UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner
`
`v.
`
`BIOGEN MA INC.,
`
`Patent Owner
`
`Case: IPR2018-01403
`Patent 8,399,514
`
`DECLARATION OF IAN MCKEAGUE, Ph.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF U.S.
`PATENT NO. 8,399,514
`
`Sawai (IPR2019-00789), Ex. 1004, p. 001
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner
`
`v.
`
`BIOGEN MA INC.,
`
`Patent Owner
`
`Case: IPR2018-01403
`Patent 8,399,514
`
`DECLARATION OF IAN MCKEAGUE, Ph.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF U.S.
`PATENT NO. 8,399,514
`
`Sawai (IPR2019-00789), Ex. 1004, p. 001
`
`
`
`TABLE OF CONTENTS
`
`Page
`
`INTRODUCTION ........................................................................................ 3
`I.
`EDUCATION AND PROFESSIONAL BACKGROUND ....................... 3
`II.
`III. MATERIALS CONSIDERED .................................................................... 6
`IV. LEGAL STANDARDS................................................................................. 6
`V.
`SUMMARY OF OPINIONS........................................................................ 8
`VI. BACKGROUND........................................................................................... 9
`A.
`Clinical Trials Investigating Dimethyl Fumarate................................. 9
`B.
`Statistical Principles ...........................................................................11
`VII. 360 MG DIMETHYL FUMARATE MOST LIKELY ACHIEVED
`STATISTICAL SIGNIFICANCE.............................................................13
`VIII. BIOGEN’S EXPERTS’ CONCLUSION THAT 480 MG
`DIMETHYL FUMARATE IS “EQUALLY” OR “SIMILARLY”
`EFFECTIVE TO 720 MG DIMETHYL FUMARATE IS
`UNSUPPORTED ........................................................................................17
`IX. BIOGEN’S STATISTICIAN DRAWS INAPPROPRIATE
`MEDICAL EFFICACY CONCLUSIONS THROUGHOUT HIS
`REPORT......................................................................................................20
`
`2
`
`Sawai (IPR2019-00789), Ex. 1004, p. 002
`
`
`
`I, Ian McKeague, Ph.D., do hereby declare:
`I.
`INTRODUCTION
`
`1.
`
`I am making this declaration at the request of Petitioner Mylan
`
`Pharmaceuticals Inc. (“Petitioner” or “Mylan”), in the matter of the Inter Partes
`
`Review (“IPR”) of U.S. Patent No. 8,399,514 (the “’514 patent”), as set forth in
`
`the above caption.
`
`II.
`
`EDUCATION AND PROFESSIONAL BACKGROUND
`
`2.
`
`I received a B.A./M.A. and M.Math in Mathematics from the
`
`University of Cambridge in 1975 and 1976, respectively. I received a Ph.D. from
`
`the University of North Carolina at Chapel Hill in 1980, authoring a Ph.D. thesis
`
`titled Covariance Operators and Their Applications in Probability and Information
`
`Theory. My curriculum vitae is attached as Exhibit A.
`
`3.
`
`After completing my Ph.D., I took a position as an Assistant Professor
`
`in the Department of Statistics at Florida State University. I held that position
`
`from 1980 to 1986, when I was promoted to Associate Professor, a title I held until
`
`1991, when I was promoted to Professor. In 1996, I was appointed to Chairman of
`
`the Department of Statistics and I held that position until 1999. From 2000 to
`
`2004, I was the Ralph A. Bradley Professor of Statistics at Florida State
`
`University. In 2004, I left that university and took a position as Professor of
`
`Biostatistics at Columbia University, a position I hold to this day. In addition, I
`
`3
`
`Sawai (IPR2019-00789), Ex. 1004, p. 003
`
`
`
`have been a visiting professor at University of Padua, Italy (1985), University
`
`Joseph Fourier, Grenoble, France (1992, 2001), and the University of California,
`
`Berkeley (1991).
