`______________________
`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.
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`
`Mail Stop Patent Board
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`ALEXANDRIA, VA 22313-1450
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` 1 Cases IPR2017-01550, IPR2017-01946, and IPR2017-01929 have been joined
`with this proceeding.
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`Apotex v. Novartis
`IPR2017-00854
`NOVARTIS 2097
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`I, Fred D. Lublin, M.D., declare as follows:
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`I.
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`Introduction
`I am the same Fred Lublin who submitted three prior declarations in
`1.
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`this matter, Exhibits 2003 and 2025 plus a Third Declaration (Ex. 2107) served on
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`January 24, 2018 correcting an error in my deposition (Ex. 1042). I submit this
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`Fourth Declaration in support of Novartis’s sur-reply, and in particular to address
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`certain opinions by Dr. Leslie Z. Benet (Ex. 1047). I use the same terms and
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`abbreviations here that I used in my prior declarations.
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`2.
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`In my Second Declaration (Ex. 2025), I described my roles in the
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`fingolimod clinical trials, and how I and others of skill in the art were surprised that
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`a dose of 0.5 mg daily proved effective for treating RRMS in Phase III trials—
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`equally effective to 1.25 mg, which had shown promise in the Phase II trial. We
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`thought 0.5 mg daily was unlikely to work. But FDA nonetheless asked Novartis to
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`include the dose in the trial, as it had done before in the context of MS drugs.
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`Novartis agreed because, while viewed as unlikely, there was some chance of
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`efficacy based on PK/PD studies showing the dose could suppress lymphocyte levels
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`in circulating blood to some degree. (See Ex. 2064 at 19 (“The 0.5 mg dose was
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`selected because it had previously shown a relevant pharmacodynamic effect in man
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`(reduction in circulating lymphocytes).”); see also to Park 2005 (Ex. 1019) and
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`Kahan 2003 (Ex. 1031).)
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`3.
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`IPR2017-00854
`U.S. Patent No. 9,187,405
`However, to protect patients against the likelihood that the dose would
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`not work, Novartis instituted a unique “futility analysis” protocol that would
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`evaluate the results for that dose (and only that dose) after six months. If the dose
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`was ineffective, that part of the trial would end. Despite that protocol, my own
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`hospital Mount Sinai still declined to participate in a trial with the dose, due to lack
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`of evidence it would work. It was a surprise when the dose was efficacious.
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`4.
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`Dr. Benet is a pharmacologist with limited experience with MS drugs
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`and no experience with fingolimod. (Ex. 2100 at 44:9-45:6.) In his Declaration, he
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`does not disagree that FDA in the past had previously pushed to conduct clinical
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`trials for regulatory reasons even if a person of skill would have thought the drug
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`unlikely to work. Nor does he identify any MS clinical trial that employed a futility
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`analysis targeted at only one dose. And he cites no instance of anyone actually
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`saying before June 2006 that he or she expected the 0.5 mg daily dose to be effective.
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`5.
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`Here, I address arguments Dr. Benet makes about the clinical trials for
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`fingolimod. I focus in particular on his contention that persons of skill would have
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`viewed public statements about the Phase III clinical trial as predicting the success
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`of the 0.5 mg daily dose. I also address Dr. Benet’s arguments about the significance
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`of the FDA’s decision to condition fingolimod’s approval on Novartis’s agreement
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`to test an even lower dose, 0.25 mg daily.
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`IPR2017-00854
`U.S. Patent No. 9,187,405
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`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
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`6.
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`the mere inclusion of 0.5 mg daily in Phase III trials as evidence the dose was
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`expected to work. This is incorrect. The 0.5 mg daily dose had never been tested in
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`RRMS patients before. The Phase II trial had tested only 1.25 mg and 5.0 mg daily.
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`As the Mount Sinai IRB had my assistant relay to Novartis (Ex. 2063 at 2), there
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`was no data to suggest that 0.5 mg daily would be effective. To the contrary, prior
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`art like Webb, Kahan 2003, and Park 2005 all pointed the other way—that 0.5 mg
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`daily was unlikely to suppress lymphocytes enough to be effective.
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`7.
