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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., )
` BRECKENRIDGE )
` PHARMACEUTICAL, INC., and )
` ROXANE LABORATORIES, INC., )
` )
` Petitioners, )
` )
` vs. ) Case IPR2016-00084
` ) U.S. Patent No.
` NOVARTIS AG, ) 5,665,772
` )
` Patent Owner. )
`
` DEPOSITION OF MARK J. RATAIN, M.D.
` Chicago, Illinois
` Friday, December 16, 2016
`
` **REVISED**
`
`Reported by:
`JANET L. ROBBINS, CSR, RPR
`JOB NO. 116752
`
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` MARK J. RATAIN, M.D.
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`Page 2
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` December 16, 2016
` 9:31 a.m.
`
` Deposition of MARK J. RATAIN, M.D., at
` 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: JONATHAN STRANG, ESQ.
` 555 Eleventh Street, NW
` Washington, DC 20004
` appeared on behalf of Par
` Pharmaceutical, Inc.;
`
` FITZPATRICK, CELLA, HARPER & SCINTO
` BY: CHARLOTTE JACOBSEN, ESQ.
` SUSANNE L. FLANDERS, ESQ.
` 1290 Avenue of the Americas
` New York, New York 10104
` appeared on behalf of Novartis AG
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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
` EXAM BY MR. STRANG 217
`
` E X H I B I T S
` IPR DESCRIPTION PG LN
` Exhibit 2220 Dose-Escalating Study 37 3
` of Capecitabine Plus
` Gemcitabine
` Combination Therapy
` in Patients with
` Advanced Cancer by R.
` Schilsky, et al.
` Exhibit 2221 Phase II Oncology 95 11
` Trials: Let's Be
` Positive by Mark J.
` Ratain
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` MARK J. RATAIN, M.D.
` (Witness sworn.)
` 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. 09:31
` A. Good morning. 09:31
` Q. Now, I know you've been deposed 09:31
` before, and so there's not a great deal of need 09:31
` to go over the ground rules. 09:31
` But just so that we have a clean 09:31
` record as before, I ask that you wait until I 09:31
` finish my question before you answer, and I 09:31
` will try to do the same with respect to your 09:31
` answers. 09:31
` Is that okay? 09:31
` A. Yes. 09:31
` Q. And if you don't understand any of 09:31
` my questions, please ask me to rephrase them or 09:31
` to clarify the terms that you don't understand. 09:31
` Can you do that? 09:32
` A. I assume you mean if I don't 09:32
`
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` understand one of your questions? 09:32
` Q. Well, hopefully it will be very few, 09:32
` but yes. 09:32
` If you don't understand one of my 09:32
` questions, then will you ask me to clarify? 09:32
` A. Yes. 09:32
` Q. And if you don't ask me to clarify, 09:32
` I'm going to assume that you understood my 09:32
` question, okay? 09:32
` A. Yes. 09:32
` Q. Okay. I'm going to give you a copy 09:32
` of your expert declaration that's been marked 09:32
` Exhibit 1119. 09:32
` Do you recognize this document? 09:32
` A. It appears, without checking every 09:32
` single page, to be complete copy of my 09:32
` declaration. 09:32
` Q. And that's your signature on Page 62 09:32
` of the declaration and 64 of the exhibit? 09:32
` A. Yes. 09:32
` Q. And do you believe that the opinions 09:32
` stated in this declaration are true and 09:32
` accurate? 09:33
` A. I do. 09:33
`
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` MARK J. RATAIN, M.D.