`
`4.
`
`I have received numerous professional honors, served as an editor on
`
`various journals, and have served on a number of professional committees. For
`
`example, I am a Fellow of the Institute of Mathematical Studies and a Fellow of
`
`the American Statistical Association. I am also an Associate Editor of the Journal
`
`of the American Statistical Association (1993–96, 2011–present), the International
`
`Journal of Biostatistics (2005–present), and Statistical Inference for Stochastic
`
`Processes (1998–present), and a former Associate Editor of the Annals of Statistics
`
`(1989–1995) and ESAIM: Probability and Statistics (2000–2005). At Florida State
`
`University, I received the Named Professorship Award (2000), the Graduate
`
`Teaching Award (1998), and the Professorial Excellence Program Award (1999). I
`
`have served on the Institute of Mathematical Statistics Fellows Committee (2008–
`
`2010); the ASA Section on Nonparametric Statistics Awards Committee (2010–
`
`2011); the NSF Statistics and Probability Program Panel (1997, 1999, 2000, 2002,
`
`2003, 2007, 2009, 2010, 2016), Special Meetings Panel (2005), Biocomplexity in
`
`the Environment Panel (2004), and Knowledge and Distributed Intelligence
`
`Program Panel (1998).
`
` 4
`
`Sawai (IPR2019-00789), Ex. 1004, p. 004
`
`
`
`5.
`
`As a biostatistician, I have more than twenty years of experience in
`
`clinical trial design and statistical analysis. I have consulted for a variety of
`
`entities regarding clinical trial design and analysis, including biopharmaceutical
`
`companies and nonprofit research centers. In particular, I have been involved in
`
`the design and analysis of numerous clinical trials, with special expertise in
`
`designing cohort studies. I have published dozens of papers analyzing clinical trial
`
`data, often including analysis regarding study methodology. I have also spoken
`
`widely at conferences, symposia, and seminars on clinical trials. For example, I
`
`was the Keynote Speaker at the Fourth Annual International Symposium on the
`
`Evaluation of Clinical Trial Methodologies and Applications in Beijing, China in
`
`2011, and I also was an invited speaker on clinical trials at the ICSA Applied
`
`Statistics Symposium in 2011.
`
`6.
`
`My research interests include functional data analysis, empirical
`
`likelihood, and non-standard asymptotics, to name a few. I am a named author on
`
`122 peer-reviewed articles, I have supervised eighteen doctoral students, and I
`
`have received grants from a number of organizations including the NIH and the
`
`NSF.
`
`7.
`
`I am being compensated at an hourly rate of $550/hour and am
`
`available to appear live for testimony in support of my opinions. My
`
`compensation in no way depends on the outcome of this proceeding. The opinions
`
` 5
`
`Sawai (IPR2019-00789), Ex. 1004, p. 005
`
`
`
`to which I will testify are based on the education, experience, training, and skill
`
`that I have accumulated in the course of my career as a biostatistician and
`
`researcher, as well as materials I have reviewed in connection with this case.
`
`III. MATERIALS CONSIDERED
`
`8.
`
`The list of materials I considered in forming the opinions set forth in
`
`this declaration is set forth in Exhibit B.
`
`IV. LEGAL STANDARDS
`
`9.
`
`I understand that this IPR involves U.S. Patent No. 8,399,514 (the
`
`“’514 patent”), which claims treating multiple sclerosis (“MS”) with about 480 mg
`
`dimethyl fumarate (“DMF”) per day. Ex. 1001. I understand that a previous IPR
`
`proceeding, brought by the Coalition for Affordable Drugs, was instituted against
`
`the same ’514 patent (“the CFAD IPR”). See IPR2015-01993. I have reviewed
`
`certain materials from the CFAD IPR, including the expert declaration of Patent
`
`Owner Biogen MA Inc.’s (“Biogen’s”) statistician. IPR2015-01993, Ex. 2038
`
`(Thisted Decl.).
