Pennell, M.D., Dudley J.
`
`Case IPR2017-01446
`
`June 6, 2018
`
`1
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
` __________
` BEFORE THE PATENT TRIAL AND APPEAL BOARD
` __________
` TARO PHARMACEUTICALS U.S.A., INC.,
` Petitioner,
` v.
` APOTEX TECHNOLOGIES, INC.,
` Patent Owner
` __________
` Case IPR2017-01446
` U.S Patent No. 7,049,328
` Title: USE FOR DEFERIPRONE
` __________
` Washington, D.C.
` Wednesday, June 6, 2018
` VIDEOTAPED CROSS-EXAMINATION
` DUDLEY J. PENNELL, M.D.
`
`202-220-4158
`
`Henderson Legal Services, Inc.
`www.hendersonlegalservices.com
`
`1 of 98
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1059
`
`

`

`Pennell, M.D., Dudley J.
`
`Case IPR2017-01446
`
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`2
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` Videotaped Cross-Examination of DUDLEY
`J. PENNELL, M.D., a witness herein, called for
`examination by counsel for Petitioner in the
`above-entitled matter, pursuant to notice, the
`witness being duly sworn by SUSAN L. CIMINELLI, CRR,
`RPR, a Notary Public in and for the District of
`Columbia, taken at the offices of Goodwin Procter,
`901 New York Avenue, N.W., Washington, D.C.
`commencing at 8:11 a.m.
`
`3
`
`APPEARANCES:
` On behalf of the Patent Owner:
` BARRY GOLOB, ESQUIRE
` W. BLAKE COBLENTZ, ESQUIRE
` AARON LUKAS, Ph.D., ESQUIRE
` Cozen O'Connor
` 1200 Nineteenth Street, N.W.
` Washington, D.C. 20036
` (202) 912-4837
` bgolob@cozen.com
` wcoblentz@cozen.com
` alukas@cozen.com
`
` On behalf of the Petitioner:
`
` HUIYA WU, ESQUIRE
` TIFFANY MAHMOOD, ESQUIRE
` Goodwin Procter, LLP
` The New York Times Building
` 620 Eighth Avenue
` New York, New York 10018
` (212) 459-7270
` hwu@goodwinlaw.com
` tmahmood@goodwinlaw.com
`
` ALSO PRESENT:
`
` Daniel Holmstock, Videographer
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`June 6, 2018
`2 (Pages 2 to 5)
`4
`
` C O N T E N T S
`DUDLEY J. PENNELL, M.D. EXAMINATION
` By Ms. Wu 7
` By Mr. Lukas 196
` By Ms. Wu 214
`
` Afternoon Session - Page 146
`
` E X H I B I T S
`EXHIBIT NO. PAGE NO.
`Exhibit 1055 Myocardial iron deposition in
` Thalassemia studies by magnetic
` resonance imaging - Mavrogeni 163
`Exhibit 1056 Non-invasive Myocardial Iron
` Assessment in Thalassemic
` Patients - Papanikolaou 165
`Exhibit 1057 Blood Journal - Pennell Group
` Article May 1, 2006 184
`
`PREVIOUSLY MARKED EXHIBITS PAGE NO.
`Exhibit 2016 14
`Exhibit 2004 34
`
`5
`PREVIOUSLY MARKED EXHIBITS PAGE NO.
`Exhibit 2003 69
`Exhibit 1001 75
`Exhibit 2026 79
`Exhibit 1037 99
`Exhibit 1010 146
`Exhibit 1012 148
`Exhibit 2033 164
`
`202-220-4158
`
`Henderson Legal Services, Inc.
`www.hendersonlegalservices.com
`
`2 of 98
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1059
`
`

