Case No. IPR2017-01446
`Coates, M.D., Thomas D. - Vol. I
`
`April 26, 2018
`
`1
`
` UNITED STATES PATENT AND TRADEMARK OFFICE
` BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`TARO PHARMACEUTICALS U.S.A., )
`INC., )
` )
` Petitioner, )
` ) Case No.
` vs. ) IPR2017-01446
` ) Volume I
`APOTEX TECHNOLOGIES, INC., )
` )
` Patent Owner. )
`__________________________________)
`
` VIDEOTAPED DEPOSITION OF THOMAS D. COATES, M.D.
` Los Angeles, California
` Thursday, April 26, 2018
`
`Reported by:
`ELIZABETH BORRELLI, CSR No. 7844, RPR
`JOB NO. 43130
`
`202-220-4158
`
`Henderson Legal Services, Inc.
`www.hendersonlegalservices.com
`
`1 of 108
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1058
`
`

`

`Case No. IPR2017-01446
`Coates, M.D., Thomas D. - Vol. I
`
`1
`
`2 3
`
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`1
`2
`3
`4
`5
`
`6789
`
`10
`11
`12
`
`13
`
`14
`
`15
`16
`
`17
`
`18
`19
`
`20
`21
`
`22
`
`23
`24
`25
`
`2
` UNITED STATES PATENT AND TRADEMARK OFFICE
` BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`TARO PHARMACEUTICALS U.S.A., )
`INC., )
` )
` Petitioner, )
` ) Case No.
` vs. ) IPR2017-01446
` vs. )
` ) Volume
`APOTEX TECHNOLOGIES, INC., )
` ) Pages 1 to 239
` Patent Owner. )
`__________________________________)
`
` Videotaped Deposition of THOMAS D. COATES,
` M.D., Volume I, taken on behalf of the
` Petitioner, at 601 South Figueroa Street, 41st
` Floor, Los Angeles, California, commencing at
` 9:07 a.m., Thursday, April 26, 2018, before
` Elizabeth Borrelli, a Certified Shorthand
` Reporter in the State of California, License
` No. 7844.
` * * *
`
`3
`
`APPEARANCES OF COUNSEL:
`
`For the Petitioner:
` GOODWIN PROCTER LLP
` BY: HUIYA WU
` BY: CHRISTOPHER J. MORTEN
` Attorneys at Law
` The New York Times Building
` 620 Eighth Avenue
` New York, New York 10018
` (212) 459-7270
` (212) 459-7114
` hwu@goodwinlaw.com
` cmorten@goodwinlaw.com
`
`1
`2
`
`3 4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`1
`
`23
`
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`April 26, 2018
`2 (Pages 2 to 5)
`4
`APPEARANCES OF COUNSEL (continued):
`
`For the Patent Owner:
` COZEN O'CONNOR
` BY: BARRY GOLOB
` BY: W. BLAKE COBLENTZ
` Attorneys at Law
` 1200 Nineteenth Street NW
` Washington, DC 20036
` (202) 912-4815 (direct)
` (202) 912-4837 (direct)
` bgolob@cozen.com
` wcoblentz@cozen.com
`
` Also Present:
` DAVID KIM, Videographer
`
`5
`
` I N D E X
`WITNESS EXAMINATION
`THOMAS D. COATES, M.D.
`By MS. WU 9, 228
`By MR. COBLENTZ 224
`
` R E F E R E N C E D E X H I B I T S
`
`EXHIBIT DESCRIPTION PAGE
`Exhibit 2002 Curriculum Vitae of Thomas 11
` Coates, M.D., 70 pages
`
`Exhibit 2001 Document titled "Declaration of 16
` Thomas D. Coates, M.D. in
` Support of Patent Owner's
` Preliminary Response," 41 pages
`Exhibit 2015 Document titled "Cardiovascular 17
` T2-star (T2*) magnetic
` resonance for the early
` diagnosis of myocardial iron
` overload," 40 pages
`Exhibit 1022 Document titled "Oral Iron 56
` Chelation with Deferiprone," 30
` pages
`Exhibit 1001 U.S. Patent 7,049,328 B2, 18 61
` pages
`
`Exhibit 1021 U.K. Patent GB 2 118 176 B, 22 64
` pages
`
`202-220-4158
`
`Henderson Legal Services, Inc.
`www.hendersonlegalservices.com
`
`2 of 108
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1058
`
`

