`
`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
`______________________
`SECOND 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
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` 1 Cases IPR2017-01550, IPR2017-01946, and IPR2017-01929 have been joined
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`with this proceeding.
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`1
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`Apotex v. Novartis
`IPR2017-00854
`NOVARTIS 2025
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`TABLE OF CONTENTS
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`Introduction and Summary ........................................................................... 1
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`My Clinical Trial Experience ....................................................................... 4
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`The Fingolimod Clinical Trials .................................................................... 6
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`A. MS Clinical Trials ........................................................................................ 6
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`i. Human Drug Clinical Trials ...................................................................... 6
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`ii. The Challenges of MS Trials ................................................................... 8
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`B. The Phase I Fingolimod Transplant Trials ................................................. 11
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`C. The Phase II MS Trial ................................................................................ 12
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`D. The Phase III Trials .................................................................................... 14
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`i. Trial Designs ........................................................................................... 15
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`ii. Doctors’ Skepticism ............................................................................... 18
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`iii. Trial Results .......................................................................................... 21
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`E. Subsequent Dosing Research ..................................................................... 23
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`I, Fred Lublin, M.D., declare as follows:
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`Introduction and Summary
`1.
`I previously submitted a declaration in this proceeding on May 2, 2017,
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`Exhibit 2003. I respectfully incorporate that declaration by reference. I use the same
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`abbreviations and terms here that I used there. I submit this new declaration to
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`provide information about fingolimod’s clinical trials.
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`2.
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`I have been involved in clinical trials for almost every MS medication
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`approved in the U.S. and Europe as of June 2006 and thereafter, as well as many that
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`were never approved. I was involved in both the Phase II and Phase III human trials
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`for fingolimod, as I describe further below.
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`3.
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`The Phase III trial for fingolimod tested two doses, 1.25 mg and 0.5 mg
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`daily. Counsel for Novartis has asked me whether the 0.5 mg dose was expected to
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`be effective. The answer is no. I and others believed the likelihood was that 0.5 mg
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`daily would be equivalent to placebo, i.e., that it would show no efficacy. Even if it
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`showed some efficacy, I am aware of no one who believed that dose would have the
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`same efficacy as 1.25 mg daily. I was very surprised when 0.5 mg daily produced
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`essentially the same results as that higher dose.
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`4.
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`As I describe below, fingolimod’s earlier Phase II MS trial had also
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`tested two doses, 5.0 mg and 1.25 mg daily. Pre-clinical and clinical studies had
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`suggested that fingolimod’s efficacy was dose-dependent. I and others therefore
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`expected the 5.0 mg dose to be more effective than the 1.25 mg dose. We were
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`surprised when the two Phase II doses showed essentially the same efficacy.
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`Because the lower 1.25 mg daily dose had also shown slightly better safety, Novartis
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`proposed to the U.S. FDA to confirm that dose’s efficacy in Phase III studies.
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`5.
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`FDA agreed to a Phase III trial for 1.25 mg daily but asked Novartis to
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`evaluate a lower dose too. At the time, a recent incident involving another drug
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`called “Tysabri” had prompted FDA to express extra concern about the safety of MS
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`medications. FDA accordingly pressed to understand fingolimod’s minimum
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`effective dose. That would allow FDA and others to understand fingolimod’s
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`optimal balance between efficacy and safety.
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`6.
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`Novartis included a 0.5 mg dose arm in the Phase III trials, but adopted
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`a novel MS trial design to account for the scenario that a 0.5 mg daily dose would
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`not be effective. A panel was tasked to conduct an early analysis of patients given
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`0.5 mg daily to evaluate if the dose was “futile” and should be discontinued before
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`the full trial was finished. I have never been involved in a Phase III MS clinical trial
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`that contained such an early “futility analysis” of one dose and not others.
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`7.
