led in
`him receiving the patent.
` Q. Your declaration includes -- I'm
`referencing now the section starting on page 7.
` A. Yes.
` Q. So your declaration includes an analysis
`of obviousness of the substitute patent claims in
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` ZUSMAN
`view of a number of -- in fact, six prior art
`references, correct?
` A. That's correct.
` Q. And this is a new combination of art that
`was not previously asserted by you in your previous
`declaration, correct?
` A. That is correct.
` Q. And did you personally select this
`combination of prior art to analyze in your
`declaration?
` A. Well, as I mentioned, in discussion with
`counsel, we talked about the reports or the
`declarations of Drs. Rader, Dr. Sacks, Dr. Gregg,
`the others who were patent owner's experts, and we
`talked about the sort of information that would be
`of value in responding to those reports. And in
`that, as a result of that discussion, these
`documents, which are of the prior art, were brought
`to my attention.
` Q. And you mean that they were brought to
`your attention by counsel?
` A. That's correct.
` Q. Let's start with the ICH-E4 document.
` So I handed you CFAD Exhibit 1046 in the
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` ZUSMAN
`1835 IPR. I think it might have a different number
`in the 1836, but we'll just stick with the one
`number.
` A. Right. We both understand what we're
`talking about.
` Q. Thanks.
` A. Right.
` Q. So what is this document?
` A. This is a document entitled "Guideline For
`Industry: Dose Response Information to Support
`Drug Registration."
` It talks about different trial design, et
`cetera, for eventually submission of information
`to -- for drug approval, if you will, by various
`regulatory bodies, is my understanding.
` Q. Is this a document that you have consulted
`in your daily work outside of litigation
`consulting?
` A. No. I hadn't been aware of this document
`prior to this litigation.
` Q. This document has a date on the cover of
`November 1994. So was it available to persons of
`skill in the art since that time?
` A. Yes.
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` Q. And the focus of this document is on how
`to obtain and use dose response information,
`correct?
` MR. CASIERI: Object to form.
` A. That's, in part, some of the information
`that's included in this document, that's correct.
` Q. What is dose response information?
` A. Well, I think it refers to how a patient
`responds or how the use of a drug impacts a
`clinical disorder related to changes in dose. So
`you might -- an example would be how to construct a
`dose response curve, which would be where you give
`various doses to a patient or a group of patients
`and then look at the clinical response of your
`dependent variable to the administration of that
`agent.
` Q. And the document indicates that the use --
`that dose response information can help identify an
`appropriate starting dose or the best way to adjust
`dosage to the needs of a particular patient or to
`find a dose beyond which increases would be
`unlikely to provide added benefit, right?
` MR. CASIERI: Object to form.
` A. Can you tell me where you're reading?
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` ZUSMAN
` Q. Yeah. I'm looking right at page 1.
` A. Yes. That's what the authors of the
`document wrote.
` Q. Turning back one page to the Table of
`Contents, there's a heading three there that says
`"Study Designs for Assessing a Dose Response."
` Do you see that?
` A. I do.
` Q. And underneath it gives four different
`trial designs, right?
` A. That's correct.
` Q. And your declaration focused only on the
`third design listed here: Forced titration,
`correct?
` A. Well, I discussed forced titration, I
`believe, in my report. I don't recall exactly on
`what page. And I think I made a number of
`references to this document.
` But forced titration would be one of the
`designs for assessing dose response that would be
`applicable to the issues that we're discussing with
`regard to lomitapide.
` Q. Is it your opinion that a person of skill
`in the art would have been motivated to use a
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`forced titration regimen for lomitapide?
` A. I think someone using a forced titration
`protocol would have a reasonable expectation of
`success.
` As I discussed in my report, there are a
`limited number of people with homozygous FH or
`HoFH, which was the target population that
`Dr. Rader was proposing to treat. And as outlined
`in my report, this forced titration protocol
`offered a very great likelihood of success, a
`reasonable likelihood of success, given how few
`patients were available in gaining the information
`that one would want to have to expand the use of
`the drug in a larger patient cohort.
` Q. Your declaration does not include a
`discussion of whether these other -- the three
`other trial designs would have been appropriate,
`correct?
` MR. CASIERI: Object to form.
` A. I believe -- although we have to find the
`specific section of the report, I believe I talk
`about why the forced titration protocol would
`provide the information that one would want to
`acquire and why this would be an expeditious route
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`to acquiring that information compared to other
`potential protocols.
` I don't know that I specifically mention
`parallel dose response or crossover dose response,
`but I did discuss why this would be an expeditious
`route to success in comparison to potentially other
`titration trial designs or protocol trial designs
`that would require more patients, longer times, and
`might not be feasible for treatment of a patient
`cohort for which there were so few subjects, such
`as those with HoFH.
` Q. What is a forced titration regimen?
` A. Forced titration regimen -- well, let's
`look how they defined it and just see what they
`called it.
` My copy doesn't have page numbers, so
`let's just see. So it's described on I guess it's
`page 11, this page was numbered, paragraph 3,
`entitled "Forced Titration." "A forced titration
`study where all patients moved through a series of
`rising doses." So that's how they defined it.