`

`Case No. IPR2017-01446
`Coates, M.D., Thomas D. - Vol. I
`
`1
`
`2
`
`3 4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`1
`2
`3
`4
`
`5 6
`
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`Exhibit 2035 Document titled "Second 75
` Declaration of Thomas D.
` Coates, M.D. in Support of
` Patent Owner's Response," 21
` pages
`Exhibit 1007 Document titled "Long-Term 87
` Trial of Deferiprone in 51
` Transfusion-Dependent Iron
` Overloaded Patients," 6 pages
`
`Exhibit 2011 Document titled "Long-Term 115
` Safety and Effectiveness of
` Iron-Chelation Therapy with
` Deferiprone for Thalassemia
` Major," 7 pages
`
`Exhibit 2016 Document titled "Comparison of 121
` effects of oral Deferiprone and
` subcutaneous desferrioxamine on
` myocardial iron concentrations
` and ventricular function in
` beta-thalassemia," 5 pages
`Exhibit 2022 Document titled "Lack of 130
` correlation between iron
` overload cardiac dysfunction
` and needle liver biopsy iron
` concentration," 2 pages
`Exhibit 2003 Document titled "Declaration of 133
` Dudley Pennell, M.D. in Support
` of Patent Owner's Preliminary
` Response," 47 pages
`
`Exhibit 2026 Document titled "Second 133
` Declaration of Dudley J.
` Pennell, M.D. in Support of
` Patent Owner's Response," 16
` pages
`
`Exhibit 1012 Document titled "Iron-Chelation 139
` Therapy with Oral Deferiprone
` in Patients with Thalassemia
` Major," 5 pages
`Exhibit 1010 Olivieri 1995 abstract, 12 201
` pages
`
`6
`
`7
`
`Exhibit 2014 Document titled "Canadian 219
` Scientists Honored for Role in
` Breakthrough Drug," 6 pages
` EXHIBITS
`
`COATES PAGE
`Exhibit 1052 U.S. Patent 4,840,958, 9 pages 58
`Exhibit 1053 Document titled "Safety profile 99
` of the oral iron chelator
` Deferiprone: a multicentre
` study," 8 pages
`
`Exhibit 1054 Document titled "Physiology and 205
` Pathophysiology of Iron
` Cardiomyopathy in Thalassemia,"
` 10 pages
`
`1
`
`2
`
`3
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`13
`
`14
`
`15
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`24
`
`25
`
`1
`
`2
`3
`
`4 5
`
`6
`7
`
`8
`
`9
`
`10
`
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`April 26, 2018
`3 (Pages 6 to 9)
`8
` LOS ANGELES, CALIFORNIA; THURSDAY, APRIL 26, 2018
` 9:07 A.M.
`
` THE VIDEOGRAPHER: We are now going on the
`video record. Today is April 26th, 2018 and the
`time is approximately 9:07 a.m. The location is 601
`South Figueroa Street, Los Angeles, California. My
`name is David Kim. I'm the video specialist
`representing Henderson Legal Services. The civil
`action number is IPR2017.01146 in the matter of Taro
`v. Apotex and the deponent is Dr. Thomas D Coates.
`The video deposition is requested by Cozen O'Connor.
` Will counsel please identify themselves
`for the record.
` MS. WU: Huiya Wu on behalf of petitioner
`Taro Pharmaceuticals of Goodwin Procter. With me is
`Chris Morten.
` Just one clarification, it's IPR2017-1446.
` THE VIDEOGRAPHER: Okay.
` MR. GOLOB: Barry Golob and Blake Coblentz
`of Cozen O'Connor for the patent owner, Apotex.
` THE VIDEOGRAPHER: The deponent may now be
`sworn in.
`///
`///
`
`9
`
` THOMAS COATES, M.D.,
` having been duly administered
` an oath in accordance with CCP 2094,
` was examined and testified as follows:
`
` EXAMINATION
`BY MS. WU:
` Q. Good morning, Dr. Coates.
` A. Good morning.
` Q. Could you please state your full name?
` A. Thomas Dwayne Coates.
` Q. My name is Huiya Wu and I'll be asking you
`questions today.
` Have you been deposed before?
` A. Yes.
` Q. How many times?
` A. I'm not sure exactly. More than five,
`less than 20.
` Q. When was your most recent deposition?
` A. Again, I don't exactly remember. Within
`the last three to five years.
` Q. So it's been a few years, so let me go --
` A. It's probably been --
` Q. -- through some ground rules.
` A. I'm sorry.
`
`202-220-4158
`
`Henderson Legal Services, Inc.
`www.hendersonlegalservices.com
`
`3 of 108
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1058
`
`