`

`Pennell, M.D., Dudley J.
`
`Case IPR2017-01446
`
`June 6, 2018
`3 (Pages 6 to 9)
`8
`
`6
`
` P R O C E E D I N G S
` THE VIDEOGRAPHER: We are now on the
`record. This is video number 1 in the video
`recorded deposition of Dr. Dudley Pennell, taken in
`the matter of Taro Pharmaceuticals USA, Inc.,
`Petitioners versus Apotex Technologies, Inc., Patent
`Owner, pending before the United States Patent and
`Trademark Office, before the Patent Trial and Appeal
`Board, IPR Number 2018-01446, for Patent Number
`7,049,328. This testimony -- deposition is being
`held at the office of Goodwin Procter, LLP, at 901
`New York Avenue, Northwest, in Washington, D.C., on
`June 6th, 2018. The time on the video screen is
`8:11 a.m.
` My name is Daniel Holmstock, and with me
`is Sue Ciminelli. We are in association with
`Henderson Legal Services, located at 1560 Wilson
`Boulevard, Suite 750, in Arlington, Virginia. For
`the record, will counsel please introduce themselves
`and whom they represent.
` MS. WU: Huiya Wu and Tiffany Mahmood,
`Goodwin Procter, on behalf of the Taro Petitioners.
`
`7
`
` MR. GOLOB: Barry Golob and Blake
`Coblentz from Cozen O'Connor, on behalf of Apotex.
`Whereupon,
` DUDLEY J. PENNELL, M.D.,
`was called as a witness by counsel for Petitioner,
`and having been duly sworn, was examined and
`testified as follows:
` EXAMINATION BY COUNSEL FOR PETITIONER
`BY MS. WU:
` Q. Good morning, Dr. Pennell.
` A. Good morning.
` Q. Have you been deposed before?
` A. No.
` Q. So because you haven't, I'll go through
`some ground rules, if that's okay.
` A. Sure. Sure.
` Q. I'll be asking questions, and you'll be
`answering questions today. I will try to ask clear
`questions, but if they are not, please let me know,
`okay?
` A. Sure.
` Q. If you answer a question, I will assume
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`you have understood it, all right?
` A. Yes. You're asking me to say yes.
`That's a nod, yes.
` Q. Next rule, which is please answer
`verbally, so the court reporter can take down your
`answers.
` A. Yes. I'm with you.
` Q. Another rule, try to wait until I finish
`my question before you answer, and I'll try to wait
`for you to finish your question -- your answer
`before I question, so that the court reporter can
`take down our questions and answers in order, all
`right?
` A. Yes. Yes.
` Q. Now, is there any reason why you can't
`give complete and accurate testimony today?
` A. No.
` Q. Are you taking any medication or anything
`like that, that might impact your testimony?
` A. No.
` Q. Now, you live overseas?
` A. Yes.
`
`9
` Q. How many days have you been in the U.S.?
` A. I arrived not yesterday, the day before.
`Monday. Monday evening.
` Q. Did you spend time preparing for your
`depositions today?
` A. Yes.
` Q. If you can, about how much time did you
`spend getting ready for this deposition, which is
`for the IPR proceeding?
` A. Several days, over the last few weeks.
` Q. Did you review your declarations that you
`submitted in the IPR proceeding in preparation for
`your depositions?
` A. Yes.
` Q. Did you notice any errors, or did you
`want to make any corrections to your opinions?
` A. No.
` Q. So let's briefly go through your
`education. You are a trained medical doctor?
` A. I am.
` Q. A cardiologist?
` A. Yes.
`
`202-220-4158
`
`Henderson Legal Services, Inc.
`www.hendersonlegalservices.com
`
`3 of 98
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1059
`
`