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`Notwithstanding that feature of the Phase III trials, physicians remained
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`concerned that 0.5 mg daily would be ineffective. A review panel at my own hospital
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`Mount Sinai in New York City balked at participating in one of the trials for fear
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`that the 0.5 mg dose would be no more effective than placebo.
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`It thus came as a total surprise when 0.5 mg daily proved to be not only
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`8.
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`effective, but essentially just as effective as 1.25 mg daily. That unexpected result
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`meant that FDA still did not have enough information to know fingolimod’s
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`minimally-effective dose. FDA accordingly approved fingolimod on condition that
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`Novartis conduct a post-marketing “Phase IV” study of an even lower dose, which
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`ended up to be 0.25 mg daily. That study’s results are not yet available. In addition,
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`others in the field conducted further experiments in search of fingolimod’s dose-
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`response curve in smaller studies that I describe below. If fingolimod’s efficacy at
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`0.5 mg daily would have been obvious in June 2006, then FDA and Novartis would
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`have started testing these lower doses at the outset, rather than wait until after the
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`Phase III trial.
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`9.
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`I describe these facts in more detail in the paragraphs to follow. I first
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`summarize my experience with MS clinical trials generally. I then describe the
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`fingolimod clinical trials, including a background on MS clinical trials and a
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`description of the fingolimod Phase I-III trials as well as post-marketing research.
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`10.
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`I was first retained to provide expert advice on Gilenya®-related
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`litigation in April 2015. In preparing my testimony in this declaration, I have worked
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`approximately 62 hours, including many hours conducting my own research into the
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`prior art. I have spoken with counsel and reviewed and commented upon drafts they
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`prepared based on our discussions. I have thoroughly reviewed the contents of my
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`final declaration and believe this document accurately sets forth my views. I reserve
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`the right to amend any part of my testimony in the event of new information brought
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`to my attention.
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` My Clinical Trial Experience
`11. As my first declaration describes (Ex. 2003 ¶¶ 8-16), I currently am a
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`Professor of Neurology and the Director of the Corinne Goldsmith Dickinson Center
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`for Multiple Sclerosis at the Icahn School of Medicine at Mount Sinai, and Attending
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`Neurologist at Mount Sinai Hospital in New York City. Mount Sinai is a teaching
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`hospital where we not only treat patients, but also conduct independent research.
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`Currently Mount Sinai hosts two laboratories run by Ph.D. biologists conducting
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`original basic science research into multiple sclerosis.
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`12. My CV (Ex. 2004) identifies 35 MS drug clinical trials in which I have
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`been Principal Investigator and some where I was Co-Investigator in the “Research
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`Grants” section beginning on Page 11. I have also served as Principal or Co-
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`Investigator on trials not listed in my CV. Principal Investigators are typically
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`responsible for designing trials, supervising their progress, and reporting on their
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`results. Among other tasks, this includes developing the statistical methods used to
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`evaluate the results, and making judgments about the doses to be tested. Co-
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`Investigators share the same functions in a group of two or more. In addition, my
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`publication list identifies 24 trials in which I have served as an advisor and/or author
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`on papers describing clinical trial results, some of which may overlap with trials in
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`which I was a Principal or Co-Investigator. I list those references in the footnote
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`below.2 I also served on steering or safety committees for these agents.
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`13. Among the drugs for which I have served these roles include all the
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`medicines approved to treat RRMS as of June 2006, such as (1) various forms of
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`interferon-beta (such as “Betaseron®”), the first-ever approved “disease modifying
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`therapy” (DMT) for MS; (2) glatiramer acetate, an approved DMT sold under the
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`brand name “Copaxone®”; (3) mitoxantrone, another approved DMT sold under the
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`name “Novantrone®”; natalizumab, a DMT sold under the brand-name “Tysabri®”;
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`plus various studies of corticosteroids for treating inflammation and symptoms in
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`MS.
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`14.