`

`Case No. IPR2017-01446
`Coates, M.D., Thomas D. - Vol. I
`
`April 26, 2018
`4 (Pages 10 to 13)
`12
`
`10
`
` Q. First ground rule being I will ask
`questions and you will --
` A. I will listen.
` Q. You will give answers, and I ask that you
`let me finish my question before you give an answer
`so that the court reporter can take down the
`testimony appropriately, okay?
` A. That's fine.
` Q. If you don't understand the question,
`please ask me to clarify, and I'll do my best to do
`that, okay?
` A. Yes.
` Q. Now, if you answer a question, I will
`assume that you have understood it. Agreed?
` A. Agreed.
` Q. If you need a break, please let me know,
`okay? But I will try to take breaks about every
`hour, all right?
` A. Yes.
` Q. If there is a question pending, I do ask
`that you answer it before we go on break, okay?
` A. Yes.
` Q. Now, is there any reason you cannot give
`complete and accurate testimony today?
` A. No.
`
`11
`
` Q. Let me hand you what's been previously
`marked as Exhibit 2002. Is this your current CV?
` A. I don't -- is there a date on this? I
`don't see it.
` THE WITNESS: Do we know when this was
`sent?
` MS. WU: I don't.
` THE WITNESS: Okay.
` MR. GOLOB: What was it attached to, so
`you can give him a timeframe?
` MS. WU: I believe this was submitted with
`your first declaration in the IPR proceeding.
` THE WITNESS: Then no, but it's like --
`let me look at the number of publications.
`BY MS. WU:
` Q. And if it helps, your declaration was
`dated September 2017.
` A. December?
` MR. GOLOB: September.
` THE WITNESS: September.
` It's -- it's quite close. There's a few
`more publications that -- that are on my most recent
`CV, but they're not -- likely not relevant to this.
`BY MS. WU:
` Q. Are you currently employed by Children's
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`Hospital of Los Angeles?
` A. Yes.
` Q. Is that a leading center for
`transfusion-dependent patients?
` A. Yes.
` Q. Since when?
` A. Probably -- probably since the mid- to
`early 1990s.
` Q. Are there other leading centers for
`transfusion-dependent patients in the US?
` A. Yes.
` Q. What are those?
` A. The major centers are us, Oakland
`Children's, Chicago, I forget -- I forget what the
`name of it. Everybody is changing their names these
`days when people give money to the universities, but
`Alexis Thompson at Chicago, Children's Hospital of
`Philadelphia, Atlanta Children's Hospital, Cornell
`University. Those are the major institutions.
`There are some other ones that are also good.
` Q. Where these centers also leading centers
`in -- since the mid-1990s?
` A. Yes. Perhaps not Chicago or Atlanta.
` Q. Oakland Children's Hospital, Philadelphia
`and Cornell were leading centers for
`
`13
`transfusion-dependent patients since the mid-1990s?
` A. Yes.
` Q. Are you aware of any societies for
`hematologists who treat transfusion-dependent
`patients?
` A. Yes.
` Q. What are the leading societies for
`hematologists who treat transfusion-dependent
`patients?
` A. Well, the major society is the American
`Society for Hematology.
` Q. Any others?
` A. Well, European Hematology, EHA, European
`Hematology Association; TIF, Thalassemia
`International --
` [Reporter requests clarification.]
` THE WITNESS: Thalassemia International
`Federation, American Society for Pediatric
`Hematology Oncology --
` [Reporter requests clarification.]
` THE WITNESS: American Society for
`Pediatric Hematology Oncology, and I'm -- I'm sure
`that there are some other similar groups in Europe
`and Italy and Greece whose names I can't pronounce
`or remember.
`
`202-220-4158
`
`Henderson Legal Services, Inc.
`www.hendersonlegalservices.com
`
`4 of 108
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1058
`
`