`

`Pennell, M.D., Dudley J.
`
`Case IPR2017-01446
`
`June 6, 2018
`4 (Pages 10 to 13)
`12
`
`10
`
` Q. You're not a hematologist, is that right?
` A. Absolutely not, no.
` Q. What experience, if any, do you have in
`hematology?
` A. My experience in hematology is limited
`only to the patients that I've seen and scanned and
`worked with through the development of the T2*
`technology, which I'm sure we'll deal with today.
` Q. When did that work begin?
` A. Approximately 1998. Actually, I could
`make one correction, I think. When I was in
`training, prior to that, I did handle the cardiac
`management of patients with thalassemia as a
`trainee.
` Q. Before you were licensed?
` A. No, no. Oh, it depends on what you mean
`by licensed. I'm sorry, that might be an American
`term. I was already a doctor, qualified. But I
`think perhaps -- I don't know what licensed means in
`the U.S. I wasn't yet a consultant, independent
`practitioner. I don't know what "licensed" means
`here. Sorry.
`
`11
`
` Q. Thanks for clarifying. What type of
`patients did you manage during your training period?
` A. So when I was in training, in my
`cardiology training, we would have handled every
`type of patient with every kind of condition, right
`up to being qualified as an independent
`practitioner.
` Q. Some of those patients were thalassemia
`patients?
` A. They were in my case, yes. That's how I
`got my interest in the area.
` Q. Do you know what chelating agents were
`being used by those thalassemia patients who you
`were seeing during your training period?
` A. Yes, way back in the '90s, it was
`deferoxamine. Should I say that word again?
`Deferoxamine. There are three iron chelators, they
`all start with D-E-F-E-R. Very difficult, they are
`to pronounce.
` Q. I agree. So in 1998, that was when you
`first started scanning thalassemia patients after
`the training period?
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` A. Correct.
` Q. What iron chelators, if any, were those
`thalassemia patients taking?
` A. In 1998, deferoxamine.
` Q. Did there come a time when you started
`working with thalassemia patients who were taking
`deferiprone?
` A. Yes.
` Q. When was that?
` A. Well, it's difficult to be accurate.
`It's not a question I've considered before, but it
`would have been within -- probably quite soon after
`we developed the technology. I'm sorry, I can't be
`more specific than that.
` Q. All right. So after 2000?
` A. Well, probably before that. I mean,
`because we got the technology up and running with a
`research grant. And we would have been looking at a
`range of patients. It's difficult for me to put a
`year on the detail you're asking.
` Q. Would you have seen thalassemia patients
`taking deferiprone after deferiprone had been
`
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`approved in Europe?
` A. When was that? Remind me.
` Q. I believe it was around 1999.
` A. Well, after '99, I think it's quite
`likely we were scanning patients on deferiprone,
`yes.
` Q. Do you understand what compassionate use
`is?
` A. I do.
` Q. Were you scanning any thalassemia
`patients taking deferiprone on a compassionate use
`basis, prior to its approval in Europe?
` A. Right. So I'm not sure if we have
`compassionate use in the UK. Let me say that from
`the outside -- outset. It might be easiest to
`answer this in a slightly different way.
` We published a paper on the use of MR in
`patients with deferiprone in the Lancet. We could
`work back from that, to work out when we first
`started analyzing patients on deferiprone.
` But I mean, I think the central date was
`the development of the technology with a research
`
`202-220-4158
`
`Henderson Legal Services, Inc.
`www.hendersonlegalservices.com
`
`4 of 98
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1059
`
`