` Q. And are you aware of any errors in 09:33
` this expert declaration? 09:33
` A. I am. 09:33
` Q. And what are they? 09:33
` A. A couple of citations. Let me find 09:33
` them. 09:33
` (Witness viewed said document.) 09:33
` BY MS. JACOBSEN: 09:33
` Q. What are you looking for? Perhaps I 09:33
` can help. 09:33
` A. Well, I'm looking for the citation 09:33
` to a Dutch monograph. 09:33
` MR. STRANG: Is that the one on 09:33
` paragraph 54? 09:33
` THE WITNESS: What number? 09:34
` MR. STRANG: Five-four. 09:34
` THE WITNESS: Five-four? 09:34
` Yes. There should be -- I think the 09:34
` correct URL just begins with "db," not with 09:34
` the h -- in other words, delete "http://." 09:34
` BY MS. JACOBSEN: 09:34
` Q. Okay. 09:34
` A. Also, in rereading my declaration, I 09:34
` noted that the URL for one of the FDA documents 09:34
`
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` had been omitted in paragraph 58. I don't have 09:34
` it handy, but I know that that was omitted. 09:34
` And it's -- I could find it now, if you want me 09:34
` to. You can work things out with counsel 09:34
` later. I don't know how you want to handle it. 09:34
` Q. That's in respect to Exhibit 1122? 09:34
` A. Yes. 09:35
` Q. Okay. 09:35
` A. It's a public government -- federal 09:35
` government document that can be readily found. 09:35
` Q. Okay. Any others? 09:35
` A. That's all I'm aware of. 09:35
` Q. So with the exception of those two 09:35
` URL citations, do you believe -- or are they 09:35
` the only errors that you're aware of in your 09:35
` expert declaration? 09:35
` A. Yes. 09:35
` Q. And you've cited a number of 09:35
` references in this expert declaration. And you 09:35
` understand that the ones that have been put 09:35
` into this case by the petitions will have the 09:35
` starting No. 1 and then are sequentially 09:35
` numbered afterwards, so it's like 09:35
` one-thousand-and-something? 09:35
`
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` Do you understand that? 09:35
` A. I was not aware of that. 09:35
` Q. But certainly in addition to 09:35
` discussing -- strike that. 09:35
` In addition to discussing references 09:36
` that Dr. Burris cited, you also added some of 09:36
` your own references to this declaration, 09:36
` correct? 09:36
` A. I added whatever references that I 09:36
` identified that were necessary to provide 09:36
` support for my opinions. 09:36
` Q. And those references that you added, 09:36
` do you believe them to be accurate and reliable 09:36
` documents? 09:36
` A. Yes. 09:36
` Q. And do you believe those exhibits 09:36
` that you added to be the type of documents that 09:36
` a person of ordinary skill in the art would 09:36
` have relied on as of whatever relevant date 09:36
` we're talking about, either in 1992 or today? 09:36
` A. I believe so. 09:36
` Q. And if you can turn to paragraph 28. 09:36
` Well, tell me, with respect to the 09:36
` documents, you wouldn't have cited them if you 09:36
`
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` MARK J. RATAIN, M.D.
` were aware of inaccuracies or incomplete 09:37
` statements in them, is that fair? 09:37
` A. No, I can't agree with that. 09:37
` Q. And why not? You would have cited 09:37
` something that you didn't believe to be 09:37
` complete or accurate? 09:37
` A. That there may be statements and 09:37
` documents that I cited that I don't agree with 09:37
` every word or every sentence or every opinion. 09:37
` So, no, I can't agree that anything I cited, 09:37
` that I would agree with 100 percent of what's 09:37
` in the document. I can't agree with that. 09:37
` Q. Okay. Can you turn to paragraph 28. 09:37
` And there in paragraph 28 right at 09:37
` the bottom you say, "For that reason, I have 09:37
` been asked to respond to these statements by 09:37
` Dr. Roush and similar statements by Dr. Burris 09:37
` as to what a POSA would have expected only in 09:38
` the context of whether these were 'unexpected 09:38
` results,' as defined above." 09:38
` Are you with me? 09:38
` A. I'm with you. 09:38
` Q. Do you need an opportunity to read 09:38
` paragraph 28? Do you want to just do that and 09:38
`
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` let me know when you've done it? 09:38
` (Witness viewed said document.) 09:38
` THE WITNESS: I have. 09:38
` BY MS. JACOBSEN: 09:38
` Q. Okay. So I was pointing you to the 09:38
` last sentence in that paragraph, and it says, 09:38
` "...I have been asked to respond to these 09:38
` statements by Dr. Roush and similar statements 09:38
` by Dr. Burris as to what a POSA would have 09:38
` expected only in the context of whether these 09:38
` were 'unexpected results,' as defined above." 09:38
` Do you see that? 09:38
` A. I do. 09:38
` Q. And so as I understand it, your 09:38