`

`Case No. IPR2017-01446
`Coates, M.D., Thomas D. - Vol. I
`
`April 26, 2018
`5 (Pages 14 to 17)
`16
`
`14
`
`BY MS. WU:
` Q. Are you a member of any of these
`societies?
` A. Yes, I am.
` Q. Which ones?
` A. American Society for Hematology, European
`Hematologic Association, American Society of
`Pediatric Hematology and Oncology.
` Q. Do these societies have meetings?
` A. Yes, they do.
` Q. Do you attend them?
` A. Yes.
` Q. Since when have you been attending
`meetings for the American Society of Hematology?
` A. My first meeting was probably in 1981,
`1982.
` Q. Is it a yearly meeting?
` A. Yes.
` Q. Did you spend any time preparing for this
`deposition?
` A. Yes.
` Q. About how long?
` A. Well, specifically for the deposition
`itself, probably 10 to 20 hours.
` Q. Did you review your declaration submitted
`
`15
`
`to the PTAB?
` MR. GOLOB: You can answer "yes" or "no."
`only.
` THE WITNESS: Yes.
`BY MS. WU:
` Q. Do you understand what I'm referring to
`when I say "PTAB"?
` A. That, I believe was the -- the patent
`office response. Thank you for asking. These terms
`are a little bit unclear, but yes.
` Q. And you recall you had two declarations
`that you submitted --
` A. Yes.
` Q. -- to the PTAB?
` A. I recall I had two declarations, yes.
` Q. In reviewing your declarations, do you
`have any corrections or updates?
` A. Well, there is one word, I believe, in the
`first declaration where we said that we developed an
`MRI technology, and the word "developed" should
`probably be "implemented and expanded upon the
`technology developed by Dr. Pennell." It's a minor
`difference, but that's the only thing.
` Q. So let's take a look at that, your first
`declaration.
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
` MS. WU: Handing you Exhibit 2001.
`BY MS. WU:
` Q. This is your first declaration, right?
` A. Yes. Now, I'm not sure I'll be able to
`find this right away.
` MR. GOLOB: She will ask a question if she
`wants to. Don't worry.
`BY MS. WU:
` Q. At the paragraph 4 on page 2 --
` A. Yes.
` Q. -- do you see, right, "I am a pediatric
`cardiologist/MRI engineer developed" --
` A. Yes.
` Q. -- "the technology to measure tissue iron
`by MRI"?
` A. Yes, I see that.
` Q. Is that the sentence in which you would
`like to make a correction to the word "developed"?
` A. Yes.
` Q. Who is the pediatric cardiologist/MRI
`engineer you refer to there?
` A. Dr. John Wood.
` Q. And are you making this distinction
`because Dr. Pennell, and not you and Dr. Wood,
`developed the MRI technology discussed?
`
`17
`
` A. Dr. Pennell developed the initial
`technology, so yes.
` Q. When was that?
` A. Dr. Pennell's paper, I believe, was in
`2001, Anderson and Pennell. I'm sure you...
` Q. Let me hand you what's been marked as
`Exhibit 2015. Is this the Anderson and Pennell
`paper you were referring to?
` A. Yes.
` Q. Okay. When did you start treating
`transfusion-dependent patients?
` A. In the late 1970s, 1980.
` Q. When did you start treating thalassemia
`patients?
` A. 1980.
` Q. Did you use Deferoxamine?
` A. Yes.
` Q. When did you first use Deferoxamine?
` A. 1980.
` Q. Have you conducted research regarding
`thalassemia patients?
` A. Yes.
` Q. When did you first start researching in
`relation to the thalassemia patients?
` MR. GOLOB: Object to the form. The
`
`202-220-4158
`
`Henderson Legal Services, Inc.
`www.hendersonlegalservices.com
`
`5 of 108
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1058
`
`