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`In addition to serving as a Principal Investigator, Co-Investigator, or
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`advisor and co-author on papers related to clinical trials, I have also regularly served
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`on clinical trial Data Safety Monitoring Boards (DSMBs), also called Data
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`Monitoring Committees (DMC). DSMBs are panels of physicians responsible for
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`monitoring safety data as it becomes available during a clinical trial. In the event a
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`serious safety issue emerges, DSMBs will advise the drug sponsor on whether to
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` 2 Articles 34, 56, 57, 59, 88, 99, 98, 99, 122, 133, 136, 137, 139, 140, 141, 160,
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`161, 165, 166, 169, 172, 180, 187, and 188.
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`adjust the trial, including possibly by ending it. I estimate that I have served on 7
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`DSMBs in my career for clinical trials involving potential MS drug therapies.
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`15. Given my experience in MS clinical trials, I have also written papers
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`about MS drug trial design, such as those listed at entries 99, 120, and 157 in my
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`CV.
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` The Fingolimod Clinical Trials
`16. Novartis conducted its fingolimod clinical trials at a unique time in the
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`development of MS medications. Several DMTs were already available in the
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`marketplace. One of those DMTs, Tysabri, had developed serious safety issues in
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`the middle of Novartis’s clinical trial program for fingolimod. These facts posed
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`special challenges for the fingolimod Phase III MS trials, as I discuss further below.
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`A. MS Clinical Trials
`17. Here I briefly describe human clinical trial protocols generally, and then
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`the specific problems with MS clinical trials.
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`i. Human Drug Clinical Trials
`18. Human clinical trials for proposed medications usually follow a
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`standard series of “Phases.” Drug development begins with pre-clinical work in
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`animals. If that work shows promise, drugs are introduced into humans for the first
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`time in “Phase I” trials. These trials typically introduce one or more low doses of
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`the compound into a small number of healthy or otherwise relatively stable human
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`volunteers to evaluate the compound’s safety and to collect pharmacological data.
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`19. Sometimes, Phase I trials are divided into Phase Ia and Ib. Phase Ia
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`trials can involve single doses given to subjects. The physician monitors for adverse
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`events, and will often also collect biological samples so that pharmacologists can
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`develop pharmacokinetic (PK) and pharamcodynamic (PD) models of the drug’s
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`behavior in humans. PK measures how the body processes a compound, whereas
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`PD measures how the drug affects one or more aspects of the subject’s physiology.
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`If the drug is deemed safe enough after Phase Ia, some clinical trial programs will
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`use a Phase Ib trial to evaluate the effects of regular dosing over a period of time.
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`20. Next, Phase II trials will test a drug’s safety and efficacy in a larger
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`population of people afflicted with the target condition, often 100-200 patients.
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`Phase II studies will often focus on identifying a candidate dose for the Phase III
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`trial. For that reason, it is common in Phase II trials to include doses expected to
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`have a range of safety and efficacy effects. These are proof of principle studies. The
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`candidate doses are usually compared to placebo or other comparator during an
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`administration period of several months.
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`21. This process allows the sponsor to develop information about the
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`balance among dose, efficacy, and safety. This information provides important tools
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`for regulators and physicians. It allows regulators to make decisions about the
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`optimal average dose for a given population, and physicians to make decisions about
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`how to vary doses for individual patients in the event the drug is ultimately approved.
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`If the Phase II trial identifies one or more doses with promising results,
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`22.
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`the sponsor usually will select the dose(s) with the optimal efficacy-safety mix to
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`include in a Phase III trial. These are large studies with potentially 1,000 or more
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`patients suffering from the targeted condition. The candidate dose(s) is compared
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`to placebo or other comparator drugs, usually in a “double-blind” fashion in which
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`neither the patients nor the administering physicians know if the patient is getting
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`the candidate drug or its comparator. Blinding is critical to limit the risk of placebo
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`effects, in which the physicians’ or patients’ expectations or hopes about the drug’s
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`performance color the trial’s results.
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`ii. The Challenges of MS Trials
`23. Clinical trials for MS patients differ somewhat from the usual pattern
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`due to the nature of the disease and its available therapies.