` opinions deal with unexpected results, and you 09:39
` have not discussed whether or not a POSA would 09:39
` have had a reasonable expectation which is part 09:39
` of a prima facie obviousness case, is that 09:39
` correct? 09:39
` A. You're correct, that my opinions 09:39
` relate only to secondary considerations. And 09:39
` the definition of unexpected results that I'm 09:39
` referring to is in paragraph 19. 09:39
` Q. And then if you could turn to 09:39
`
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` Section V which starts on the next page. 09:39
` A. I'm sorry. Oh, Section V? 09:39
` Q. Yes, Page 11. Do you want to just 09:39
` take a minute for that? 09:39
` This summarizes the opinions that 09:40
` you've provided in your declaration, is that 09:40
` correct, paragraphs 29 and 30 of Section V? 09:40
` A. That was my attempt to summarize my 09:40
` opinions, yes. 09:40
` Q. And in this declaration, you've not 09:40
` disputed that others tried and failed to 09:40
` develop effective therapies for advanced RCC or 09:40
` breast cancer prior to October 1992, correct? 09:40
` A. I do not have any opinions in my 09:40
` declaration regarding I guess what you're 09:40
` referring to as failure by others. 09:40
` Q. Okay. And you also have not 09:40
` disputed that everolimus has received industry 09:40
` praise, correct? 09:41
` A. I do not have any opinions regarding 09:41
` that in my declaration. 09:41
` Q. And you've also not provided any 09:41
` opinions on whether AFINITOR® is a commercial 09:41
` success, correct? 09:41
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` A. That's correct. 09:41
` Q. Can you turn to paragraph 32. And 09:41
` on the second half of that paragraph on 09:41
` Page 14, there's a sentence that says, "I 09:41
` understand from Dr. Jorgensen's." 09:41
` Do you see that? 09:41
` A. I see that. Let me read it. 09:41
` (Witness viewed said document.) 09:41
` THE WITNESS: I see it. 09:41
` BY MS. JACOBSEN: 09:41
` Q. And so you say, "I understand from 09:41
` Dr. Jorgensen's declaration that C40 09:41
` modifications to rapamycin (e.g., everolimus) 09:41
` would have reasonably been expected to preserve 09:41
` the pharmacological activity of rapamycin." 09:42
` Do you see that? 09:42
` A. Yes. 09:42
` Q. And so as I understand it, the basis 09:42
` for your opinion that C40 modifications to 09:42
` rapamycin would not have been reasonably 09:42
` expected to preserve the pharmacological 09:42
` activity -- sorry, strike that. I'll try that 09:42
` sentence again. I did not intend to add a 09:42
` "not." So strike that. 09:42
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` As I understand it, the basis for 09:42
` your opinion that C40 modifications to 09:42
` rapamycin, e.g., everolimus, would have 09:42
` reasonably been expected to preserve the 09:42
` pharmacological activity of rapamycin is based 09:42
` on Dr. Jorgensen's declaration, is that 09:42
` correct? 09:42
` A. Well, it's in part. I also discuss 09:42
` this in paragraph 43 where I cite other -- 09:43
` other prior art, other patents disclosing C40 09:43
` derivatives that teach the same concept. 09:43
` Q. So the basis for your opinion with 09:43
` regard to C40 modifications is Dr. Jorgensen's 09:43
` declaration and then what is discussed in 09:43
` paragraph 43 of your declaration, is that 09:43
` correct? 09:43
` A. Yes. 09:43
` Q. And is that the totality of the 09:43
` bases for your opinions with respect to the 09:43
` C40 modification specifically? 09:43
` A. Well, I can't come up with any 09:43
` independent firsthand opinions related to the 09:43
` chemical modifications and the impact of such. 09:43
` I have to rely on the opinions of others, both 09:43
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` Dr. Jorgensen and other patentees. 09:43
` Q. And why can't you come up with any 09:43
` independent firsthand opinions with respect to 09:44
` those matters? 09:44
` A. I'm not a chemist. 09:44
` Q. And can we go to paragraphs 101 to 09:44
` 106, please, in your expert declaration. 09:44
` And if you want to take a moment to 09:44
` familiarize yourself with those paragraphs, 09:44
` that's fine. Let me know when I can ask 09:44
` questions. 09:44
` (Witness viewed said document.) 09:44
` THE WITNESS: Did you say 101 to 09:44
` 106? 09:45
` BY MS. JACOBSEN: 09:45
` Q. Yes. 09:45
` A. I've gone through that. 09:45
` Q. Okay. Great. 09:45
` So just starting with paragraph 101, 09:45
` and the first sentence of that paragraph is 09:46
` that, "It is not surprising that there is 09:46
` evidence of rapamycin's clinical efficacy in 09:46
` the same tumor types as everolimus because both 09:46
` compounds act by inhibiting the protein mTOR 09:46
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` MARK J. RATAIN, M.D.