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`As Dr. Benet does not dispute, FDA had for regulatory reasons
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`previously pushed to test lower drug doses that a person of skill would have thought
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`unlikely to work. I describe that history in my Second Declaration. (Ex. 2025 ¶¶ 5,
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`39-42.) RRMS is a chronic lifelong disease that presents unique safety risks. A two-
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`year trial may be inadequate to surface all safety issues, as had proven the case just
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`before the fingolimod clinical trials with Tysabri. (Id. ¶ 41.) FDA accordingly has
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`a strong safety interest in identifying the bottom end of the dose response curve.
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`8.
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`Given this history, plus the absence of any prior data on 0.5 mg daily
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`in RRMS patients, a person of skill would not read any expectation of efficacy into
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`a previously-untested dose’s inclusion in Phase III trials. Commentators at the time
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`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
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`in the Phase III trial. As I showed in my Second Declaration (at ¶¶ 48-49),
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`commentators described the Phase III trial as designed to “confirm” the Phase II
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`results for 1.25 mg daily, but merely to “evaluate” the 0.5 mg daily dose. That
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`difference in language reflects a difference in expectation about the doses. It was
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`not necessarily the case that the 0.5 mg arm of the Phase III clinical trial would have
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`resulted in efficacy.
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`9.
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`Dr. Benet argues (at ¶ 86) that Novartis’s description of the trial in an
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`April 2006 press release and a related report (Chavez) shows that 0.5 mg was
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`expected to work. (Exs. 2072, 2031.) These references quote doctors praising the
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`results of the Phase II trial, and saying that the Phase III trial would seek to “confirm”
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`the Phase II trial results. As I explained in my Second Declaration, this language
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`referred to the 1.25 mg dose, which was part of the Phase II and III trials. It did not
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`refer to the 0.5 mg dose, which was not part of the Phase II trial. Dr. Benet, however,
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`characterizes the statement as referring to both doses in the Phase III trials, 1.25 and
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`0.5, and from this contends that Novartis viewed 0.5 mg daily as just as likely to
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`work as 1.25 mg. (Ex. 1047 ¶ 86.)
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`10. A person of skill in June 2006 would not have read these documents as
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`Dr. Benet contends. The Phase II results that the Phase III trials were seeking to
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`“confirm” were for 1.25 mg. The 0.5 mg dose had never been tested in MS patients.
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`IPR2017-00854
`U.S. Patent No. 9,187,405
`Results for that dose accordingly could not be “confirmed.” Rather, as the Doggrell
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`paper stated (Ex. 2036 at 385), the 0.5 mg daily dose was just being “evaluated.”
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`That in fact is how Mount Sinai apparently understood things. The Mount Sinai IRB
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`objected only to the trials’ use of a 0.5 mg daily dose, not to the 1.25 daily dose. As
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`Mount Sinai pointed out, 0.5 mg daily had never been tested in RRMS patients
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`before. That was well-known in the field.
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`11.
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`I testified about this issue in my deposition in this case, in the following
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`back and forth. As I explained, the Phase III trial announcements would tell a person
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`of skill only that 0.5 mg daily was being “tested,” not that it would be effective;
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`efficacy or lack thereof would not be known until the trial was over:
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`Q. …You agree that a person of ordinary skill in the art as of the 6th
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`of April 2006 would understand from the disclosure of the Chavez
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`reference, that in the FREEDOM study, there is no loading dose
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`regimen administered immediately preceding the daily dose of 0.5
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`milligrams Fingolimod?
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`A. Yes.
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`Q. And you also agree that the person of ordinary skill in the art on that
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`date would understand that that daily dose is administered to RRMS
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`patients who have a need for reducing, preventing, or alleviating
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`U.S. Patent No. 9,187,405
`relapses who have a need for RRMS treatment, and who have a need
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`for slowing the progression of RRMS. Correct?
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`*******
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`A. No. They would understand that a study was being done to test that
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`dose.
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`(Ex. 1042 at 238:23-239:21.)
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`12. Merely testing a dose of course is no guarantee that it will work. Phase
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`III trials often fail for lack of efficacy even for doses that were promising at Phase
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`II. Here, the 0.5 mg daily dose had not even been tested in Phase II. That alone
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`made the odds of failure much higher than normal, without even accounting for the
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`prior papers suggesting the dose would not suppress lymphocytes enough to be
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`effective. A person of skill would have known that 0.5 mg was an unproven dose
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`and nothing in the prior developmental program said it would be effective.