`
`10.
`
`I have been informed of the relevant legal principles as part of
`
`preparing and forming my opinions set forth in this declaration. I have applied my
`
`understanding of those principles in forming my opinions. My understanding of
`
`those principles is summarized below.
`
` 6
`
`Sawai (IPR2019-00789), Ex. 1004, p. 006
`
`
`
`11.
`
`I have been informed that Mylan bears the burden of proving
`
`unpatentability by a preponderance of the evidence, which means that Mylan must
`
`show that more likely than not, the claims of the ’514 patent are invalid. I
`
`understand that one way to cancel patent claims is to find that they are obvious
`
`over the prior art. I understand that unpatentability, including obviousness, is
`
`assessed from the viewpoint of a person of ordinary skill in the art (“POSA”) at the
`
`patent’s priority date.
`
`12.
`
`I understand that the obviousness inquiry is a question of law based on
`
`four factual inquiries: (1) the scope and content of the prior art (i.e., the literature
`
`existing at the time of the patent’s priority date), (2) the differences between the
`
`prior art and the claims, (3) the level of ordinary skill in the art, and (4) secondary
`
`considerations of non-obviousness, which may rebut evidence that a patent’s
`
`claims are obvious.
`
`I also understand that to demonstrate obviousness based on
`
`multiple pieces of prior art, or changing something from what was disclosed in the
`
`prior art, Mylan must prove that a POSA would have been motivated to combine
`
`the prior art, and would have had a reasonable expectation of success in making
`
`that change or combination to come to the claimed invention.
`
`13.
`
`I have been told that one secondary consideration of non-obviousness
`
`is unexpected results. I further understand that, to show unexpected results, Patent
`
`Owner Biogen must prove that the alleged invention produced benefits that were
`
` 7
`
`Sawai (IPR2019-00789), Ex. 1004, p. 007
`
`
`
`unexpected in light of the prior art, from the viewpoint of a POSA at the patent’s
`
`priority date.
`
`I understand that the parties can look to references and other
`
`evidence after a patent’s priority date to assess unexpected results.
`
`14.
`
`I have been told that evidence of secondary considerations such as
`
`unexpected results is only relevant to the obviousness analysis if the patentee can
`
`show a direct link, or nexus, between the secondary consideration and the claims of
`
`the patent, and that the evidence must be commensurate in scope with the asserted
`
`claims. I also understand that for results to be considered unexpected for these
`
`purposes, there must be a substantial difference from the prior art. In other words,
`
`a difference of kind, and not merely of degree.
`
`V.
`
`SUMMARY OF OPINIONS
`
`15.
`
`From my review of certain materials relating to my opinions herein
`
`from the CFAD IPR, I understand that Biogen’s experts argued that 360 mg
`
`DMF/day did not achieve statistically significant efficacy in treating MS. It is my
`
`opinion that 360 mg DMF/day most likely achieved statistically significant
`
`efficacy, as detailed below in the Fox and Gold book chapter and the EMA Report.
`
`16. Also from my review of certain materials from the CFAD IPR, I
`
`understand that Biogen’s experts conclude that 480 mg is similarly effective to 720
`
`mg/day DMF, relying on data from Biogen’s phase III clinical studies.
`
`It is my
`
`opinion that Biogen’s phase III clinical trials do not allow for any such conclusion
`
` 8
`
`Sawai (IPR2019-00789), Ex. 1004, p. 008
`
`
`
`to be drawn. Instead, one can only conclude from the studies’ design that both 480
`
`and 720 mg DMF produced statistically significant results over placebo in certain
`
`efficacy endpoints—the relative efficacy of the two doses cannot be compared to
`
`one another.
`
`17.