` (mammalian Target Of Rapamycin)." 09:46
` Do you see that? 09:46
` A. Yes. 09:46
` Q. So as I understand it, it's your 09:46
` opinion that there are no differences that are 09:46
` unexpected because rapamycin and everolimus 09:46
` both inhibit mTOR? 09:46
` A. Actually, my opinion is that there's 09:46
` no -- no differences in properties. 09:46
` Q. I understand that. And one reason 09:46
` why it's not unexpected -- there's no results 09:46
` that are unexpected to you is that they're both 09:46
` mTOR inhibitors, is that correct? 09:46
` A. No. My opinion is that there are no 09:46
` unexpected differences in results. And not 09:46
` only that, there are no -- no differences in 09:47
` properties, and that's because both drugs are 09:47
` mTOR inhibitors. And, therefore, it's not 09:47
` surprising that there are no differences 09:47
` because both drugs have the same molecular 09:47
` target. 09:47
` Q. Okay. And so whether or not you're 09:47
` surprised by the results is based on your 09:47
` knowledge of the molecular target of both 09:47
`
`TSG Reporting - Worldwide 877-702-9580
`
`NOVARTIS EXHIBIT 2223
`Par v. Novartis, IPR 2016-00084
`Page 16 of 221
`
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` MARK J. RATAIN, M.D.
` everolimus and rapamycin, correct? 09:47
` A. That's not what I said. 09:47
` Q. Okay. Then what did you say? 09:47
` A. I said there are -- there are no 09:47
` unexpected differences. Not only -- and there 09:47
` are no -- no differences -- no significant 09:47
` differences in properties. And it's not 09:47
` surprising that there are no significant 09:47
` differences in properties. 09:47
` So there are neither differences nor 09:47
` unexpected differences, and it's not unexpected 09:47
` that there are no differences. 09:48
` Q. And it's not unexpected that there 09:48
` are no differences because both everolimus and 09:48
` rapamycin inhibit mTOR, is that correct? 09:48
` A. Yes. 09:48
` Q. And if we can look at paragraphs 101 09:48
` to 105 now. And can you just agree that the 09:48
` articles that you cite in those paragraphs were 09:48
` all published after 1992? 09:48
` (Witness viewed said document.) 09:48
` THE WITNESS: Yes. 09:49
` BY MS. JACOBSEN: 09:49
` Q. And so there's information in those 09:49
`
`TSG Reporting - Worldwide 877-702-9580
`
`NOVARTIS EXHIBIT 2223
`Par v. Novartis, IPR 2016-00084
`Page 17 of 221
`
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` MARK J. RATAIN, M.D.
` publications that would not have been known to 09:49
` a POSA as of October 1992? 09:49
` A. In these publications, of course, 09:49
` but I think in 1992 a POSA would have expected 09:49
` that rapamycin and everolimus would have 09:49
` similar pharmacological properties based on the 09:49
` other -- the rest of my report. 09:49
` Q. Okay. But I just want to focus on 09:49
` 101 to 105. And in respect to the opinions 09:49
` that are expressed in those paragraphs, the 09:49
` publications that you're relying on are all 09:49
` published after 1992? 09:49
` A. That's right. 09:49
` Q. And then in paragraph 106, you cite 09:49
` a U.S. patent application publication. 09:50
` Do you see that? 09:50
` A. Yes. 09:50
` Q. And I just want to confirm the date 09:50
` of that with you. 09:50
` So this is Exhibit 1106 that I've 09:50
` just handed to you. 09:50
` Do you recognize this document? 09:50
` A. This is one of many patent 09:50
` applications I actually found that have 09:50
`
`TSG Reporting - Worldwide 877-702-9580
`
`NOVARTIS EXHIBIT 2223
`Par v. Novartis, IPR 2016-00084
`Page 18 of 221
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` MARK J. RATAIN, M.D.
