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` MARK J. RATAIN, M.D.
` UNITED STATES PATENT AND TRADEMARK OFFICE
` _________________________________________
`
` BEFORE THE PATENT TRIAL AND APPEAL BOARD
` _________________________________________
` PAR PHARMACEUTICAL, INC., )
` )
` Petitioner, )
` )
` vs. ) Case IPR2016-01479
` ) Patent 9,006,224
` NOVARTIS AG, )
` )
` Patent Owner. )
`
` DEPOSITION OF MARK J. RATAIN, M.D.
` Chicago, Illinois
` Monday, April 17, 2017
`
`Reported by: JANET L. ROBBINS, CSR, RPR
`Job No: 121162
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`NOVARTIS EXHIBIT 2040
`Par v. Novartis, IPR 2016-01479
`Page 1 of 332
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` MARK J. RATAIN, M.D.
` UNITED STATES PATENT AND TRADEMARK OFFICE
` _________________________________________
`
` BEFORE THE PATENT TRIAL AND APPEAL BOARD
` _________________________________________
` PAR PHARMACEUTICAL, INC., )
` )
` Petitioner, )
` )
` vs. ) Case IPR2016-01479
` ) Patent 9,006,224
` NOVARTIS AG, )
` )
` Patent Owner. )
`
` DEPOSITION OF MARK J. RATAIN, M.D.
` Chicago, Illinois
` Monday, April 17, 2017
`
`Reported by: JANET L. ROBBINS, CSR, RPR
`Job No: 121162
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`NOVARTIS EXHIBIT 2040
`Par v. Novartis, IPR 2016-01479
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` MARK J. RATAIN, M.D.
`
`Page 2
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` April 17, 2017
` 9:29 a.m.
`
` Deposition of MARK J. RATAIN, M.D., at
` Latham & Watkins LLP, 330 North Wabash Avenue,
` Suite 2800, Chicago, Illinois, pursuant to
` notice, before JANET L. ROBBINS, Illinois
` Certified Shorthand Reporter, Registered
` Professional Reporter.
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` MARK J. RATAIN, M.D.
` A P P E A R A N C E S:
` LATHAM & WATKINS
` BY: BRENDA DANEK, ESQ.
` 330 North Wabash Avenue
` Chicago, IL 60611
` appeared on behalf of Petitioner;
`
` FITZPATRICK CELLA HARPER & SCINTO
` BY: CHARLOTTE JACOBSEN, ESQ.
` LAURA FISHWICK, ESQ.
` 1290 Avenue of the Americas
` New York, NY 10104
` appeared on behalf of the Patent Owner.
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`NOVARTIS EXHIBIT 2040
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` MARK J. RATAIN, M.D.
` I N D E X
`
` WITNESS:
` MARK J. RATAIN, M.D.
`
` PAGE
` EXAM BY MS. JACOBSEN 5
`
` E X H I B I T S
`
` EXHIBIT DESCRIPTION PG LN
` Exhibit 2038 Transplantation of 318 4
` Azaserine-Induced
` Carcinomas of
` Pancreas in Rats
` Exhibit 2039 Adenocarcinoma of the 319 8
` Pancreas in
` Azaserine-treated
` Rats
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` MARK J. RATAIN, M.D.