`
`Finally, after reviewing Biogen’s statistician’s report in the CFAD
`
`IPR, I find most of his opinions inappropriate, because they are far outside the
`
`scope of a statistician’s expertise. Dr. Thisted is a statistician, not a medical doctor
`
`or pharmacokinetics/pharmacodynamics (“PK/PD”) expert, yet he opined that a
`
`POSA would not have expected 480 mg/day DMF to be therapeutically effective,
`
`because it was closer in proximity to a dose he deemed therapeutically ineffective
`
`(360 mg/day) than to 720 mg/day.
`
`VI. BACKGROUND
`
`A.
`
`18.
`
`Clinical Trials Investigating Dimethyl Fumarate
`
`The Kappos 2006 study was a randomized, double-blind, placebo-
`
`controlled phase II study testing three separate doses of BG00012 (DMF) in
`
`patients with relapsing-remitting multiple sclerosis (RRMS), the results of which
`
`are reported in Kappos 2006. Ex. 1007 (Kappos 2006) at 27. This study included
`
`a placebo arm, as well as three different doses of DMF—120 mg/day, 360 mg/day,
`
`and 720 mg/day. Id. The study measured the drug’s effect on brain lesion activity
`
`by measuring the total number of gadolinium-enhancing (Gd +) lesions in MRI
`
` 9
`
`Sawai (IPR2019-00789), Ex. 1004, p. 009
`
`
`
`scans as the primary endpoint. Id. Kappos 2006 reported that “BG00012 (720
`
`mg/day) significantly reduced the mean number of new Gd + lesions (the primary
`
`end point) compared with placebo.” Id. Kappos 2006 concluded that “BG00012
`
`significantly reduces brain lesion activity, in a dose-dependent manner, as
`
`measured by MRI in patients with RRMS over 24 weeks of treatment.” Id.
`
`19.
`
`The DEFINE study was a randomized, double-blind, placebo-
`
`controlled phase III study, the results of which are reported in the Gold 2012
`
`publication. Ex. 1038 (DEFINE paper). The DEFINE study included three arms:
`
`480 mg/day DMF, 720 mg/day DMF, and placebo. Id. at 1. The primary objective
`
`of the DEFINE study was “to determine whether BG00012, when compared with
`
`placebo, is effective in reducing the proportion of relapsing subjects at 2 years.”
`
`See, e.g., id. at 45. The secondary and tertiary objectives similarly measured
`
`effects of the DMF doses individually against placebo. See, e.g., id. at 45–46, 57–
`
`58. The study concluded that “both BG-12 regimens, as compared with placebo,
`
`significantly reduced the proportion of patients who had a relapse, the annualized
`
`relapse rate, the rate of disability progression, and the number of lesions on MRI.”
`
`Id. at 1.
`
`20.
`
`The CONFIRM study was a randomized, double-blind, placebo-
`
`controlled phase III study, the results of which are reported in the Fox 2012
`
`publication. Ex. 1039 (CONFIRM paper). The CONFIRM study included four
`
`10
`
`Sawai (IPR2019-00789), Ex. 1004, p. 010
`
`
`
`arms: 480 mg/day DMF, 720 mg/day DMF, 20 mg/day glatiramer acetate, and
`
`placebo. Id. at 1–2. The primary objective of the CONFIRM study was “to
`
`determine whether BG00012, when compared with placebo, is effective in
`
`reducing the proportion of relapsing subjects at 2 years.” Id. at 46. The secondary
`
`and tertiary objectives similarly measured effects of the DMF doses individually
`
`against placebo. See, e.g., id. at 46–47, 58–59. The publication reporting the
`
`CONFIRM results clarified that “[t]he study was not designed to test the
`
`superiority or noninferiority of BG-12 versus glatiramer acetate.” Id. at 1. The
`
`study concluded that “BG-12 (at both doses) and glatiramer acetate significantly
`
`reduced relapse rates and improved neuroradiologic outcomes relative to placebo.”
`
`Id.
`
`B.