`

`Pennell, M.D., Dudley J.
`
`Case IPR2017-01446
`
`14
`
`grant that we gained in 1998. That's -- the first
`authored paper was Anderson, LJ, in the Lancet.
` Q. Let me hand you what's been previously
`marked as Exhibit 2016.
` (Exhibit No. 2016 was
` previously marked.)
`BY MS. WU:
` Q. Dr. Pennell, is Exhibit 2016 the
`publication that reflects your initial work with
`deferiprone-taking thalassemia patients?
` A. Yes. Yes.
` Q. And that work started in May 1999?
` A. I'm looking at -- under the methods,
`where I think you're referring to that. It says we
`included patients who received chelation with
`deferiprone alone for longer than three years,
`between May 1999 and December 2000.
` So I think that means that we did the
`scans between May 1999 and December 2000. That's my
`interpretation. I must say I haven't looked at this
`paper for a long time, but the patients had received
`chelation for more than three years. And the
`
`15
`duration indicated is only 18 months, which would
`indicate to me that we did the scanning between May
`1999 and December 2000. And that's compatible with
`my recollection of the time course of development of
`the technology.
` Q. Do you have any experience with
`diagnosing whether a person has thalassemia?
` A. No.
` Q. Other than scanning thalassemia patients,
`are you involved in any other aspects of their
`treatment?
` A. No.
` Q. What involvement, if any, do you have
`with respect to determining the dosage amounts of a
`chelating agent for thalassemia patients?
` A. I don't determine that at all.
` Q. You've never done that?
` A. No, that's for my hematology colleagues.
` Q. And how was it your work during your
`training period with thalassemia patients piqued
`your interest in this area?
` A. Well, I suppose it's like all things in
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`June 6, 2018
`5 (Pages 14 to 17)
`16
`life. Sometimes something comes across your path
`that you don't expect, or don't understand. And as
`you say, it piques your interest. And before you
`know it, you've gone off in that direction rather
`unexpectedly.
` So I was as a registrar, we say in
`England, I'm sorry I don't know what the equivalent
`is here, but I would be around 30 years old,
`something equivalent to whatever you do here. It's
`an internship or something like that.
` And I will be working under a consultant,
`so someone in charge of the service. And this
`particular consultant was Malcolm Walker. And I was
`one of his trainees. And the thalassemia patients
`were referred to Dr. Walker for cardiology
`assessment from the hematologist.
` And I would have seen some of those
`patients in training. So I'm familiar with some of
`the difficulties of handling the cardiovascular
`aspects of thalassemia patients, but I wasn't
`responsible for their treatment of iron chelation.
` Q. What sorts of cardiological assessments
`
`17
`were made by Dr. Walker with respect to thalassemia
`patients during the time that you were training with
`him?
` A. Physical examination. Obviously, taking
`a history, which is critical for all of these
`things. And then cardiovascular assessments. The
`key ones being an electrocardiogram and an
`echocardiogram. There are a large range of other
`cardiovascular assessments that are possible, but
`these are the most important. And in 1995,
`somewhere around there, I'm sorry I don't have the
`exact date, those would have been the assessments
`that we would have been doing.
` Q. What's the difference between
`electrocardiogram and echocardiogram assessment?
` A. So the electrocardiogram, or I think you
`call it EKG here, we say ECG in the United Kingdom,
`is a recording of the electrical activity of the
`heart.
` And typically, we would have -- well,
`typically, we do have 10 electrodes attached, one on
`both arms, one on both legs, six across the chest.
`
`202-220-4158
`
`Henderson Legal Services, Inc.
`www.hendersonlegalservices.com
`
`5 of 98
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1059
`
`

`

`Pennell, M.D., Dudley J.
`
`Case IPR2017-01446
`
`June 6, 2018
`6 (Pages 18 to 21)
`20
`
`18
`
`And this can show abnormalities, primarily of the
`rhythm of the heart. And that is important because
`thalassemia patients may develop arrhythmias. And
`they can need treatment, and they may result in
`symptoms which may need treatment.
` The echocardiogram is an imaging
`technique. It uses high frequency waves of sound,
`ultrasound, above perhaps 20,000 hertz. And a
`transducer, which is placed on the chest. And the
`connection for the sound is made through a jelly
`that you put on the patient's chest. You move the
`transducer around to interrogate different portions
`of the heart.
` And that primarily, for thalassemia
`patients, would have been to check the entire
`structure of the heart, the valves, the arteries,
`and the veins. And of course, the function. So how
`well the heart is pumping to eject the blood with
`each heartbeat, which is a parameter we call the
`ejection fraction.
` Q. Is LVF an echocardiogram assessment?
` A. It can be. There are many ways of
`
`19
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`assessing that.
` Q. What other ways are there of assessing
`echo -- heart function of the echocardiogram?
` A. So perhaps we just stick to ejection
`traction. Heart function is a rather large subject.
`Ejection fraction. We can do that through echo.
`Historically, that has been the main technique,
`echocardiography, echo, for short.
` There are nuclear medicine techniques.
`And there is a number of ways of measuring the
`ejection fraction with those, the commonality being
`the injection of a radioactive substance. The
`radioactivity has a short half-life, so it's not --
`we hope not injurious to the body. And as the
`radioactivity decays and gives out typically a gamma
`ray, we can detect that with a rather large camera.
`And that sophisticated technique, there is several
`ways of using that to measure the ejection fraction.
` Then we have cardiovascular magnetic
`resonance. We call that CMR for short. With CMR,
`we use radio waves to measure the concentration of
`hydrogen in the tissues. Hydrogen is effectively
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`water or fat that allows us to see the distribution
`of the soft tissues. With those soft tissues, we
`can take high quality, and highly reproducible
`images of the heart, that give us the gold standard
`for ejection fraction.
` Then there is CT, computer tomography,
`which relies on x-rays. X-rays, in general, we try
`to avoid in medicine, but it is possible to do it.
`We can measure the ejection fraction with CT, but I
`have to say that we almost never do that. And I'm
`not sure it's ever been used in thalassemia
`patients.
` And then finally, there are invasive
`techniques to measure the ejection fraction. And
`again, this is not something we would do in
`thalassemia patients, but in patients who have had a
`heart attack, for example, we can pass a long thin
`tube, a little bit like these tubes, they are called
`a catheter, either from the groin or from the wrist
`around into the heart. Inject some dye into the
`heart, to see how well the heart is contracting. So
`I think that's all the main ways of measuring this.
`
`21
`
` Q. And these ways of measurements also
`existed in the 1990s?
` A. So catheter-based angiography, yes.
`Nuclear medicine, there was one technique that you
`could do at that time, that was called MUGA
`scanning, had a number of other -- what's the word,
`other titles that were the same. Radionuclide
`ventriculography, MUGA, which is multiple gated
`acquisition scan. CT wasn't possible in those days.
`MR was possible, and echo was possible.
` Q. So where does LVF fall into this list of
`techniques?
` MR. GOLOB: Object to the form.
`BY MS. WU:
` Q. So LVF is a measurement of ejection
`fraction?
` A. Yes.
` Q. And so each of these different techniques
`gives a measurement for LVF?
` A. Yes, that's correct.
` Q. All right.
` A. May I just say, those techniques do a lot
`
`202-220-4158
`
`Henderson Legal Services, Inc.
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`6 of 98
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1059
`
`