` Q. And is that also how you would define it?
` A. I think --
` MR. CASIERI: Object to form.
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` A. Yeah. I think that is not an unreasonable
`definition.
` Q. This document does not address a situation
`where a drug has dose-dependent side effects,
`correct?
` A. I don't recall reading the document with
`that question in mind. I could read it again for
`you if you'd like, but I don't specifically recall
`looking at that -- looking at it with that in mind.
` Q. In paragraph 38 of your declaration --
` A. Yes, I have it.
` Q. -- you have some quotes here from page 4
`of the ICH-E4 document, right?
` A. I do.
` Q. And those quotes actually come from a
`section that's titled "Problems With Titration
`Design," right?
` A. Right. That's from the section of the
`document which comes under Purpose of Dose Response
`Information, paragraph D, "Problems With Titration
`Designs."
` Q. And one of the problems with titration
`designs that the ICH-E4 document identifies on
`page 4, it says, "Historically, this approach has
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`often led to a dose that was well in excess of what
`was really necessary," correct?
` A. I'm sorry. I didn't see where you were
`reading.
` Q. Page 4.
` A. Yes. And at what point?
` Q. Heading D, about halfway through the
`paragraph, do you see it says "historically, this
`approach has often led to a dose that was well in
`excess of what was really necessary"?
` A. Yes, I see that sentence.
` Q. And that paragraph ends with a statement
`that says that "this approach is discouraged,"
`doesn't it?
` MR. CASIERI: Object to form.
` A. Well, this -- that phrase that you just
`read comes as part of an example for the treatment
`of patients with AIDS. And they are talking about
`the use of this approach in less urgent cases, the
`approach is discouraged. So it's qualified by the
`example that they cited in this particular
`paragraph.
` Q. And the approach we're talking about here
`in this paragraph is dose titration to some
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`effectiveness or safety endpoint, right?
` A. Yes, that's correct, that's the first
`sentence of the paragraph.
` Q. And so this paragraph is actually saying
`that "overall, a dose titration to some
`effectiveness or safety endpoint is discouraged
`unless urgent cases," correct?
` MR. CASIERI: Object to form.
` A. Well, specifically using the example of
`AIDS as an urgent case, I think that dose titration
`protocols are used, certainly. In other disease
`states, I'm aware of such dose titration protocols.
`So they suggest it might be discouraged, but it is
`still also sometimes valuable and utilized in other
`clinical disease circumstances.
` Q. Turning to page 11, please, the section on
`Forced Titration.
` A. In the ICH-E4?
` Q. Yes.
` A. Yes.
` Q. Actually, on the last sentence of that
`section, which is on page 12, it says that "one
`benefit of a forced titration regimen is that it
`can provide clear evidence of effectiveness,"
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`right?
` A. I'm sorry, I lost track of where you are.
` Q. The last sentence of the section on Forced
`Titration.
` A. On page 12?
` Q. Yeah.
` A. So it says, "If there's a concurrent
`placebo group, a forced titration protocol can
`provide clear evidence of effectiveness and
`especially valuable in helping choose doses for a
`parallel dose response study," which would be a
`different type of trial that might be valuable and
`might even be required for eventual registration of
`a drug, and its, for example, FDA approval were it
`to be in this country.
` Q. So do you agree that one benefit of a
`forced titration regimen is that it can provide
`clear evidence of effectiveness?
` A. Certainly. Yes, that is one way to
`acquire information with regard to effectiveness.
` Q. As of 2004 lomitapide was already known to
`be effective for lowering cholesterol, right?
` A. Yes, it had been reported to do so.
` Q. Now, you mentioned that doing the forced
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`titration regimen can then help choose doses for a
`parallel dose response study, right?
` MR. CASIERI: Object to form.
` A. Well, that's what the authors of this
`document stated.
` Q. So the point of doing the forced titration
`then is not to find a treatment regimen for
`patients, correct?
` A. Well, it can be. I believe I cited one of
`the reasons in my report why a forced titration
`protocol would be valuable in the treatment of
`HoFH.
` You have a very limited number of
`patients. If you wanted to start off, for example,
`with a parallel dose response study, you would have
`to have multiple groups, multiple numbers of
`patients in order to complete such a trial. In the
`case of HoFH, given the limited number of patients
`to which any investigator might have access, I
`would note that Dr. Rader studied six patients in
`his protocol. A parallel dose response study would
`for all practical purposes be impractical or
`perhaps even unfeasible because he would not have
`access to a sufficient number of patients to do a
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` ZUSMAN
`trial that would have any statistical validity.
` So the forced titration protocol, as noted
`in my report, would be a direct route to acquire
`the information that one would want to have with
`regard to the use of this drug and the target
`population for which it is intended.
` Q. Are there other study designs that are
`appropriate for use with a small number of
`patients?