`
`Statistical Principles
`
`21. One of the main goals of statistics is to evaluate whether study results
`
`are meaningful. The most common way to draw this conclusion is by measuring
`
`whether results achieve “statistical significance.” This is necessary because studies
`
`measure a particular result or outcome at the sample, and the sample is ideally
`
`representative to a population of people. The end goal is to extrapolate the study’s
`
`results to the population to draw conclusions about that population. At a high
`
`level, if a study result achieves statistical significance, it means that the
`
`11
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`Sawai (IPR2019-00789), Ex. 1004, p. 011
`
`
`
`investigator has sufficiently ruled out the possibility that the result was merely due
`
`to random chance (as opposed to, for example, a treatment effect).
`
`22.
`
`In the clinical trial context, studies can be designed to compare
`
`treatments. Phase III clinical trials typically have two arms (but sometimes have
`
`more)—a treatment arm and a comparator arm. The comparator arm can comprise
`
`a placebo comparator or an active comparator, which allows the treatment arm to
`
`be compared with another effective intervention. A well-designed clinical trial
`
`allows the investigator to measure the effectiveness of a treatment over the placebo
`
`or active comparator. This type of clinical trial is called a “superiority” trial,
`
`because it is proactively designed to test whether a treatment has a statistically
`
`significant effect compared with a placebo or control.
`
`23. Other types of study designs are available if a superiority trial design
`
`is not feasible or desired. For example, clinical trials can be designed as non-
`
`inferiority studies, which (when designed correctly) can measure whether a
`
`particular treatment is not materially worse than the control. See, e.g., Ex. 1049
`
`(FDA Guidance) at 5. Part of the correct design of a non-inferiority trial is the pre-
`
`specification of the study’s non-inferiority margin(s) before commencing the trial.
`
`Id. at 7–17, 22–34.
`
`If an investigator desires to establish the equivalence of two
`
`active treatments to one another, the investigator must conduct a properly designed
`
`non-inferiority trial.
`
`12
`
`Sawai (IPR2019-00789), Ex. 1004, p. 012
`
`
`
`VII. 360 MG DIMETHYL FUMARATE MOST LIKELY ACHIEVED
`STATISTICAL SIGNIFICANCE
`
`24.
`
`In the CFAD IPR, I understand that Biogen’s experts argued that 360
`
`mg/day DMF did not achieve statistical significance in certain efficacy variables in
`
`the Kappos 2006 study, and that CFAD supplied no evidence to counter that point.
`
`However, the Kappos 2006 study most likely achieved statistically significant
`
`results for both 360 mg and 720 mg DMF.
`
`25.
`
`For example, in 2011, Biogen’s main expert in the CFAD IPR—Dr.
`
`Rudick—edited a book chapter that acknowledged that the 360 mg/day group in
`
`the Kappos 2006 study most likely achieved statistical significance. Ex. 1036 (Fox
`
`and Gold Book Chapter)1 at 5–7. Specifically, after noting that the phase II study
`
`reported in Kappos 2006 did not technically achieve statistical significance for the
`
`two lower DMF doses tested (120 mg/day and 360 mg/day), the chapter observes,
`
`“However, the middle (240 mg/d)2 [sic] dose group had a 76% higher mean
`
`1 This book chapter was edited by Biogen’s CFAD IPR expert, Dr. Richard
`
`Rudick. Notably, the two authors of the book chapter are Robert Fox and Ralf
`
`Gold, the lead authors on the CONFIRM and DEFINE study publications,
`
`respectively. Dr. Gold was also an investigator on the Kappos phase II trial. See
`
`Ex. 1048 (Kappos 2008) at 9.
`
`2 It is my understanding that this number is supposed to be 360 mg/day, and not
`
`13
`
`Sawai (IPR2019-00789), Ex. 1004, p. 013
`
`
`
`number of Gd-enhancing lesions at baseline, which may have obscured a
`
`treatment effect.” Id. at 6 (emphasis added). In the next sentence, the chapter
`
`goes on to say, “If the primary outcome is re-displayed as % reduction from each
`
`group’s baseline enhancing lesion activity, a dose-response becomes more
`
`apparent (Fig. 31.4).” Id.