`

`Case No. IPR2017-01446
`Coates, M.D., Thomas D. - Vol. I
`
`April 26, 2018
`6 (Pages 18 to 21)
`20
`
`18
`
`question before was "conduct research" and this
`question says "researching."
` MS. WU: I'm happy to rephrase, Barry.
`BY MS. WU:
` Q. When did you first conduct research
`regarding thalassemia patients?
` A. 2000, 2001.
` Q. What did that research involve?
` A. Dr. Wood and I were studying methodology
`of measuring iron in the heart using magnetic
`resonance imaging.
` Q. Why were you and Dr. Wood interested in
`measuring iron in the heart in 2000 or 2001?
` MR. GOLOB: Object to the form.
` THE WITNESS: Well, we -- in specifically
`-- well, because he's a cardiologist, number one,
`and actually, to be truthful, we were interested in
`quantifying, non-invasively, iron in general in
`patients with iron overload. And prior to that time
`and prior to Dr. Pennell -- actually Pennell's paper
`was with heart only. It wasn't related to the total
`body iron. So total body iron was really more of
`our -- our actual focus, more of an unmet need. And
`these measurements are quite complex, quite
`difficult. Prior to that time, there were really no
`
`19
`accurate or acceptable measurements of iron by MRI
`at all prior to Pennell. And Dr. Wood is a Ph.D. in
`MRI engineering, and so we started to do research on
`the actual physics of the measurement systems and
`trying to enhance prior work of Pennell and
`colleagues to make measurements in the liver and
`measurements of total body iron, and also to
`implement the Pennell technology.
`BY MS. WU:
` Q. So in your work with Dr. Wood you've
`described, does that involve MRI T2* measurements?
` A. Yes.
` Q. Did you have any experience with MRI T2
`measurements?
` A. No, I -- I didn't.
` Q. Did your colleague, Dr. Wood, have
`experience with MRI T2 measurements?
` A. Yes.
` Q. How do you know that?
` A. Because he and I discussed this. We
`discussed this particular with whether we were going
`to use T2 or T2* for measurement of liver iron, and
`also one of the motivations of this was the fact
`that -- I mean, T2 is a reasonable approach for the
`liver, but by that time, we knew that T2 was not
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`acceptable for a measurement of heart iron. So we
`-- and he knew that and, in fact, that's how our
`conversations and bid got started was the inadequacy
`of previous attempts to make those measurements, you
`know, prior to 2001, 2002.
` Q. So is it fair to say that prior to 2000,
`you did not have experience with T2?
` A. Me, personally, prior to Dr. Wood's
`joining our team, in -- actually, 1999, he joined,
`and we worked on this in 2001, 2002. Prior to that
`time, I had no detailed experience with trying to
`use T2. We were aware that people had tried to do
`it and that it didn't work, but we didn't try to do
`it.
` Q. So when you said you did not have detailed
`experience of trying to use T2, is it fair to say
`you didn't have any experience using T2 prior to
`2000?
` A. I was trying to do it. No, I had no
`experience at all. I was trying to do it.
` Q. Did you and Dr. Wood publish any paper
`regarding your work on T2*?
` A. Yes.
` Q. Is that reflected in your CV?
` A. Yes.
`
`21
`
` Q. Where is that reflected in your CV?
` A. That's a paper with -- where Dr. -- in
`2005 in the journal Blood. Dr. Wood is the first
`author. I'm the senior author, where we published
`the calcu- -- the calibration of liver iron
`measurement using T2 and T2*. There are a number of
`other publications of me and Dr. Wood that are
`related in my CV.
` Q. If you'll take a look with me at your CV,
`Exhibit 2002.
` A. Do you have a page number?
` Q. Unfortunately, it was produced without
`page numbers. But if you could take a look at the
`list of publications about halfway through.
` A. Is there a reference number?
` Q. I'm looking at references 74 and 75. Are
`you there?
` A. Yes. And those are not -- well...
` Q. Are those the papers you're referring to?
` A. No.
` Q. All right. If you could look back one
`page to reference 69. Is that the reference you're
`referring to?
` A. That's --
` MR. GOLOB: Okay. There's more than one.
`
`202-220-4158
`
`Henderson Legal Services, Inc.
`www.hendersonlegalservices.com
`
`6 of 108
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1058
`
`