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`24. MS is a disease in which the immune system attacks the central nervous
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`system. The cause is unknown. The disease strikes women more than men in their
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`20s to 40s, and will progress over the course of decades. There is no cure for MS
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`and the patients will have the disease for the rest of their lives. As of June 2006, MS
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`was typically categorized into four disease courses, of which relapsing-remitting
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`multiple sclerosis (RRMS) was the most common.
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`25. As I describe in my first declaration (Ex. 2003 ¶¶ 46-47), RRMS
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`manifests as episodes or “relapses” in which the patient experiences a period of
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`inflammation and accompanying symptoms, followed by a period of “remission.”
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`As the disease progresses, patients may accumulate symptoms that persist during the
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`remission phase, and eventually may transition into a phase in which symptoms
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`begin to accumulate continuously. Patients experience the disease and its effects in
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`widely disparate ways. The type of symptoms, the time between relapses, relapse
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`duration, relapse severity, and the extent of residual effects all vary considerably
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`from patient to patient.
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`26. These features of the disease along with developments in therapeutic
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`approaches have presented several challenges to MS clinical trial design.
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`27. First, the high level of inter-patient variation makes it difficult to
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`evaluate new drug therapies. To identify a positive therapeutic signal, an RRMS
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`clinical trial typically must have a large testing population and long duration, often
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`about two years. Only in those circumstances can a trial produce a statistically
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`reliable measure of efficacy.
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`28. Second, the need for long-duration studies poses its own problem.
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`Patients in placebo-controlled trials would be at risk of going without treatment for
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`two years if they receive the placebo in the trial. During that time, the disease could
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`progress, and their condition could worsen. In the 1980s, when no medications
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`existed that could modify the course of the disease, this was not a problem. Patients
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`on placebo were no worse off than they would have been without treatment. But
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`beginning in the 1990s, such medications began to establish a track record of
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`successfully helping affect the course of the disease.
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`29. That presented dilemmas for MS trial designers. Placebo-controlled
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`trials are the gold-standard when evaluating new drugs. It is possible to design trials
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`that use approved medicines as comparators, but these trials are less likely to produce
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`data useful in evaluating the tested compound. At the very least, such trials would
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`require more patients and/or a longer duration to produce enough data to do so.
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`30. Third, RRMS’s inter-patient variability also complicates how to
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`measure a compound’s effectiveness. There are no definitive MS biomarkers. So
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`far, the most useful are MRI scans of a patient’s CNS, which look for characteristic
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`lesions to assess disease activity and progression. In addition to that technique,
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`physicians have adopted various scoring systems to measure disease progression
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`based on a patient’s symptoms and signs. These measures suffer from at least some
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`degree of subjectivity on the part of both the patient and the physician, a difficulty
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`compounded by MS patients’ susceptibility to placebo effects and the high inter-
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`patient variability in how the disease manifests. A patient’s belief that a treatment
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`is working can make clinical scoring difficult.
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`31. All of these complications make MS clinical trials inherently
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`complicated and more difficult to predict than those involving many other
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`conditions.
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`B.
`The Phase I Fingolimod Transplant Trials
`32. Fingolimod’s Phase I trials were conducted in stable kidney transplant
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`patients to test safety and collect PK/PD data. Physicians first introduced fingolimod
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`into humans in a Phase Ia single-dose study described in the Budde reference (Ex.
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`1008). Thereafter, physicians conducted a Phase Ib multi-dose study over 28 days
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`as reported in the Kahan 2003 reference (Exhibit 1031). In addition, another study
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`detailed PK/PD data for daily doses over a 12 week period, as reported in the Park
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`abstract and paper at Exhibits 2048 and 1019.