` (Witness sworn.) 09:29
` MARK J. RATAIN, M.D.,
`called as a witness herein, having been first
`duly sworn, was examined and testified as
`follows:
` EXAMINATION
`BY MS. JACOBSEN:
` Q. Good morning, Dr. Ratain. 09:29
` A. Good morning, Ms. Jacobsen. 09:29
` Q. Now, I know you've been deposed 09:29
`before, but I'll just remind you of the ground 09:29
`rules which will help us to have a clean record 09:29
`for today. 09:29
` The first is that we should try not 09:29
`to speak over each other so that the 09:29
`stenographer can get all of our questions and 09:29
`answers down. Is that okay? 09:30
` A. Yes. 09:30
` Q. And I ask that you answer to the 09:30
`best of your ability, unless you're instructed 09:30
`by your counsel not to answer a question. 09:30
` Do you understand that? 09:30
` A. Yes. 09:30
` Q. Is there any reason why you can't 09:30
`
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`answer to the best of your ability today? 09:30
` A. Not that I know of. 09:30
` Q. Okay. If you don't understand one 09:30
`of my questions, will you ask me to rephrase 09:30
`it? 09:30
` A. I will. 09:30
` Q. And if you don't ask me to rephrase 09:30
`it, I'm going to assume that you understood my 09:30
`question. 09:30
` Do you understand that? 09:30
` A. I do. 09:30
` Q. Now, I know you've been deposed 09:30
`before, but approximately how many times? 09:30
` A. In total over my entire career? 09:30
` Q. Yes. 09:30
` A. I'm not sure I can give you a good 09:30
`answer. Probably between 50 and 100. 09:30
` Q. Approximately how many of those 09:30
`depositions were in connection with patent 09:30
`cases? 09:31
` A. Just a fraction of them. 09:31
` Q. What kind of fraction? 09:31
` A. Maybe ten. 09:31
` Q. And in those cases, were you 09:31
`
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` MARK J. RATAIN, M.D.
`providing expert testimony on behalf of the 09:31
`generic pharmaceutical company? 09:31
` MS. DANEK: Objection, form. 09:31
` THE WITNESS: I'm trying to 09:31
` understand whether I properly understand 09:31
` your question, so... 09:31
`BY MS. JACOBSEN: 09:31
` Q. In the patent cases in which you've 09:31
`testified, you were providing expert testimony 09:31
`on behalf of a company, is that right? 09:31
` A. Yes. 09:31
` Q. In each of those cases, was the 09:31
`company that you were providing expert 09:31
`testimony on behalf of a generic pharmaceutical 09:31
`company? 09:31
` A. Yes. Well, I guess my answer is yes 09:31
`in the sense that it was on behalf of a company 09:32
`that was seeking -- that was being sued for 09:32
`infringement or was arguing that a patent was 09:32
`invalid. Some of these companies, I 09:32
`understand, often also have brand name drugs. 09:32
` So if that was your question -- if 09:32
`that was the point of your question, I think 09:32
`that's my answer. But as you're aware, there 09:32
`
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`are companies that have both brand name drugs 09:32
`and generic drugs, and I don't know whether 09:32
`they're properly called a generic company or 09:32
`not. 09:32
` Q. But these were companies that at 09:32
`least as part of their business was providing 09:32
`generic medicines, is that right? 09:32
` A. Well, I would say part of Novartis' 09:32
`business is providing generic medicines, so I'm 09:32
`not sure how you classify Novartis. 09:32
` Q. If we assume that Novartis is a 09:32
`banded pharmaceutical company, the Sandoz 09:32
`company is separate from Novartis and provides 09:33
`generics, then with that understanding of the 09:33
`kind of breakdown, were you acting on behalf of 09:33
`generic pharmaceutical companies? 09:33
` MS. DANEK: Objection, form. 09:33
` THE WITNESS: Well, I'm not sure 09:33
` what you would consider Teva is, for 09:33
` example. 09:33
`BY MS. JACOBSEN: 09:33
` Q. So one of them would be Teva. 09:33
` Can you think of other companies -- 09:33
`have you testified on behalf of Teva? 09:33
`
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` A. I have. 09:33
` Q. Can you name other companies in 09:33
`which you've testified on behalf of? 09:33
` THE COURT REPORTER: I'm sorry. I'm 09:33
` having a little trouble with the volume.
` MS. JACOBSEN: Okay. Sure.