`

`Case No. IPR2017-01446
`Coates, M.D., Thomas D. - Vol. I
`
`April 26, 2018
`7 (Pages 22 to 25)
`24
`
`22
`
` THE WITNESS: Yeah.
` MR. GOLOB: 69, do you --
` MS. WU: That's a --
` MR. GOLOB: -- want to clarify?
` MS. WU: That's a good point.
` MR. GOLOB: Just the title or something
`because...
`BY MS. WU
` Q. Is there -- Dr. Coates, is there more than
`one list of publications in your...
` A. There's a list of abstracts. Let me make
`sure we're in the -- and then there's a list of --
`of full papers.
` Q. All right. I'm looking at the
`peer-reviewed papers.
` A. Peer-reviewed papers.
` MR. GOLOB: What's the -- what's the title
`and stuff that you're looking at in No. 69?
` MS. WU: All right. And I see reference
`69 reads, "Wood, J.C.," and the article is entitled
`"Myocardial iron loading in transfusion-dependent
`thalassemia and sickle-cell disease," published in
`Blood, 2004.
` THE WITNESS: Yes.
`BY MS. WU:
`
`23
`
` Q. Do you see that?
` A. Yes, but that's -- well, that -- that is a
`paper that we wrote on the topic of T2* in the
`heart. There's a later paper in 2005, which was the
`seminal paper on measurement of liver iron, also
`first author Wood.
` Q. Is that any of references 74, 75 or 76 on
`the next page?
` A. No. 75.
` Q. So the Wood paper of 2005 you're referring
`to is entitled "MRI R2 and R2* Mapping Accurately
`Estimate Hepatic Iron Concentration in
`Transfusion-Dependent Thalassemia and Sickle-Cell
`Disease Patients"; is that right?
` A. Yes.
` Q. Is reference 69 the article entitled
`"Myocardial iron loading and transfusion-dependent
`thalassemia and sickle-cell disease" your first
`publication regarding thalassemia?
` A. I would have to read through all of these
`to see. It was one of the early ones. It looks
`like it might be the first one, yes.
` Q. Have you used Deferiprone?
` A. Yes.
` Q. When was the first time?
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
` A. I'm not going to be able to remember the
`exact date. We used it under compassionate use
`protocol probably around 2005, 2006. I'm guessing
`at that date. I specifically remember the patient,
`but I don't remember the exact date.
` Q. Are you certain that you used Deferiprone
`after the year 2000?
` A. Yes.
` Q. Are you certain that you used Deferiprone
`for the first time after the year 2000?
` A. Yes.
` Q. Have you used Deferasirox?
` A. Yes.
` Q. When did you first use that drug?
` A. In probably around 2003. We were of
`the --
` MR. GOLOB: She just asked you when.
` THE WITNESS: Yeah.
`BY MS. WU:
` Q. In what context did you first use
`Deferasirox?
` A. We were one of the sites involved in the
`phase three clinical trials of Deferasirox for the
`treatment of iron overload in thalassemia.
` Q. Have you participated in clinical trials
`
`25
`
`regarding iron chelators?
` A. Yes, I have.
` Q. Which ones?
` A. The 105 study from Novartis looking at
`thalassemia and iron overload. The Novartis trial
`looking at Deferasirox in sickle-cell disease.
` MR. GOLOB: Before you go on, I just want
`to caution you that if it's not public, that this is
`a public proceeding.
` THE WITNESS: Yes, these are published --
` MR. GOLOB: Okay.
` THE WITNESS: -- papers. I'm the senior
`author on the sickle-cell Deferasirox paper. The --
`yeah. And then we have -- Dr. Wood and I have a
`study looking at Deferasirox in thalassemia that was
`published in Blood.
`BY MS. WU:
` Q. Have you participated in clinical studies
`for Deferiprone?
` MR. GOLOB: I'll object to the form.
` THE WITNESS: No.
`BY MS. WU:
` Q. Have you participated in clinical studies
`for Deferoxamine?
` A. Not specifically focused on Deferoxamine.
`
`202-220-4158
`
`Henderson Legal Services, Inc.
`www.hendersonlegalservices.com
`
`7 of 108
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1058
`
`