`

`Pennell, M.D., Dudley J.
`
`Case IPR2017-01446
`
`June 6, 2018
`7 (Pages 22 to 25)
`24
`
`22
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`of different things, so we did many, many things
`with those imaging techniques, but it is possible to
`measure ejection fraction using all of them.
` Q. You said that CMR, I believe, was the
`gold standard?
` A. Yes.
` Q. Is that a standard for today?
` A. In 2018 today, yes. In 1998, I think,
`2000, I think it was probably a gold standard then
`as well.
` Q. And would that have been the MUGA
`iteration of CMR back in the 1990s?
` A. No. So there is an error there. So
`nuclear medicine has a number of techniques that can
`be used to measure ejection fraction. The MUGA scan
`is a nuclear medicine technique. And that has a
`number of other names, as I mentioned to you. I
`know this is a bit confusing. MR is just MR, or
`cardiac MR, CMR. So MUGA scanning is a radionuclide
`technique, which comes under the umbrella of nuclear
`medicine, with injectable radioactive isotopes.
` Q. So CMR is a subset of nuclear --
`
`23
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` A. No, CMR uses radio waves, and is
`completely separate from nuclear techniques.
` Q. So did the CMR evaluation techniques
`exist back in the 1990s?
` A. Yes, they did. Yes.
` Q. And under the umbrella of nuclear
`medicine techniques, of which MUGA scans are one.
` A. Correct.
` Q. That existed back in the 1990s?
` A. Yes, absolutely. There are other
`techniques in nuclear medicine which are present
`today, which were not present in 1998-2000.
` Q. Okay. So let's focus on LVF. In the
`1990s, were there a certain level or ranges of
`levels that were considered normal in thalassemia
`patients?
` MR. GOLOB: Object to the form.
` THE WITNESS: The answer is yes. The
`answer is a little more complicated than you might
`imagine. So if we base our answer on the year 2000,
`which is easier to say 2000, perhaps, if that's okay
`with you. A normal ejection fraction is in the
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`range 55 to 70, but the normal range varied a little
`bit between the techniques. And thalassemia
`patients, it's well-recorded, have ejection
`fractions which, on the whole, are slightly higher.
`BY MS. WU:
` Q. Do you mean higher in the 55 to 70 range,
`or do you mean that this range is higher than for
`non-thalassemia patient?
` A. Thalassemia patients tend to have a
`slightly higher ejection fraction for all sorts of
`physiological reasons.
` Q. So this 55 to 70 range is --
` A. It's an approximate. These things are
`very approximate.
` Q. So the approximate range of 55 to 75 for
`LVF is -- reflects a range for a normal thalassemia
`patient?
` A. Approximately, yes. But can I use the
`word approximately, because biological variation is
`very substantial.
` Q. What level or levels of LVF is considered
`abnormal in thalassemia patients?
`
`25
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` A. Well, levels below those numbers,
`obviously. There are a number of things that affect
`the ejection fraction. Age. How recently you've
`had a blood transfusion. The body surface area.
`The hemoglobin level.
` So I'm afraid it's quite difficult to
`give you an exact answer to your question, unless we
`were to consider it for a considerable period of
`time. We can do that, if you wish, but I mean, I
`think as a broad brush stroke, 55 to 70 is
`considered a normal range. And we can explore it if
`you wish.
` Q. All right. So would you agree that as of
`2000, doctors treating thalassemia patients consider
`LVF in the range of approximately 55 to 70 normal
`for thalassemia, and levels below that to be
`abnormal?
` A. That is approximately true.
` Q. LVF is a measure of heart function, is
`that right?
` A. Correct.
` Q. Would you agree that LVF of less than 56
`
`202-220-4158
`
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`7 of 98
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`Taro Pharmaceuticals, Ltd.
`Exhibit 1059
`
`