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`13. Dr. Benet contends (at ¶ 82) that Novartis must have thought 0.5 mg
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`would be effective because Novartis had an empirical basis for including the 0.5 mg
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`daily dose in the trial, and drug sponsors usually do not waste money on frivolous
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`exercises. Those facts shed no light on whether a person of skill would view the
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`dose’s inclusion in the Phase III trial as reflecting an expectation that the dose would
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`work. Having enough evidence to justify the testing of a dose and enough evidence
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`to believe it is likely to be effective are different things.
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`14. Here, the FDA had asked Novartis to test a 0.5 mg dose, a request that
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`an applicant would have to take very seriously. Prior studies showed that 0.5 mg
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`daily would suppress lymphocytes to some extent. That was enough to justify testing
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`the dose. Novartis thus undertook a trial of that dose, but only subject to a unique
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`6-month futility review—precisely because of doubts the dose would work. The
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`evidence suggested that 0.5 mg daily would not suppress enough lymphocytes to be
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`effective. That led me and others to be skeptical the dose would work.
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`15. Dr. Benet discounts (at ¶¶ 83-84) the futility analysis as showing
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`concern that 0.5 mg daily would not be effective. I submitted the futility analysis as
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`evidence consistent with my memory that I and others did not believe the 0.5 mg
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`daily dose was likely to be effective. Dr. Benet argues that the futility analysis
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`merely built a Phase II into a Phase III trial, proceeding with both simultaneously.
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`But that fails to grasp the significance of the futility study and is at best a hindsight
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`driven analysis of what occurred. Dr. Benet points to no facts from that time to
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`support his view. I am aware of no RRMS drug trial that has ever had an interim
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`futility analysis directed to only one of two doses. That feature reflects concern
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`about only the 0.5 mg dose, not the 1.25 mg dose. That is consistent with my
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`memory that I and other MS physicians familiar with fingolimod were skeptical that
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`the 0.5 mg daily dose would be effective.
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`16. Other evidence, too, is consistent with that memory. As I addressed in
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`my Second Declaration (at ¶ 61), I was responsible for a Phase III trial in a different
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`form of MS—the INFORMS trial for PPMS. We did not include 0.5 mg daily in
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`that trial at all precisely because we thought 0.5 mg daily would not work. Similarly,
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`Mount Sinai was skeptical too. And the authors of the paper publishing the
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`TRANSFORMS results likewise highlighted that 0.5 mg daily had been expected to
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`produce “submaximal” lymphocyte suppression. (Ex. 2035 at 411.) A person of
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`skill would have understood that the authors made that point because the prevailing
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`view had been that maximal suppression was essential to efficacy for fingolimod.
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`17. Dr. Benet does not address the PPMS trial. But he does argue (at ¶ 98-
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`99) that the TRANSFORMS paper’s observation that 0.5 mg was not expected to
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`provide maximal lymphocyte suppression is beside the point. He contends that
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`maximal suppression was not needed for efficacy, citing to various sources. But Dr.
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`Benet was not involved at the time, and his reading is based on hindsight. In fact,
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`maximal suppression was generally viewed as essential for fingolimod’s efficacy.
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`That is why the point was called out in the TRANSFORMS paper. There would
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`have been no other reason to make that observation in that paper. The authors did
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`so because the TRANSFORMS results for the 0.5 mg daily dose were a surprise.
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`18. Petitioners and Dr. Benet say also (Paper 49 at 22-23) that Mount
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`Sinai’s decision not to participate in the TRANSFORMS trial, but to participate in
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`the FREEDOMS II trial, was due to the “complications” from the TRANSFORMS
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`trial having an active comparator rather than a placebo as the standard of comparison
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`with fingolimod. I do not know why the Mount Sinai IRB declined to participate in
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`TRANSFORMS, but did participate in the later FREEDOMS II trial. I think a likely
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`explanation is that the IRB agreed to the FREEDOMS II placebo-controlled trial
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`because patients there necessarily undertook the risk that they might be given an
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`ineffective compound—the placebo. So the possibility that the 0.5 mg daily dose
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`would also be ineffective presented fewer recruiting and other problems. In
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`TRANSFORMS, however, all patients were supposed to be given a compound
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`known or expected to be effective in treating their condition. But as the IRB pointed
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`out, there was no data showing that 0.5 mg daily would in fact be effective, so the
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`IRB declined to participate in the trial. That would explain why the statements of
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`the IRB were so focused on the lack of evidence that 0.5 mg would be effective.