` THE COURT REPORTER: So if you
` can --
` MS. JACOBSEN: Okay. 09:33
`BY MS. JACOBSEN: 09:33
` Q. So you've indicated that you've 09:33
`testified on behalf of Teva. 09:33
` Can you tell me any other companies 09:33
`on which you have testified on behalf of? 09:33
` MS. DANEK: And, Dr. Ratain, I just 09:33
` caution you not to reveal any confidential 09:33
` information of other third parties in your 09:33
` response. 09:33
` THE WITNESS: I can't give you a 09:33
` complete list. That's for sure. So if 09:33
` you're just asking me to name some of the 09:33
` companies, I can give you some. I 09:34
` certainly can't give you a complete list. 09:34
` ///
`
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`BY MS. JACOBSEN: 09:34
` Q. Well, give me those ones that you 09:34
`can remember sitting here now. 09:34
` MS. DANEK: Again, subject to any 09:34
` concerns regarding third-party confidential 09:34
` information. 09:34
` THE WITNESS: So Fresenius Kabi, 09:34
` Roxane, Amerigen. I just can't -- Mylan. 09:34
` I'm just blocking on the names. There are 09:34
` many generic companies that often get tied 09:34
` together in a joint defense group, so 09:34
` that's where my problem is here, sitting 09:34
` here today. 09:34
` Apotex. If you name one, I'll tell 09:34
` you yes or no. That might be easier if you 09:34
` really want to try and be more complete
` here. 09:34
`BY MS. JACOBSEN: 09:34
` Q. Well, you've also testified on 09:34
`behalf of Breckenridge, correct? 09:34
` A. Yes. 09:34
` Q. And you're here today on behalf of 09:34
`Par? 09:34
` A. Yes. 09:35
`
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` Q. All right. We have a binder for 09:35
`you. I'm handing you a binder. I thought that 09:35
`would be easier than multiple individual 09:35
`documents. 09:35
` Starting at Tab 3 and forward, the 09:35
`tabs correspond to the exhibit numbers in this 09:35
`IPR. So, for example, if we want to talk about 09:35
`Exhibit 1026, you'll find that behind Tab 26, 09:35
`okay? 09:35
` Just so you understand, so you see, 09:35
`for example (indicating). 09:35
` A. Thank you. 09:35
` Q. And I see you've already turned to 09:35
`Exhibit 1003. 09:35
` Is that a copy of your expert 09:35
`declaration that you submitted in this IPR? 09:35
` A. It looks like it, but I can't tell 09:35
`you with certainty unless I were to review 09:36
`every page. 09:36
` Q. Okay. If you turn to Page 68 of the 09:36
`declaration, which is the last page, there's a 09:36
`signature. 09:36
` Is that your signature? 09:36
` A. Yes. 09:36
`
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` MARK J. RATAIN, M.D.
` Q. I'm assuming this is a complete copy 09:36
`of your declaration. 09:36
` Are you aware of any errors in the 09:36
`declaration? 09:36
` A. I think I spotted some minor typos 09:36
`as I was reading through it. 09:36
` Q. Anything substantive that you would 09:36
`like to change? 09:36
` A. No. 09:36
` Q. And this declaration contains the 09:36
`reasons why you reached the conclusion that 09:36
`claims 1 to 3 of the '224 patent would have 09:36
`been obvious, is that right? 09:36
` A. It represents the reasons, excluding 09:36
`any opinions I might have on secondary 09:36
`considerations and response to opinions that 09:37
`your experts might put forward. 09:37
` Q. Understood. 09:37
` Did you do anything to prepare for 09:37
`today's deposition? 09:37
` A. Yes. 09:37
` Q. What did you do? 09:37
` A. I read the -- my declaration 09:37
`multiple times. I read the petition that was 09:37
`
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`filed. I read the decision of the Board, the 09:37
`institution. I read Dr. Kulke's declaration. 09:37
`I read many, if not all, of the prior art 09:37