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`33. Neither Budde nor Kahan 2003 measured clinical efficacy, i.e., the
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`drug’s ability to prevent organ transplant rejection. By design, the Phase I trials did
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`not allow for that analysis. The tested patients were already stable. No change in
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`their medical condition was measured. Fingolimod was introduced only over a short
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`period into stable patients. Instead, each study assessed fingolimod’s safety, and
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`further collected PK and PD data for a variety of doses, including 0.5 mg daily.
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`34. PD analysis focused on what was believed to be fingolimod’s primary
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`mechanism of action, the sequestration of lymphocyte white blood cells in lymphatic
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`tissue outside the blood stream. That process was believed to inhibit the immune
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`system mechanisms responsible for organ transplant rejection and at least some
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`autoimmune diseases. The Phase Ia Budde study was only single-dose and in any
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`event too small to detect the relationship, but the daily-dose studies in Kahan 2003
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`and the Park papers showed that fingolimod’s effect on lymphocyte sequestration
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`was dose-dependent. (Kahan 2003, Ex. 1031 at 1081; Park 2003, Ex. 2048 at 333;
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`Park 2005, Ex. 1019 at 683.) That is, higher doses suppressed circulating
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`lymphocytes to a greater degree than lower doses.
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`C. The Phase II MS Trial
`35. Novartis proceeded into Phase II trials for RRMS based on the Phase I
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`transplant studies. I was on the MS Phase II trial DSMB. The Kappos 2005 abstract
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`(Ex. 1007) reports the trial’s design and results.
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`36. The study involved testing doses of 5.0 and 1.25 mg daily in 281
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`patients with RRMS over six months compared to placebo. (Ex. 1007 at II/41.)
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`Patients had monthly MRI brain scans and two neurological assessments at the 3-
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`month and 6-month points. (Id.) Using these benchmarks, the study showed that
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`both doses resulted in fewer brain lesions in MRI scans, with the 5.0 mg dose
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`producing somewhat fewer average lesions than the 1.25 mg dose. (Id.) Similar
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`effects were found when measuring the volume of existing lesions. (Id.) Likewise,
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`fingolimod reduced relapses below placebo levels, and to an equal extent for both
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`doses. (Id.) The study authors concluded that “[t]here was no compelling dose-
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`related difference in efficacy on MRI or clinical endpoints” between the doses.” (Id.)
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`In addition, “[t]reatment was generally well tolerated[.]” (Id.) However, “[a]dverse
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`events were more common in the 5 mg group,” though the authors characterized
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`these as “mild.” (Id.)
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`37.
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`I was surprised that the 5.0 mg and 1.25 mg daily produced essentially
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`the same efficacy results. Based on (i) pre-clinical and the Phase I PK/PD data; (ii)
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`the results in the transplant context; and (iii) the belief that the mechanism of action
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`for suppressing transplant rejection and helping RRMS were the same, I expected
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`the higher 5.0 mg daily dose to be more effective than the 1.25 mg daily dose.
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`38. The pre-clinical and Phase I data had shown that higher doses
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`suppressed lymphocytes to a greater extent than lower doses, and that greater
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`suppression yielded better clinical results. The transplant studies had shown that
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`doses of 1.0 mg daily were not effective, but that doses of 2.5 mg daily and 5.0 mg
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`daily were effective. I therefore expected the 5.0 mg daily dose to be more effective
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`than 1.25 mg daily.
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`39.
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`I later learned that FDA was dissatisfied with the Phase II trial’s failure
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`to identify a minimum effective dose. FDA accordingly pushed Novartis to include
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`a lower dose in the Phase III trial. FDA had taken similar steps in other MS drug
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`trials. In the 1990s, FDA had pushed a sponsor to test a lower dose of interferon-
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`beta that those in the field did not expect to work. (IFNB Study, Ex. 2073.) I was
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`involved in that trial.
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`40. Because MS disease-modifying therapies are designed to be used for
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`an extended period—possibly for the patient’s entire lifetime—FDA wants to
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`understand the drug’s safety-efficacy profile. A clinical trial will test the drug’s
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`safety over two years, but for some medications safety problems will not become
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`apparent until later. It is important for FDA to understand the drug’s profile to be
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`able to provide guidance if such problems later develop.