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`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
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`19.
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`wanted to test the 0.5 mg daily dose to explore when fingolimod ceased being
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`effective (the “minimum effective dose”). As I pointed out, if 0.5 mg had been
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`predictably effective, then FDA would have asked Novartis to test an even lower
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`dose. 2 In fact, when 0.5 mg daily proved equally effective with 1.25 mg daily, FDA
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`still had not discovered the minimum effective dose. FDA accordingly committed
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`Novartis to test an even lower dose after approval, 0.25 mg.
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`20. Dr. Benet questions (at ¶¶ 90-94) whether FDA made the testing of that
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`lower dose a condition of approval. I was a first-hand witness and can confirm that
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`the relevant committee within FDA recommended that Novartis undertake a post-
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`approval commitment to test a lower dose. I attended the final approval meeting
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`between Novartis and that FDA committee where this issue was discussed. As stated
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`in the FDA approval letter, Novartis committed to test that lower dose. (Ex. 2037
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`at 7.)
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` 2 Petitioners say (Paper 49 at 4-5) that I admitted in my deposition that it was
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`“routine” for a drug sponsor to seek to identify the safest effective dose. That is
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`not my full testimony. I explained that the interest in such a dose varied by
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`molecule. (Ex. 1042 at 167:3-6 (“Sometimes that means looking for a minimally
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`effective dose. Sometimes not. Some types of molecules that’s tougher to do.”)
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`Here, after the Phase II trial showing that 1.25 was effective and safe enough for
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`human use, a person of skill would have thought there was no need to probe for
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`even lower doses. 1.25 mg was more than good enough. But FDA had other
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`interests and wanted to understand the behavior of even lower doses.
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`21. Dr. Benet then argues (at ¶ 93) that FDA’s interest in Novartis’s
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`commitment was “not . . . unreasonable” after the Phase III results for 0.5 mg daily.
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`Dr. Benet describes such post-approval commitments as “routine in clinical trials[.]”
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`(Id.) Post-approval commitments are quite frequent, but Dr. Benet misses the point.
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`Dr. Benet does not dispute that FDA wanted to test 0.5 mg daily in the first place to
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`find the minimum effective dose. Nor does he disagree that, if it were obvious that
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`0.5 mg daily were not that dose, then FDA would have asked Novartis to test an even
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`lower dose in the Phase III trial.
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`22. As I explained in my Second Declaration (at ¶ 40), FDA’s desire to
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`identify the lowest effective dose in this context is driven by safety concerns. FDA
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`accordingly would want access to that information as soon as possible, to be able to
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`use it in addressing any safety issues. FDA would not ask for Novartis to test a dose
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`that obviously would not provide the information FDA sought. For these reasons, I
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`stand by the assessment in my Second Declaration that FDA’s imposition of a post-
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`approval commitment shows further that 0.5 mg daily was not in fact an obviously
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`effective dose.
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`23. Under penalty of perjury, all statements made herein of my own
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`knowledge are true, and I believe all statements made herein on information and
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`belief to be true. I have been warned and am aware that willful false statements and
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`IPR2017-00854
`U.S. Patent No. 9,187,405
`the like are punishable by fine or imprisonment or both under Section 1001 of Title
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`18 of the United States Code.
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`24.
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`In signing this Declaration, I understand that it will be filed as evidence
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`in a contested case before the Patent Trial and Appeal Board of the United States
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`Patent and Trademark Office. I acknowledge that I may be subject to cross-
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`examination in the case and that cross-examination will take place in the United
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`States. If cross-examination is required of me, I will appear for cross-examination
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`within the United States during the time allotted.
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`DATED: March 23, 2018
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`IPR2017-00854
`U.S. Patent No. 9,187,405
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`By: _________________________
` Fred D. Lublin, M.D.
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