`

`Case No. IPR2017-01446
`Coates, M.D., Thomas D. - Vol. I
`
`April 26, 2018
`8 (Pages 26 to 29)
`28
`
`26
`
` Q. Can you explain what you mean by that?
` A. Well, the Novartis Deferasirox studies,
`Deferoxamine was the other part of a prospective
`randomized trial.
` Q. Now, I understand you're not a
`cardiologist; is that right?
` A. That's correct.
` Q. But you have some understanding of heart
`disease; is that right?
` A. Yes, I do.
` Q. What's the difference between heart
`disease and iron-induced heart disease?
` MR. GOLOB: Object to the form.
` THE WITNESS: Well, the way that you
`phrased this, there's an implication of what is
`causing cardiac dysfunction. So there are many
`things that cause heart disease. We now understand
`that iron is one of those things.
`BY MS. WU:
` Q. When did doctors first understand that
`iron is one cause of heart disease?
` A. Probably not clearly until we were able to
`directly quantify the relation between iron in the
`heart and cardiac function. Back in --
` Q. When was that?
`
`27
`
` A. Well, prior to 2001 and prior to the
`Pennell paper, we had no way premortem of knowing
`that a patient had iron in their heart. And so
`prior to that time, there was no way to understand
`whatsoever that there was any relationship between
`those two things at all.
` Q. Prior to 2000, were there any biopsies
`done of the heart to determine if iron was the cause
`of heart disease?
` A. People had done that, but it wasn't --
`certainly, it wasn't common -- commonly done at all,
`because it's dangerous.
` Q. How about kind of postmortem autopsies to
`determine whether there was iron in the heart
`causing heart failure?
` A. Well, again, prior to 2000, there was a
`lot of autopsy data on patients with -- with iron
`overload. At autopsy, it's not possible to
`determine what's causing what. At autopsy, the
`patients that died from transfusional iron overload
`had iron everywhere.
` Q. So is it your opinion that prior to 2000,
`doctors were not aware that iron was a cause of
`heart disease?
` MR. GOLOB: Object to the form.
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
` THE WITNESS: Prior to 2000, we knew that
`patients -- well, let me ask you: Do you mean at
`all, or do you mean patients with
`transfusion-dependent thalassemia?
`BY MS. WU:
` Q. Thank you. Let me reask that.
` Prior to 2001, is it your opinion that
`doctors were not aware that iron was a cause of
`heart disease for thalassemia or
`blood-transfusion-dependent patients?
` A. Prior to that time, there really wasn't a
`direct causal connection between those two things.
`We knew that patients with thalassemia died of heart
`problems. We knew that they died of many other
`things. But since no one had ever made a
`measurement and determined that there was any
`relationship between the degree of iron content and
`the degree of cardiac dysfunction or the frequency
`of cardiac dysfunction, we -- we really didn't know.
`We just knew that they had a lot of iron, and that
`they died, and this is one of the reasons that they
`died. And at autopsy, there was iron in the heart
`and the pancreas and everywhere.
` Q. Do you understand what the phrase "iron
`overload of the heart" means?
`
`29
`
` A. Yes.
` Q. What does it mean?
` A. To me, it means that there's a higher
`level of iron in the heart than the normal level of
`iron.
` Q. Do all blood-transfusion-dependent
`patients risk iron overload of the heart?
` A. Yes, there is risk.
` Q. Do all blood-transfusion-dependent
`patients risk iron-induced cardiac disease?
` A. There is risk, but because there's a risk,
`it doesn't mean that heart disease or iron overload
`is present.
` Q. For the purposes of this case, have you
`used the phrase "cardiac disease" synonymously with
`"heart disease"?
` MR. GOLOB: Object to the form.
` THE WITNESS: Yes.
`BY MS. WU:
` Q. How does iron induce heart disease?
` A. Do you mean based upon what we understood
`prior to 2000, or what we understand in 2018?
` Q. Today, how does iron induce heart disease?
` A. In 2018 we know that iron enters the
`heart. It interferes with excitation contraction
`
`202-220-4158
`
`Henderson Legal Services, Inc.
`www.hendersonlegalservices.com
`
`8 of 108
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1058
`
`