` similar -- draw similar conclusions. 09:50
` Q. And this is the one, though, that's 09:50
` referred to in paragraph 106, correct? 09:51
` A. Yes. 09:51
` Q. And can you see next to the 09:51
` paragraph numbered 22 on the front page, it 09:51
` says "Filed: November 13, 2014"? 09:51
` A. Yes. 09:51
` Q. And in paragraph 60 on the front 09:51
` page, it discusses related U.S. application 09:51
` data, and the earliest date in that 09:51
` paragraph is July 21st, 2014? 09:51
` A. I see that. Actually, that's not 09:51
` true. 09:51
` Q. Oh, sorry. 09:51
` A. The earliest date is November 13th, 09:51
` 2013. 09:51
` Q. That's correct. Thank you. 09:51
` So the earliest related U.S. 09:51
` application data that's referred to on 1106 is 09:51
` November the 13th, 2013, correct? 09:51
` A. Correct. 09:51
` Q. And so the information contained in 09:51
` this patent application would not have been 09:51
`
`TSG Reporting - Worldwide 877-702-9580
`
`NOVARTIS EXHIBIT 2223
`Par v. Novartis, IPR 2016-00084
`Page 19 of 221
`
`

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` MARK J. RATAIN, M.D.
` available to a POSA as of October 1992? 09:52
` A. Well, that's not why I cited it. I 09:52
` was not citing this for what a person of 09:52
` ordinary skill would know in 1992. So I 09:52
` don't -- I cited it for different reasons. 09:52
` Q. I just want to make sure that we're 09:52
` clear on the record about what was known in 09:52
` 1992 and what was known afterwards. That's 09:52
` just why I'm going through this exercise. 09:52
` A. I didn't cite this for purposes of 09:52
` supporting any opinions about what would a 09:52
` person would have known in 1992. 09:52
` Q. So you're not suggesting that the 09:52
` information contained in this would have been 09:52
` known to a POSA in October 1992? 09:52
` A. No. I'm citing this now as to what 09:52
` Novartis believes about the similarities of 09:52
` everolimus and rapamycin, that basically 09:52
` Novartis itself basically considers them to be 09:52
` effectively interchangeable. 09:52
` Q. And then let's look at a couple of 09:52
` the other references that you cite in these 09:53
` paragraphs 101 to 106. So I'm handing you 09:53
` Exhibit 1102. 09:53
`
`TSG Reporting - Worldwide 877-702-9580
`
`NOVARTIS EXHIBIT 2223
`Par v. Novartis, IPR 2016-00084
`Page 20 of 221
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` MARK J. RATAIN, M.D.
` A. Can you point me to where I cited 09:53
` this? 09:53
` Q. It's in the section 101 to 105. 09:53
` A. Let me find the exact place. 09:53
` I see that I cite it in 09:53
` paragraph 101 and in paragraph 102 and in 09:53
` paragraph 105. 09:54
` Q. Okay. So can you turn to Page 527 09:54
` of Exhibit 1102. And you'll see there's a 09:54
` section entitled "Focus on mTOR." 09:54
` Do you see that? 09:54
` A. I see that. 09:54
` Q. And the beginning of that section 09:54
` says, "mTOR was identified in 1994..." 09:54
` Do you see that? 09:54
` A. I see that. 09:54
` Q. So mTOR was not known in October of 09:54
` 1992, correct? 09:54
` A. It had not yet been identified. 09:54
` Q. So as of October 1992, a person of 09:54
` ordinary skill in the art would not have known 09:54
` that rapamycin's immunosuppressant activity 09:54
` stems from its inhibition of mTOR, correct? 09:54
` A. In 1992, a person of ordinary skill 09:54
`
`TSG Reporting - Worldwide 877-702-9580
`
`NOVARTIS EXHIBIT 2223
`Par v. Novartis, IPR 2016-00084
`Page 21 of 221
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` MARK J. RATAIN, M.D.
` would have p

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