`documents cited in my declaration. And I met 09:37
`with counsel. 09:37
` Q. And for how long did you meet with 09:37
`counsel? 09:37
` A. We met most of the day on Friday. 09:37
` Q. Was that the only meeting that you 09:38
`had? 09:38
` A. Yes. 09:38
` Q. And approximately how long did that 09:38
`last? 09:38
` A. Well, I think we started around 9:30 09:38
`and I think we finished up sometime after 4. 09:38
` Q. When you say you met with counsel, 09:38
`was that Brenda Danek that's sitting with you? 09:38
` A. Yes. 09:38
` Q. Was anyone else present to that 09:38
`meeting? 09:38
` A. No. 09:38
` Q. You've indicated that you reviewed 09:38
`the expert declaration of Dr. Kulke. 09:38
` Did you also review the references 09:38
`
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`that were discussed by Dr. Kulke? 09:38
` A. I think so. It's possible I didn't 09:38
`review them all. 09:38
` Q. Okay. Did you review the expert 09:38
`declaration of Dr. Kulke submitted in 09:38
`connection with the petition for IPR that was 09:38
`filed by Roxane? 09:39
` A. I looked at that, not -- I don't 09:39
`believe I looked at it in this past week, but I 09:39
`had seen that previously. 09:39
` Q. Okay. Have you seen the expert 09:39
`declaration submitted by Dr. Kulke in 09:39
`litigation in the District Court in Delaware 09:39
`between Novartis and Roxane? 09:39
` A. Not to my knowledge. 09:39
` Q. And in preparing for today's 09:39
`deposition, did you review any documents that 09:39
`were not cited either in your expert 09:39
`declaration or Dr. Kulke's expert declaration? 09:39
` A. Not specifically. I mean, what I'm 09:39
`saying, I've reviewed as part of my work, but 09:39
`nothing that I'm going to be relying on for my 09:39
`opinions today. 09:39
` Q. Okay. Do you know Dr. Kulke? 09:39
`
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` A. We've met before. 09:39
` Q. What do you know about him? 09:39
` A. Well, he basically studies 09:40
`neuroendocrine tumors and sees a lot of 09:40
`patients with neuroendocrine tumors at the 09:40
`Dana-Farber Institute. He's written about 09:40
`this. He's also a co-investigator in a trial 09:40
`that I was co-leading on neuroendocrine cancer. 09:40
`And he's generally a well-respected clinical 09:40
`investigator. 09:40
` Q. Do you consider him to be an expert 09:40
`in pancreatic neuroendocrine tumors? 09:40
` A. I don't have any reason to, you 09:40
`know, argue against that as a general 09:40
`statement. I mean, if you're asking me for an 09:40
`expert opinion as to whether he's an expert, I 09:40
`guess I really haven't considered that, sitting 09:40
`here today. But I, sitting here today, don't 09:40
`find a problem with that statement. 09:41
` Q. Okay. So I want to start with some 09:41
`terminology just so that we're on the same page 09:41
`going forward in this deposition, and I want to 09:41
`agree on what we understand certain terms to 09:41
`mean. And then we'll proceed on that 09:41
`
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`understanding of those terms unless one of us 09:41
`indicates otherwise. Okay? 09:41
` A. Okay. 09:41
` Q. So the first term is one that we've 09:41
`already briefly discussed and that's pancreatic 09:41
`neuroendocrine tumors. 09:41
` And those are one type of tumor of 09:41
`the pancreas, correct? 09:41
` MS. DANEK: Objection, form. 09:41
` THE WITNESS: Maybe I don't 09:41
` understand your question. 09:41
`BY MS. JACOBSEN: 09:41
` Q. Are pancreatic neuroendocrine tumors 09:41
`one type of tumor that arises in the pancreas? 09:41
` A. Yes. 09:42
` Q. And pancreatic neuroendocrine tumors 09:42
`can be abbreviated PNETs, P-N-E-T, and a little 09:42
`"s" if you're talking in the plural? 09:42