`

`Case No. IPR2017-01446
`Coates, M.D., Thomas D. - Vol. I
`
`April 26, 2018
`9 (Pages 30 to 33)
`32
`
`30
`
`coupling. It interferes with the mitochondrial
`function of the heart and causes significant
`production of reactive oxygen species, which are
`damaging to the various functions within the heart.
` Q. Prior to 2001 did iron behave the same way
`with respect to the heart?
` MR. GOLOB: Well, object to the form. Are
`you asking for thalassemia patients or just in
`general?
` MS. WU: I'm not sure it makes a
`difference.
`BY MS. WU:
` Q. Did you understand the question?
` A. Could you repeat the question, please?
` Q. Sure. The prior question I asked you was
`about how iron induces heart disease in 2018, okay?
`My question is, does iron -- scratch that.
` Did iron behave the same way prior to 2001
`as it does today?
` A. Well --
` MR. GOLOB: Object to the form.
` THE WITNESS: Prior to 2001, we didn't
`understand any of this. You need to understand that
`there's been a tremendous increase in our
`understanding of the basic biochemistry in molecular
`
`31
`
`biology of iron in general and with respect to the
`heart since that time. Prior to 2001, none of this
`was known. The biology of iron -- I understand the
`question you're asking me to be is the biology of
`iron the same in 2018 as it was in 2001? The
`biology was not known in 2001. The biology is the
`same. I'm sure that evolution hasn't changed --
`Mr. Darwin is good, but he's not that good.
`Evolution hasn't changed between 2001 and 2018. So
`the biology, the biochemistry and the molecular
`biology are the same.
`BY MS. WU:
` Q. So if I understand your answer correctly,
`are you saying that iron enters the heart in the
`same way and causes damage in the same way, but that
`understanding wasn't elucidated until after 2001?
` A. Significantly, yeah.
` MR. GOLOB: I'll object to the form of the
`question. I think it mischaracterize