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UNITED STATES PATENT AND TRADEMARK OFFICE
`______________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________
`APOTEX INC., APOTEX CORP., ARGENTUM PHARMACEUTICALS LLC,
`ACTAVIS ELIZABETH LLC, TEVA PHARMACEUTICALS USA, INC., SUN
`PHARMACEUTICAL INDUSTRIES, LTD., SUN PHARMACEUTICAL
`INDUSTRIES, INC., AND SUN PHARMA GLOBAL FZE,
`Petitioners,
`V.
`NOVARTIS AG,
`Patent Owner.
`______________________
`Case IPR2017-008541
`U.S. Patent No. 9,187,405
`______________________
`FOURTH DECLARATION OF FRED D. LUBLIN, M.D.
`
`
`Mail Stop Patent Board
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`ALEXANDRIA, VA 22313-1450
`
`
`
`
` 1 Cases IPR2017-01550, IPR2017-01946, and IPR2017-01929 have been joined
`with this proceeding.
`
`
`
`
`
`Apotex v. Novartis
`IPR2017-00854
`NOVARTIS 2097
`
`

`

`I, Fred D. Lublin, M.D., declare as follows:
`
`I.
`
`Introduction
`I am the same Fred Lublin who submitted three prior declarations in
`1.
`
`this matter, Exhibits 2003 and 2025 plus a Third Declaration (Ex. 2107) served on
`
`January 24, 2018 correcting an error in my deposition (Ex. 1042). I submit this
`
`Fourth Declaration in support of Novartis’s sur-reply, and in particular to address
`
`certain opinions by Dr. Leslie Z. Benet (Ex. 1047). I use the same terms and
`
`abbreviations here that I used in my prior declarations.
`
`2.
`
`In my Second Declaration (Ex. 2025), I described my roles in the
`
`fingolimod clinical trials, and how I and others of skill in the art were surprised that
`
`a dose of 0.5 mg daily proved effective for treating RRMS in Phase III trials—
`
`equally effective to 1.25 mg, which had shown promise in the Phase II trial. We
`
`thought 0.5 mg daily was unlikely to work. But FDA nonetheless asked Novartis to
`
`include the dose in the trial, as it had done before in the context of MS drugs.
`
`Novartis agreed because, while viewed as unlikely, there was some chance of
`
`efficacy based on PK/PD studies showing the dose could suppress lymphocyte levels
`
`in circulating blood to some degree. (See Ex. 2064 at 19 (“The 0.5 mg dose was
`
`selected because it had previously shown a relevant pharmacodynamic effect in man
`
`(reduction in circulating lymphocytes).”); see also to Park 2005 (Ex. 1019) and
`
`Kahan 2003 (Ex. 1031).)
`
`
`
`
`
`

`

`
`
`
`
`3.
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`However, to protect patients against the likelihood that the dose would
`
`not work, Novartis instituted a unique “futility analysis” protocol that would
`
`evaluate the results for that dose (and only that dose) after six months. If the dose
`
`was ineffective, that part of the trial would end. Despite that protocol, my own
`
`hospital Mount Sinai still declined to participate in a trial with the dose, due to lack
`
`of evidence it would work. It was a surprise when the dose was efficacious.
`
`4.
`
`Dr. Benet is a pharmacologist with limited experience with MS drugs
`
`and no experience with fingolimod. (Ex. 2100 at 44:9-45:6.) In his Declaration, he
`
`does not disagree that FDA in the past had previously pushed to conduct clinical
`
`trials for regulatory reasons even if a person of skill would have thought the drug
`
`unlikely to work. Nor does he identify any MS clinical trial that employed a futility
`
`analysis targeted at only one dose. And he cites no instance of anyone actually
`
`saying before June 2006 that he or she expected the 0.5 mg daily dose to be effective.
`
`5.
`
`Here, I address arguments Dr. Benet makes about the clinical trials for
`
`fingolimod. I focus in particular on his contention that persons of skill would have
`
`viewed public statements about the Phase III clinical trial as predicting the success
`
`of the 0.5 mg daily dose. I also address Dr. Benet’s arguments about the significance
`
`of the FDA’s decision to condition fingolimod’s approval on Novartis’s agreement
`
`to test an even lower dose, 0.25 mg daily.
`
`
`
`2
`
`