`
`26.
`
`In other words, Drs. Gold and Fox recognized that the group of
`
`patients receiving 360 mg/day DMF had about a 75% higher mean number of Gd+
`
`lesions at baseline, and that may have affected the study’s original conclusion that
`
`360 mg/day DMF did not rise to the level of statistical significance in the primary
`
`outcome. Drs. Gold and Fox then went a step further and adjusted the data to
`
`remove this perceived bias, thereby demonstrating a stronger dose response
`
`relationship.
`
`27.
`
`The European Medicines Agency made a similar observation in 2013.
`
`See Ex. 1037 (EMA Report) at 33–34, 79. While analyzing the results of the phase
`
`II dose response study within a larger evaluation of Biogen’s Tecfidera® (DMF)
`
`drug, the EMA initially acknowledged that only the highest dose (720 mg/day
`
`DMF) appeared to achieve statistical significance. Id. at 34, 79. However, it
`
`240 mg/day. This is because the Phase II study the book chapter is discussing did
`
`not test any dose of 240 mg/day, and the “middle dose group” depicted in the
`
`figures referenced in this section of the book chapter is 360 mg/day.
`
`14
`
`Sawai (IPR2019-00789), Ex. 1004, p. 014
`
`
`
`noticed that “[t]here were considerable imbalances at baseline for the mean
`
`number of Gd-enhancing lesions across the groups (notably in the 120 mg TID
`
`[i.e., 360 mg/day] group which presented patients with higher disease activity i.e.
`
`higher number of Gd enhancing lesions).” Id. at 34 (emphasis added); see also id.
`
`at 79 (same). The EMA Report went on to describe that once the data were
`
`reanalyzed, “BG00012 [DMF] 120 mg TID [i.e., 360 mg/day] also provided
`
`statistically significant results for the primary endpoint (p=0.009).” Id. at 34
`
`(emphasis added); see also id. at 79 (same).
`
`28.
`
`I understand that in the CFAD IPR, Biogen’s statistician, Dr. Thisted,
`
`attempted to distance the EMA Report’s observations, on the basis that it was a
`
`post hoc analysis. See IPR2015-01993, Ex. 2038 (Thisted Decl.) ¶¶ 25–33. A post
`
`hoc analysis is an analysis that is performed after obtaining data in a study. Post
`
`hoc analyses can sometimes be less reliable than pre-defined analyses, because the
`
`analyses may not be specifically planned out before commencing the study and
`
`obtaining some data. Therefore, an investigator must be careful not to allow a
`
`study’s results to suggest a particular hypothesis that is likely to lead to a desired
`
`positive result. However, post hoc analyses can be useful in certain situations,
`
`such as for understanding how a key imbalance at baseline may have affected the
`
`study’s original results.
`
`15
`
`Sawai (IPR2019-00789), Ex. 1004, p. 015
`
`
`
`29.
`
`Post hoc analyses can be appropriate in certain circumstances—in
`
`fact, it is my opinion that this is precisely one circumstance in which a post hoc
`
`analysis is appropriate. Namely, the EMA Report noticed (as did Drs. Rudick,
`
`Gold and Fox in their book chapter) that the 360 mg/day group had a higher
`
`number of Gd-enhancing lesions at baseline. Ex. 1037 (EMA Report) at 34, 79. In
`
`my opinion, the number of Gd-enhancing lesions at baseline is a very reasonable
`
`covariate to build into a regression model to conduct a post hoc analysis with the
`
`goal of controlling for possible bias affecting this study’s results. For example,
`
`this variable can be measured accurately, and is clearly related to the endpoint
`
`investigated in the study—indeed, it was related to the primary endpoint in the
`
`Kappos 2006 study. Ex. 1007 (Kappos 2006) at 27.
`
`30.