` A. Well, anything can be abbreviated as 09:42
`anything. So I'm not sure really -- if you're 09:42
`asking me is PNET a common abbreviation for 09:42
`pancreatic neuroendocrine, then the answer is 09:42
`yes. But it can be abbreviated as XYZQ. It 09:42
`would be up to the inventor, I guess. 09:42
`
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` Q. If we're referring to the 09:42
`literature, Dr. Ratain, we'll often see the 09:42
`abbreviation P-N-E-T, and that refers to 09:42
`pancreatic neuroendocrine tumors, correct? 09:42
` A. That's one abbreviation. They're 09:42
`sometimes also abbreviated as GEP. 09:42
` Q. We'll come to GEP in a minute. 09:42
` If I refer to PNETs in this 09:42
`deposition, will you understand that to be a 09:42
`reference to pancreatic neuroendocrine tumors? 09:42
` A. Yes. 09:43
` Q. PNETs are tumors of the endocrine 09:43
`pancreas, is that right? 09:43
` A. Yes. 09:43
` Q. And endocrine, that's 09:43
`E-N-D-O-C-R-I-N-E, right? 09:43
` A. Yes. 09:43
` Q. So PNETs are a type of 09:43
`neuroendocrine tumor? 09:43
` A. Yes. 09:43
` Q. And neuroendocrine tumors, if we 09:43
`abbreviate them to NETs, will you understand 09:43
`what I mean? 09:43
` A. That's fine. 09:43
`
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` Q. So NETs arise from cells of the 09:43
`neuroendocrine system, is that right? 09:43
` A. Well, that's actually a little more 09:43
`complicated than it sounds because cells can 09:43
`dedifferentiate. They can differentiate 09:44
`different ways. 09:44
` And so I'm not sure that it's so 09:44
`straightforward. In other words, we don't 09:44
`fully understand exactly how tumors develop 09:44
`from an early stem cell. 09:44
` We know that there are, for example, 09:44
`mixed tumors where you can have mixed tumors 09:44
`that are, for example, acinar and 09:44
`neuroendocrine, mixed tumors, so that implies
`that it's not so straightforward. 09:44
` Q. Okay. So the neuroendocrine tumors, 09:44
`what would a person of ordinary skill in 09:44
`November of 2005 understand as to the origin of 09:44
`neuroendocrine tumors? 09:45
` MS. DANEK: Objection, form. 09:45
` THE WITNESS: I'm not sure they 09:45
` would have any specific understanding. I'm 09:45
` not really sure what you're asking me. 09:45
` ///
`
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`BY MS. JACOBSEN: 09:45
` Q. What cell type would a person of 09:45
`ordinary skill in the art understand 09:45
`neuroendocrine tumors to arise from -- sorry, 09:45
`strike that. 09:45
` As of November 2005, would a person 09:45
`of ordinary skill in the art have an 09:45
`understanding of the cell type from which 09:45
`neuroendocrine tumors arise? 09:45
` A. Not necessarily. 09:45
` Q. And why do you say "not 09:45
`necessarily"? 09:45
` A. Because, for example, you can have 09:45
`poorly differentiated neuroendocrine cancers 09:45
`that we don't fully understand how those cells 09:45
`develop. 09:45
` Cells can -- you know, we -- all 09:45
`cells start from a common cell. And so we know 09:45
`or hypothesize that there are these earlier 09:45
`cells that lead into all kinds of different 09:46
`directions. And so there are cells that can 09:46
`differentiate different ways. 09:46
` Carcinomas can be undifferentiated. 09:46
`They can be poorly differentiated. They can be 09:46
`
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`well differentiated. They can have mixed 09:46
`features. There are many cancers that have 09:46
`neuroendocrine features, so -- and we don't 09:46
`know exactly how those develop. 09:46
` Q. You mentioned in that answer poorly 09:46
`differentiated cancer. 09:46
` What is a poorly differentiated 09:46
`cancer? 09:46