`

`
`
`
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`II. Analysis
`A. The Public Phase III Trial Documents Created No
`Expectation About the Efficacy of the 0.5 mg Dose
`Dr. Benet first argues (at ¶ 82) that a person of skill would have viewed
`
`6.
`
`the mere inclusion of 0.5 mg daily in Phase III trials as evidence the dose was
`
`expected to work. This is incorrect. The 0.5 mg daily dose had never been tested in
`
`RRMS patients before. The Phase II trial had tested only 1.25 mg and 5.0 mg daily.
`
`As the Mount Sinai IRB had my assistant relay to Novartis (Ex. 2063 at 2), there
`
`was no data to suggest that 0.5 mg daily would be effective. To the contrary, prior
`
`art like Webb, Kahan 2003, and Park 2005 all pointed the other way—that 0.5 mg
`
`daily was unlikely to suppress lymphocytes enough to be effective.
`
`7.
`
`As Dr. Benet does not dispute, FDA had for regulatory reasons
`
`previously pushed to test lower drug doses that a person of skill would have thought
`
`unlikely to work. I describe that history in my Second Declaration. (Ex. 2025 ¶¶ 5,
`
`39-42.) RRMS is a chronic lifelong disease that presents unique safety risks. A two-
`
`year trial may be inadequate to surface all safety issues, as had proven the case just
`
`before the fingolimod clinical trials with Tysabri. (Id. ¶ 41.) FDA accordingly has
`
`a strong safety interest in identifying the bottom end of the dose response curve.
`
`8.
`
`Given this history, plus the absence of any prior data on 0.5 mg daily
`
`in RRMS patients, a person of skill would not read any expectation of efficacy into
`
`a previously-untested dose’s inclusion in Phase III trials. Commentators at the time
`3
`
`
`
`

`

`
`
`
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`indeed drew a distinction in how they discussed the 1.25 mg and 0.5 mg daily doses
`
`in the Phase III trial. As I showed in my Second Declaration (at ¶¶ 48-49),
`
`commentators described the Phase III trial as designed to “confirm” the Phase II
`
`results for 1.25 mg daily, but merely to “evaluate” the 0.5 mg daily dose. That
`
`difference in language reflects a difference in expectation about the doses. It was
`
`not necessarily the case that the 0.5 mg arm of the Phase III clinical trial would have
`
`resulted in efficacy.
`
`9.
`
`Dr. Benet argues (at ¶ 86) that Novartis’s description of the trial in an
`
`April 2006 press release and a related report (Chavez) shows that 0.5 mg was
`
`expected to work. (Exs. 2072, 2031.) These references quote doctors praising the
`
`results of the Phase II trial, and saying that the Phase III trial would seek to “confirm”
`
`the Phase II trial results. As I explained in my Second Declaration, this language
`
`referred to the 1.25 mg dose, which was part of the Phase II and III trials. It did not
`
`refer to the 0.5 mg dose, which was not part of the Phase II trial. Dr. Benet, however,
`
`characterizes the statement as referring to both doses in the Phase III trials, 1.25 and
`
`0.5, and from this contends that Novartis viewed 0.5 mg daily as just as likely to
`
`work as 1.25 mg. (Ex. 1047 ¶ 86.)
`
`10. A person of skill in June 2006 would not have read these documents as
`
`Dr. Benet contends. The Phase II results that the Phase III trials were seeking to
`
`“confirm” were for 1.25 mg. The 0.5 mg dose had never been tested in MS patients.
`
`
`
`4
`
`

`

`
`
`
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`Results for that dose accordingly could not be “confirmed.” Rather, as the Doggrell
`
`paper stated (Ex. 2036 at 385), the 0.5 mg daily dose was just being “evaluated.”
`
`That in fact is how Mount Sinai apparently understood things. The Mount Sinai IRB
`
`objected only to the trials’ use of a 0.5 mg daily dose, not to the 1.25 daily dose. As
`
`Mount Sinai pointed out, 0.5 mg daily had never been tested in RRMS patients
`
`before. That was well-known in the field.
`
`11.
`
`I testified about this issue in my deposition in this case, in the following
`
`back and forth. As I explained, the Phase III trial announcements would tell a person
`
`of skill only that 0.5 mg daily was being “tested,” not that it would be effective;
`
`efficacy or lack thereof would not be known until the trial was over:
`
`Q. …You agree that a person of ordinary skill in the art as of the 6th
`
`of April 2006 would understand from the disclosure of the Chavez
`
`reference, that in the FREEDOM study, there is no loading dose
`
`regimen administered immediately preceding the daily dose of 0.5
`
`milligrams Fingolimod?
`
`*******
`
`A. Yes.
`
`Q. And you also agree that the person of ordinary skill in the art on that
`
`date would understand that that daily dose is administered to RRMS
`
`patients who have a need for reducing, preventing, or alleviating
`
`
`
`5
`
`