`

`Pennell, M.D., Dudley J.
`
`Case IPR2017-01446
`
`June 6, 2018
`8 (Pages 26 to 29)
`28
`
`26
`
`percent indicates arrhythmia?
` A. No.
` Q. Okay.
` A. No.
` Q. Why not?
` A. Well, because they are two fundamentally
`different concepts.
` Q. Okay.
` A. The echocardiogram shows an ejection
`fraction is telling us that if the heart, in
`diastole, when the heart is relaxed, there is -- has
`100 mls of blood in it. 56 mls of that blood has
`gone out of the heart when the heart has contracted.
`So that's the percentage of blood that's left in the
`heart.
` Arrhythmias tell us whether the heart is
`contracting in a normal rhythmic pattern at about
`one beat per second -- one beat per second, yes. So
`if the heart is beating at one beat per second, in
`the way I'm trying to demonstrate with my hands,
`that would be a normal rhythm. But clearly, if the
`heart is doing this, that's not a normal rhythm.
`
`27
`
`And so the rhythm, and the amount that the heart
`eject are not the same concept.
` Q. Is an LVF of less than 56 percent
`indicative of heart failure?
` A. Right. So that's quite a difficult
`question.
` Q. Why?
` A. Well, because the relationship -- heart
`failure is a condition that we typically associate
`with symptoms. And the association between ejection
`fraction symptoms is quite loose. This is something
`that's been known for decades. So I can't answer
`your question with a yes or a no, because it doesn't
`use the patient's symptoms in the question.
` Q. What were symptoms associated with heart
`failure in the 1990s?
` A. Okay. So there are many of them. The
`most prominent is probably breathlessness. Another
`prominent symptom is fatigue. Patients may complain
`that their ankles are swollen. And these are the
`main symptoms that a heart failure patient would
`complain of. They may complain of palpitations in
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`the heart.
` So heart failure is a syndrome of not
`only symptoms, but also signs. So of course, the
`signs are things the doctor finds, rather than the
`patient complains about. The patient will say, I am
`breathless. They don't tell you, I have an
`arrhythmia on my ECG.
` So when the doctor looks at a patient, he
`may see swollen ankles. He may find fluid in the
`lungs on a chest x-ray. He may find the heart rate
`is increased on an ECG. He may find the ejection
`fraction is low, that's not always the case. And
`there are blood tests, of course, which corroborate,
`or would indicate to you that a heart failure
`diagnosis is the correct diagnosis.
` Now, you have to put this constellation
`of signs and symptoms together to make an accurate
`diagnosis.
` Q. So when there is a diagnosis of heart
`failure, a doctor would understand that these
`symptoms would have been looked at, and the tests
`that you described would have been run, right?
`
`29
`
` A. So would you just repeat that?
` Q. Sure.
` A. I didn't quite follow it.
` Q. So when there is a diagnosis of heart
`failure, as a cardiologist --
` A. Right.
` Q. -- you would assume that the patient's
`symptoms would have been checked out and the various
`cardiac tests would have been run?
` A. Yes. For me to make a diagnosis of heart
`failure, I would have to examine the patient. And I
`would want to see the results of the tests. But the
`examination of the patient is very critical.
` Q. And that practice you just explained,
`that would have been true back in pre-2000?
` A. Yes, absolutely.
` Q. And that practice would have been common
`among cardiologists?
` A. 100 percent universal.
` Q. Now, you've heard of the NYHA criteria?
` A. Yes.
` Q. So that's a set of criteria that tries to
`
`202-220-4158
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`www.hendersonlegalservices.com
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`8 of 98
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1059
`
`