`
`I also find an unambiguous description of the post hoc analysis in the
`
`EMA Report, which strengthens my opinion that the analysis conducted was
`
`appropriate in this situation. See, e.g., Ex. 1037 (EMA Report) at 34 (“CHMP
`
`requested analyses using the number of baseline Gd-enhancing lesions as
`
`covariates”); 34 (“correcting for the baseline number of Gd-enhancing lesions in
`
`the statistical models as a covariate”); 79 (same). This is all the detail necessary to
`
`inform one that the post hoc analysis conducted was a linear regression that used
`
`the number of baseline Gd-enhancing lesions as the sole covariate.
`
`16
`
`Sawai (IPR2019-00789), Ex. 1004, p. 016
`
`
`
`VIII. BIOGEN’S EXPERTS’ CONCLUSION THAT 480 MG DIMETHYL
`FUMARATE IS “EQUALLY” OR “SIMILARLY” EFFECTIVE TO
`720 MG DIMETHYL FUMARATE IS UNSUPPORTED
`
`31.
`
`I understand that in the CFAD IPR, all of Biogen’s experts interpreted
`
`the results of Biogen’s phase III studies, DEFINE and CONFIRM, to conclude that
`
`480 mg/day DMF is similarly or equivalently efficacious to 720 mg/day DMF. It
`
`is my opinion that the DEFINE and CONFIRM studies only allow for the
`
`conclusion that each respective dose (480 mg/day or 720 mg/day) is efficacious
`
`over placebo, and these studies do not allow for comparing the equivalency of the
`
`two DMF doses tested.
`
`32.
`
`The DEFINE and CONFIRM trials investigated the efficacy of two
`
`different doses of DMF, 480 mg/day (the dosage claimed in the ’514 patent) and
`
`720 mg/day. Ex. 1038 (DEFINE paper) at 1; Ex. 1039 (CONFIRM paper)3 at 1.
`
`Both studies measured the effect of these two dosages against placebo in certain
`
`efficacy endpoints. See, e.g., Ex. 1038 (DEFINE paper) at 45 (“The primary
`
`objective of this study is to determine whether BG00012, when compared with
`
`placebo, is effective in reducing the proportion of relapsing subjects at 2 years.”);
`
`Ex. 1039 (CONFIRM paper) at 46 (same). These trials were superiority trials vs.
`
`3 The CONFIRM study also included an arm administering patients a different
`
`multiple sclerosis drug, glatiramer acetate. Ex. 1039 (CONFIRM paper) at 1–2.
`
`17
`
`Sawai (IPR2019-00789), Ex. 1004, p. 017
`
`
`
`placebo only—they investigated whether each individual dose—480 mg/day and
`
`720 mg/day DMF—was superior to placebo.
`
`33. Neither study investigated the relative efficacy of 480 mg/day DMF
`
`as compared to 720 mg/day DMF. In other words, neither study was designed to
`
`measure whether 480 mg/day DMF was less effective, equally as effective, or
`
`more effective than 720 mg/day DMF. When I reviewed the DEFINE and
`
`CONFIRM publications, both publications appropriately limited the conclusions to
`
`the efficacy of each dose as compared to placebo—not as compared to the other
`
`DMF dose. See, e.g., Ex. 1038 (DEFINE paper) at 1 (“[B]oth BG-12 regimens, as
`
`compared with placebo, significantly reduced the proportion of patients who had a
`
`relapse, the annualized relapse rate, the rate of disability progression, and the
`
`number of lesions on MRI.”);4 Ex. 1039 (CONFIRM paper) at 1 (“BG-12 (at both
`
`4 See also Ex. 1038 (DEFINE paper) at 4 (“The proportion of patients who had at
`
`least one relapse of multiple sclerosis by 2 years was significantly reduced with
`
`each BG-12 regimen as compared with placebo.”); 6 (“As compared with placebo,
`
`BG-12 reduced the risk of confirmed progression of disability”); 7 (“As compared
`
`with placebo, BG-12 reduced the number of new or enlarging hyperintense lesions
`
`on T2-weighted images”); 9 (“BG-12, as compared with placebo, significantly
`
`reduced the proportion of patients who had a relapse by 2 years, the annualized rate
`
`of relapse, and the cumulative progression of disability.”)