`

`
`
`
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`relapses who have a need for RRMS treatment, and who have a need
`
`for slowing the progression of RRMS. Correct?
`
`*******
`
`A. No. They would understand that a study was being done to test that
`
`dose.
`
`(Ex. 1042 at 238:23-239:21.)
`
`12. Merely testing a dose of course is no guarantee that it will work. Phase
`
`III trials often fail for lack of efficacy even for doses that were promising at Phase
`
`II. Here, the 0.5 mg daily dose had not even been tested in Phase II. That alone
`
`made the odds of failure much higher than normal, without even accounting for the
`
`prior papers suggesting the dose would not suppress lymphocytes enough to be
`
`effective. A person of skill would have known that 0.5 mg was an unproven dose
`
`and nothing in the prior developmental program said it would be effective.
`
`13. Dr. Benet contends (at ¶ 82) that Novartis must have thought 0.5 mg
`
`would be effective because Novartis had an empirical basis for including the 0.5 mg
`
`daily dose in the trial, and drug sponsors usually do not waste money on frivolous
`
`exercises. Those facts shed no light on whether a person of skill would view the
`
`dose’s inclusion in the Phase III trial as reflecting an expectation that the dose would
`
`work. Having enough evidence to justify the testing of a dose and enough evidence
`
`to believe it is likely to be effective are different things.
`
`
`
`6
`
`

`

`
`
`
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`14. Here, the FDA had asked Novartis to test a 0.5 mg dose, a request that
`
`an applicant would have to take very seriously. Prior studies showed that 0.5 mg
`
`daily would suppress lymphocytes to some extent. That was enough to justify testing
`
`the dose. Novartis thus undertook a trial of that dose, but only subject to a unique
`
`6-month futility review—precisely because of doubts the dose would work. The
`
`evidence suggested that 0.5 mg daily would not suppress enough lymphocytes to be
`
`effective. That led me and others to be skeptical the dose would work.
`
`15. Dr. Benet discounts (at ¶¶ 83-84) the futility analysis as showing
`
`concern that 0.5 mg daily would not be effective. I submitted the futility analysis as
`
`evidence consistent with my memory that I and others did not believe the 0.5 mg
`
`daily dose was likely to be effective. Dr. Benet argues that the futility analysis
`
`merely built a Phase II into a Phase III trial, proceeding with both simultaneously.
`
`But that fails to grasp the significance of the futility study and is at best a hindsight
`
`driven analysis of what occurred. Dr. Benet points to no facts from that time to
`
`support his view. I am aware of no RRMS drug trial that has ever had an interim
`
`futility analysis directed to only one of two doses. That feature reflects concern
`
`about only the 0.5 mg dose, not the 1.25 mg dose. That is consistent with my
`
`memory that I and other MS physicians familiar with fingolimod were skeptical that
`
`the 0.5 mg daily dose would be effective.
`
`
`
`7
`
`

`

`
`
`
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`16. Other evidence, too, is consistent with that memory. As I addressed in
`
`my Second Declaration (at ¶ 61), I was responsible for a Phase III trial in a different
`
`form of MS—the INFORMS trial for PPMS. We did not include 0.5 mg daily in
`
`that trial at all precisely because we thought 0.5 mg daily would not work. Similarly,
`
`Mount Sinai was skeptical too. And the authors of the paper publishing the
`
`TRANSFORMS results likewise highlighted that 0.5 mg daily had been expected to
`
`produce “submaximal” lymphocyte suppression. (Ex. 2035 at 411.) A person of
`
`skill would have understood that the authors made that point because the prevailing
`
`view had been that maximal suppression was essential to efficacy for fingolimod.
`
`17. Dr. Benet does not address the PPMS trial. But he does argue (at ¶ 98-
`
`99) that the TRANSFORMS paper’s observation that 0.5 mg was not expected to
`
`provide maximal lymphocyte suppression is beside the point. He contends that
`
`maximal suppression was not needed for efficacy, citing to various sources. But Dr.
`
`Benet was not involved at the time, and his reading is based on hindsight. In fact,
`
`maximal suppression was generally viewed as essential for fingolimod’s efficacy.
`
`That is why the point was called out in the TRANSFORMS paper. There would
`
`have been no other reason to make that observation in that paper. The authors did
`
`so because the TRANSFORMS results for the 0.5 mg daily dose were a surprise.
`
`18. Petitioners and Dr. Benet say also (Paper 49 at 22-23) that Mount
`
`Sinai’s decision not to participate in the TRANSFORMS trial, but to participate in
`
`
`
`8
`
`