`

`Pennell, M.D., Dudley J.
`
`Case IPR2017-01446
`
`30
`
`set forth the different classes and severity of
`symptoms for heart failure?
` A. Yes, you can think of it as pigeonholing,
`to give some broad indication of where the patient's
`symptoms lie on the spectrum from absolutely
`continuously breathless doing nothing, through to
`not having any symptoms at all at the moment.
` And it's a useful classification, broadly
`speaking, because it will label, when you write a
`research paper, to characterize your population.
`You can indicate what percentage of patients lie in
`these pigeonholes, in these categories.
` Q. And so when there is a mention of heart
`failure, is there kind of a level of understanding
`of what that means to cardiologists as of 2000?
` A. Yes.
` Q. And what was that understanding?
` A. I believe I'm correct in saying, although
`I should have the date right in front of me, that we
`had New York Heart Association heart failure
`rankings in the year 2000. And we would have used
`them then. I mean, I think it's worth bearing in
`
`31
`mind, typically, when you see a patient with heart
`failure, we would typically have said mild,
`moderate, and severe, as an alternative to 2, 3, 4.
` Q. And I think we started down this
`discussion when you mentioned that Dr. Walker did
`cardiac consultations. Do you do cardiac
`consultations for thalassemia patients?
` A. In 2018, no, I don't. I haven't done
`cardiac consultations for about 10 years.
` Q. You stopped doing consultations in the
`mid-2000s?
` A. Well, I mean, I don't have that date in
`front of me. And of course, I could find it out,
`but that is approximately correct. The burden of
`work that I was doing, administratively and
`research-wise, led me to give up those cardiology
`clinics. And I have been doing a more managerial,
`supervisory, and research role, and less clinical
`work since that time. And it was approximately
`mid-2000s.
` Q. So during the time that you were doing
`clinical consultations with thalassemia patients,
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`June 6, 2018
`9 (Pages 30 to 33)
`32
`what evaluations did you do, beyond scanning work?
` A. Well, the most important I mentioned
`already. You have to talk to the patient, because
`everything starts in medicine with a history. If
`the patient says, I'm not breathless, that's a very
`good start to everything. If a patient is
`breathless, that's never a good start. And then we
`have the examination, which is critical. And then
`you have the tests. It's a sort of triangle.
` Q. When a cardiologist collects patient
`history, and does a physical examination, that
`doctor cannot be blinded to the patient's chelation
`treatment, is that right?
` A. It depends on the circumstances.
` Q. Okay.
` A. When I saw patients in 1995-ish, around
`there, my responsibility was to look at, for
`example, arrhythmias and heart failure. But the
`chelation regime was not a concern of mine.
` Q. When you examine a thalassemia patient,
`can you tell if that patient is taking subcutaneous
`deferoxamine?
`
`33
`
` A. Not usually. I mean, I think if you go
`looking for it, you could. If you specifically ask
`the patient, where do you do your injections, can I
`see the injection sites? And then they say, well,
`actually, I take an oral treatment. That's a
`different matter.
` Q. So injection sites on thalassemia
`patients are not visible to a car