` A. A poorly differentiated cancer is 09:46
`one that bears little resemblance to normal 09:46
`tissue. 09:46
` Q. Okay. And what is the significance 09:46
`of them being poorly differentiated? Does it 09:46
`mean you can't tell the tissue of origin? 09:47
` A. Sometimes. 09:47
` Q. Is there any other feature of a 09:47
`poorly differentiated tumor that a person of 09:47
`ordinary skill in the art would be aware of in 09:47
`November of 2005? 09:47
` A. A person of ordinary skill would 09:47
`understand that poorly differentiated tumors 09:47
`tend to grow more quickly, tend to be more 09:47
`responsive to chemotherapy than 09:47
`well-differentiated tumors. 09:47
`
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` Q. What are well-differentiated tumors? 09:47
` A. Well-differentiated tumors are 09:47
`tumors that in some situations a pathologist 09:47
`may have difficulty distinguishing from a 09:47
`benign tumor. 09:47
` Q. Would a person of ordinary skill in 09:47
`the art know what the cell type of origin was 09:47
`for a well-differentiated tumor? 09:47
` MS. DANEK: Objection, form. 09:47
` THE WITNESS: Sometimes. 09:47
`BY MS. JACOBSEN: 09:47
` Q. Is that generally the case? 09:47
` A. Well, in -- in medicine, we don't 09:48
`really assume anything. So you can see a 09:48
`well-differentiated cancer. And, say, if you 09:48
`have a well-differentiated adenocarcinoma of 09:48
`the breast sitting in a breast mass that stains 09:48
`positive for estrogen receptors, you have a 09:48
`pretty good idea that it's coming from the 09:48
`breast. 09:48
` A lot of times we have tumors where 09:48
`we don't know where they start and, therefore, 09:48
`we can't say what the cell of origin is. 09:48
` Q. Is it significant, the cell of 09:48
`
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`origin? 09:48
` A. What's significant is really the 09:48
`features of the tumor. So, for example, if you 09:48
`have a patient with liver metastases and the 09:48
`tumor is well differentiated and has 09:48
`somatostatin receptors on it, that's a tumor 09:48
`that you would say, well, this is most likely 09:49
`metastasis from a pancreatic neuroendocrine 09:49
`tumor because it has somatostatin receptors on 09:49
`it, which is one of the hallmarks of many 09:49
`pancreatic neuroendocrine tumors. 09:49
` Q. So you're saying that the mere 09:49
`presence of somatostatin receptors on a tumor 09:49
`would indicate that it's a pancreatic 09:49
`neuroendocrine tumor? 09:49
` MS. DANEK: Objection, form, 09:49
` mischaracterizes testimony. 09:49
` THE WITNESS: What I said was that 09:49
` if you have a tumor that's in the liver, 09:49
` histologically it looks like a 09:49
` well-differentiated neuroendocrine tumor 09:49
` and it has somatostatin receptors, you 09:49
` would assume that's a pancreatic 09:49
` neuroendocrine tumor even if you didn't see 09:49
`
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` a tumor in the pancreas. 09:49
`BY MS. JACOBSEN: 09:49
` Q. What did you mean by histologically 09:49
`looks like a neuroendocrine tumor? 09:49
` A. Histologically means that when a 09:50
`pathologist looks at it under the microscope. 09:50
` Q. What are the histological features 09:50
`of a pancreatic neuroendocrine tumor? 09:50
` A. You'd have to ask a pathologist. 09:50
` Q. It's not something you're familiar 09:50
`with? 09:50
` A. It's not something that I'm -- it's 09:50
`outside the scope of my report, and it's not 09:50
`something that I'm prepared to testify on today 09:50
`because I'm not a pathologist. I don't spend 09:50
`time looking at these tumors under the 09:50
`microscope. 09:50
` Q. Understood. 09:50
` You also menti
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