` A. Well, I imagine there might be. But I
`think as outlined in this document and as I
`suggested in my report, this is a direct route, if
`you will, to the information one would want. And
`it offers the most reasonable likelihood of
`success, reasonable expectation of success that one
`would acquire the information needed to use the
`drug more widely in the HoFH patient population.
` Q. And when you say that it would provide a
`reasonable expectation that one would be able to
`acquire the information needed, what information is
`that?
` A. Well, one would be looking for information
`about the efficacy, tolerability, and safety, which
`is the purpose of any study, in essence, prior to
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`submission of information to the Food & Drug
`Administration or any other regulatory body. So
`Dr. Rader's protocol was designed to look at the
`effect of various doses, the safety of various
`doses, and the response to various doses of the
`patients who participated in his clinical trial.
` Q. But the tolerability and safety would not
`have been known before carrying out the study,
`right; that's something you would learn in carrying
`out the forced titration study?
` MR. CASIERI: Object to form.
` A. Well, I think there was a reasonable
`expectation that Dr. Rader expected a certain
`outcome. I think the data that was available prior
`to that point in the prior art, the combination of
`documents that I've cited in my report would
`provide him with the information that ultimately
`led to the design of his study. And in particular,
`with regard to the forced titration protocol, this
`document really lays out quite clearly the benefits
`of a forced titration protocol in a patient
`population such as those with HoFH to potentially
`be treated with a drug such as lomitapide. So I
`think there was a reasonable expectation that
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` ZUSMAN
`Dr. Rader would acquire the information that would
`provide additional insight into the use of the
`drug. But I think it was obvious that it would
`have been successful, at least to me, based on the
`combination of the prior art documents that I've
`cited in my report.
` Q. And what benefits of a forced titration
`regimen are you saying are elucidated in this
`document?
` A. Well, I think I address this directly in
`my report. Shall we go to that section of the
`report?
` So this looks like it's on page 5 of my
`report. Oh, that's just where I cite it. I think
`I reference it at different points in the report.
` So I believe the first time I mention it
`is on page 8 where I say, quote, using lomitapide
`as taught by Wetterau in view of the ICH-E4, which
`is this document, Chang, the Guidance for Industry
`document of 2002, the Reigner document, and the
`'653 patent, one would have done so with a
`reasonable expectation of success. Going on in the
`next paragraph, "The use of this document along
`with those other documents would have provided a
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` ZUSMAN
`reasonable expectation of success."
` In paragraph 32, once again citing the use
`of this document and how it would have been obvious
`to a person of ordinary skill in the art with
`reference specifically to substitute claim 11.
` Q. Okay. Let me just interrupt you because
`what I'm looking for specifically is what in
`ICH-E4, what benefits of a forced titration regimen
`are stated in that document?
` MR. CASIERI: Object to form.
` A. In my report?
` Q. In the ICH-E4.
` A. I'm sorry. What is in ICH-E4 that I've
`cited in my document as a benefit or independent of
`the report?
` Q. You mentioned in an earlier answer that
`ICH-E4 specifies that there's some benefits of
`using a forced titration regimen, and I wanted to
`know what those benefits are.
` A. Oh, okay.
` I believe I cited that in my report and I
`believe that discussion begins with paragraph 38.
`So summarizing, paragraph 38 begins "ICH-E4 teaches
`administration of an effective compound comprising
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` ZUSMAN
`a step-wise increasing dose level."
` Moving on, paragraph 39 teaches that
`ICH-E4 that a forced titration may use fewer
`patients; that in paragraph 40 there were a minimum
`number of patients. In paragraph 41, concluding
`that the forced titration dose escalation protocol
`taught by ICH-E4 would have been preferred when
`designing a clinical trial and that the forced
`titration protocol is safer for patients as
`outlined in 42, as outlined in 43 with regard to
`safety, 44 about the final dose and gradual
`titration, 45 as well.
` So I think all of those paragraphs would
`summarize my thoughts with regard to the benefits
`of the forced titration protocol as taught by
`ICH-E4 on pages 4, 11 to 12, 9, and 14 specifically
`as referenced in my report.
` MR. CASIERI: I just want to make sure
`we're all looking at the same one. Which one
`were -- in the beginning of the deposition you
`decided to look at one --
` THE WITNESS: 1835.
` MS. HARDMAN: 1835, Exhibit 1049.
` Q. So in a forced titration regimen, the
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` ZUSMAN
`doses move -- the doses increase over time; is that
`correct?
` A. That's correct.
` Q. And for a drug that is known to have
`dose-dependent side effects, it's not necessarily
`safer to keep increasing the dose, correct?
` A. Well, one is acquiring information with
`regard to the dose and the relationship to side
`effects. So it is reasonable to increase the dose.
`Obviously, in any clinical protocol involving a
`patient, one would want to have safety language, if
`you will, in the protocol for how that patient
`would be treated in the event of the development of
`a serious adverse experience. So that forced
`titration protocol allows you to acquire
`information about both efficacy and safety as you
`move through the titration process, as is outlined
`in the document itself, and as I've noted in my
`report.
` Q. The ICH-E4 document on page 11 --
` A. Yes, I have it.
` Q. -- the section on f
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