`

`
`
`
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`the FREEDOMS II trial, was due to the “complications” from the TRANSFORMS
`
`trial having an active comparator rather than a placebo as the standard of comparison
`
`with fingolimod. I do not know why the Mount Sinai IRB declined to participate in
`
`TRANSFORMS, but did participate in the later FREEDOMS II trial. I think a likely
`
`explanation is that the IRB agreed to the FREEDOMS II placebo-controlled trial
`
`because patients there necessarily undertook the risk that they might be given an
`
`ineffective compound—the placebo. So the possibility that the 0.5 mg daily dose
`
`would also be ineffective presented fewer recruiting and other problems. In
`
`TRANSFORMS, however, all patients were supposed to be given a compound
`
`known or expected to be effective in treating their condition. But as the IRB pointed
`
`out, there was no data showing that 0.5 mg daily would in fact be effective, so the
`
`IRB declined to participate in the trial. That would explain why the statements of
`
`the IRB were so focused on the lack of evidence that 0.5 mg would be effective.
`
`B. The FDA’s Post-Approval Requirement to Test
`a 0.25 mg Daily Dose
`I showed in my Second Declaration (at ¶¶ 39, 53, 55, 64) that FDA
`
`19.
`
`wanted to test the 0.5 mg daily dose to explore when fingolimod ceased being
`
`effective (the “minimum effective dose”). As I pointed out, if 0.5 mg had been
`
`predictably effective, then FDA would have asked Novartis to test an even lower
`
`
`
`9
`
`

`

`
`
`
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`dose. 2 In fact, when 0.5 mg daily proved equally effective with 1.25 mg daily, FDA
`
`still had not discovered the minimum effective dose. FDA accordingly committed
`
`Novartis to test an even lower dose after approval, 0.25 mg.
`
`20. Dr. Benet questions (at ¶¶ 90-94) whether FDA made the testing of that
`
`lower dose a condition of approval. I was a first-hand witness and can confirm that
`
`the relevant committee within FDA recommended that Novartis undertake a post-
`
`approval commitment to test a lower dose. I attended the final approval meeting
`
`between Novartis and that FDA committee where this issue was discussed. As stated
`
`in the FDA approval letter, Novartis committed to test that lower dose. (Ex. 2037
`
`at 7.)
`
`
` 2 Petitioners say (Paper 49 at 4-5) that I admitted in my deposition that it was
`
`“routine” for a drug sponsor to seek to identify the safest effective dose. That is
`
`not my full testimony. I explained that the interest in such a dose varied by
`
`molecule. (Ex. 1042 at 167:3-6 (“Sometimes that means looking for a minimally
`
`effective dose. Sometimes not. Some types of molecules that’s tougher to do.”)
`
`Here, after the Phase II trial showing that 1.25 was effective and safe enough for
`
`human use, a person of skill would have thought there was no need to probe for
`
`even lower doses. 1.25 mg was more than good enough. But FDA had other
`
`interests and wanted to understand the behavior of even lower doses.
`
`
`
`10
`
`

`

`
`
`
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`21. Dr. Benet then argues (at ¶ 93) that FDA’s interest in Novartis’s
`
`commitment was “not . . . unreasonable” after the Phase III results for 0.5 mg daily.
`
`Dr. Benet describes such post-approval commitments as “routine in clinical trials[.]”
`
`(Id.) Post-approval commitments are quite frequent, but Dr. Benet misses the point.
`
`Dr. Benet does not dispute that FDA wanted to test 0.5 mg daily in the first place to
`
`find the minimum effective dose. Nor does he disagree that, if it were obvious that
`
`0.5 mg daily were not that dose, then FDA would have asked Novartis to test an even
`
`lower dose in the Phase III trial.
`
`22. As I explained in my Second Declaration (at ¶ 40), FDA’s desire to
`
`identify the lowest effective dose in this context is driven by safety concerns. FDA
`
`accordingly would want access to that information as soon as possible, to be able to
`
`use it in addressing any safety issues. FDA would not ask for Novartis to test a dose
`
`that obviously would not provide the information FDA sought. For these reasons, I
`
`stand by the assessment in my Second Declaration that FDA’s imposition of a post-
`
`approval commitment shows further that 0.5 mg daily was not in fact an obviously
`
`effective dose.
`
`*
`
`
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`
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`*
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`
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`
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`
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`*
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`23. Under penalty of perjury, all statements made herein of my own
`
`knowledge are true, and I believe all statements made herein on information and
`
`belief to be true. I have been warned and am aware that willful false statements and
`
`
`
`11
`
`

`

`
`
`
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`the like are punishable by fine or imprisonment or both under Section 1001 of Title
`
`18 of the United States Code.
`
`24.
`
`In signing this Declaration, I understand that it will be filed as evidence
`
`in a contested case before the Patent Trial and Appeal Board of the United States
`
`Patent and Trademark Office. I acknowledge that I may be subject to cross-
`
`examination in the case and that cross-examination will take place in the United
`
`States. If cross-examination is required of me, I will appear for cross-examination
`
`within the United States during the time allotted.
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`12
`
`

`

`
`
`DATED: March 23, 2018
`
`
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`
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`
`
`
`
`
`
`By: _________________________
` Fred D. Lublin, M.D.
`
`
`
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`
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`

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