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`41.
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`In 2005, FDA was confronted with exactly this situation. An approved
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`drug called “Tysabri” had developed serious safety issues with prolonged use. Some
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`patients developed a serious, potentially fatal brain infection. FDA temporarily had
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`to suspend Tysabri’s approval. This experience had made FDA and the community
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`of MS physicians especially sensitive to identifying safe doses for MS medications.
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`42.
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`In addition, safety-efficacy information can help physicians adjust
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`doses for individual patients. If a patient suffers an unusual reaction to the drug, this
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`data can allow the physician to explore using lower doses if warranted to try to solve
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`the problem. For a drug that affects two of the most complex systems in the human
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`body—the immune and nervous systems—the ability to adjust dosing to fit
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`individual patients can be valuable.
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`D. The Phase III Trials
`43. Against this backdrop, I participated in an advisory board of physicians
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`that helped Novartis to design the Phase III trials. I attended an advisory board
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`meeting in Vienna in June 2005 that included many of the physicians involved in the
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`clinical trials, including Dr. Kappos (the author of Kappos 2005). I additionally
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`ended up taking a senior role in the paper publishing the results of one of those trials,
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`as I discuss further below.
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`i. Trial Designs
`44. While I do not recall the details of the meeting in Vienna, I do recall
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`being involved in discussions with Novartis personnel and other advisory board
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`members about different dose tracks for the Phase III trials. Our focus was on
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`confirming the 1.25 mg daily dose as the effective dose. We debated whether and
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`how to include the lower dose FDA wanted. As I describe above (¶ 27), there are
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`serious risks involved in including a potentially ineffective dose in a Phase III
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`clinical trial. Patients taking that dose run the risk that their disease will progress,
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`unchecked, for two years. That risk is inherent in a Phase III trial with a placebo,
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`but including a potentially ineffective dose in the trial could double the number of
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`patients exposed to that risk.
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`45. Novartis ultimately adopted a novel trial design to mitigate this risk.
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`Novartis conducted three Phase III trials: FREEDOMS I, FREEDOMS II, and
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`TRANSFORMS. The two FREEDOMS trials evaluated 1.25 mg and 0.5 mg daily
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`against placebo. Due to FDA-related delays, FREEDOMS I began to recruit patients
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`first, in 2006. FREEDOMS II started later. TRANSFORMS evaluated the same
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`doses as the FREEDOMS trials, comparing their performance not to placebo but
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`rather to another approved MS medication, Avonex (interferon).
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`46.
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`48. Consistent with Novartis’s focus on the 1.25 mg dose, Novartis publicly
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`described its Phase III trial program as designed to “confirm” the Phase II results.
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`Novartis’s press release describing the trial quoted Dr. Paul O’Connor, MD, of St.
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`Michael’s Institute, in Toronto, Canada, as stating that “’[w]e hope that the
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`magnitude of benefits shown in the Phase II study can be confirmed in the larger
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`scale Phase III study program, which is currently being initiated.’” (Novartis Press
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`Release, Ex. 2072 at 1; Chavez, Ex. 2031 at 1.) The press release also quoted Dr.
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`Kappos describing “’the Phase III clinical program’” as seeking to “’confirm[] the
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`promise of the Phase II results[.]’” (Novartis Press Release, Ex. 2072 at 2; Chavez,
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`Ex. 2031 at 2.) These statements were all referring to the 1.25 mg dose used in the
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`Phase II trial. At that time, there was no experience at all with a 0.5 mg dose because
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`that dose had not yet been administered to any MS patient.
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`49. Others in the field repeated this description and likewise described the
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`Phase III trial as seeking to “confirm” the “exciting” Phase II results. (Budde 2006,
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`Ex. 2030 at 22.) The lower dose was included just “to be evaluated.” (Doggrell
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`2007, at 385.)
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`ii. Doctors’ Skepticism
`50. Perhaps because Novartis’s focus was so clearly on the 1.25 mg dose,
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`at least some doctors expressed open skepticism about including the 0.5 mg dose
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`arm in the Phase III trials at all.
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`51.
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`In the Spring of 2007, Novartis asked the hospital where I work, Mount
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`Sinai in New York, to participate in the TRANSFORMS trial. Mount Sinai, like
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`other hospitals, has a panel to review clinical trial requests called an “Institutional
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`Review Board,” or “IRB.” Mount Sinai’s IRB is made up of physicians, researchers,
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`nurse practitioners, and others. They will review clinical trial requests and can
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`conduct their own research analysis to decide whether to participate in a clinical trial.
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`iii. Trial Results
`In 2010, Dr. Kappos and others published their findings from the
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`59.
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`FREEDOMS I trial in the New England Journal of Medicine, the Kappos 2010
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`reference (Ex. 1038).
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`60. Contrary to expectations, the FREEDOMS I results did far more than
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`“confirm” the Phase II study. It dramatically extended those results. Kappos 2010
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`showed that the 1.25 mg and 0.5 mg doses were equally effective. (Ex. 1038 at 390.)
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`Both doses equally reduced relapses, inhibited lesion formation, and slowed
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`disability progression. (Id. at 390-94.) I was surprised by the results.
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`61. At the time, I was involved in the FREEDOMS II trial, and also was
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`an investigator on another trial called INFORMS that tested fingolimod in a different
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`form of MS called “Primary Progressive” MS, or “PPMS.” INFORMS was a large
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`Phase III trial involving 970 patients observed over 3-5 years starting in September
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`2008. We were so skeptical that 0.5 mg daily would not be effective that we did not
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`even include that dose in the INFORMS PPMS trial at all.
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`62. Some of this surprise can be seen in the Cohen paper on the
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`TRANSFORMS trial. (Ex. 2035.) That paper reported that “[t]he selection of the
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`dose of fingolimod was based on [PK] and [PD] considerations from earlier studies,
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`which suggested that a dose of 1.25 mg would be fully effective.” (Id. at 411.) The
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`“lower dose of 0.5 mg … was expected to have a submaximal effect on lymphocyte
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`recirculation,” and thus submaximal (if any) efficacy. (Id.) Contrary to
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`expectations, however, the 0.5 mg daily dose was “at least as effective” as 1.25 mg
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`daily. (Id.)
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`63.
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`I was senior author on the final Phase III trial paper for FREEDOMS
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`II. We likewise found that the two doses were equally effective, to the extent our
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`data covered both doses. (Calabresi 2014, Ex. 2042 at 545,) (When the
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`FREEDOMS I results became available, we had discontinued the 1.25 mg daily dose
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`and switched all patients to the 0.5 mg daily dose.)
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`E.
`Subsequent Dosing Research
`64. The Phase III results left Novartis and FDA in the much same position
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`as the Phase II results—without enough data to identify the minimally effective dose.
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`FDA accordingly made it a condition of approval for the 0.5 mg daily dose that
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`Novartis would conduct a Phase IV study 0.25 mg daily. (FDA Approval Letter,
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`Ex. 2037 at 7.) In addition, physicians published studies of lower dosing regimens
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`utilizing less-than-daily dosing, such as every-other-day dosing. (Tanaka 2013, Ex.
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`2067; Yamout 2015, Ex. 2068; Zecca 2017, Ex. 2069.)
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`65. The results of the Phase IV study are not yet available. Of course, if
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`the 0.5 mg dose results had been expected in June 2006, then FDA would have
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`pushed Novartis to experiment with an even lower dose earlier in the Phase III trials
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`to identify the lowest dose showing any efficacy.
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`*
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`66. 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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`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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`In signing this Declaration, I understand that it will be filed as evidence
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`67.
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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 c
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