`
`18
`
`Sawai (IPR2019-00789), Ex. 1004, p. 018
`
`
`
`doses) and glatiramer acetate significantly reduced relapse rates and improved
`
`neuroradiologic outcomes relative to placebo.”).5 The CONFIRM paper even
`
`reminds the reader that the active arms are not to be compared to one another. Ex.
`
`1039 (CONFIRM paper) at 1 (“The study was not designed to test the superiority
`
`or noninferiority of BG-12 versus glatiramer acetate.”); see also id. at 3 (same).6
`
`34. Any conclusion that 480 mg/day DMF is similarly or equivalently
`
`efficacious to 720 mg/day DMF would be incorrect and misleading. I have
`
`reviewed the supplementary appendices attached to both papers reporting the
`
`DEFINE and CONFIRM study results, which includes the clinical trial protocols
`
`for each study. Ex. 1038 (DEFINE paper) at 33–126; Ex. 1039 (CONFIRM paper)
`
`5 See also Ex. 1039 (CONFIRM paper) at 5 (“As compared with placebo, twice-
`
`daily BG-12, thrice-daily BG-12, and glatiramer acetate significantly reduced the
`
`risk of relapse”); 9 (“The CONFIRM study showed that in patients with relapsing-
`
`remitting multiple sclerosis, BG-12 at a dose of 240 mg two or three times daily, as
`
`compared with placebo, significantly reduced the rate of relapse, the proportion of
`
`patients with a relapse, and disease activity as measured by a range of MRI end
`
`points.”).
`
`6 In fact, the CONFIRM paper notes (Ex. 1039 at 10) that the BG-12 and
`
`glatiramer acetate active arms of the CONFIRM study were only able to be
`
`compared in an indirect manner by using a post hoc analysis.
`
`19
`
`Sawai (IPR2019-00789), Ex. 1004, p. 019
`
`
`
`at 34–127. My review has identified that the DEFINE and CONFIRM studies
`
`were not designed to compare the 480 mg/day dose to the 720 dose—they were
`
`simply designed as superiority studies to measure superiority over placebo only.
`
`See, e.g., Ex. 1038 (DEFINE paper) at 45 (“The primary objective of this study is
`
`to determine whether BG00012, when compared with placebo, is effective in
`
`reducing the proportion of relapsing subjects at 2 years.”); Ex. 1039 (CONFIRM
`
`paper) at 46 (same). Therefore, any conclusion comparing the equivalency of
`
`these two doses based on the results of the DEFINE and CONFIRM studies would
`
`be improper.
`
`IX. BIOGEN’S STATISTICIAN DRAWS INAPPROPRIATE MEDICAL
`EFFICACY CONCLUSIONS THROUGHOUT HIS REPORT
`
`35. While reviewing Biogen’s statistician’s expert report from the CFAD
`
`IPR, I observed that Dr. Thisted made sweeping conclusions on the therapeutic
`
`efficacy of the drug that exceed the expertise of a statistician. The main argument
`
`of Dr. Thisted’s declaration—that a POSA would not have expected 480 mg/day
`
`DMF to be therapeutically effective—is an argument a statistician is not qualified
`
`to make. See IPR2015-01993, Ex. 2038 (Thisted Decl.) ¶¶ 19–24, 33, 44–46.
`
`Throughout his report, Dr. Thisted drew conclusions about the expected medical
`
`efficacy of dimethyl fumarate to treat multiple sclerosis. See, e.g., id. ¶¶ 44
`
`(“[B]ased on Kappos 2006, a person of ordinary skill in the art would not have
`
`expected that increasing the dose by an additional 33% (to 480 mg/day) would
`
`20
`
`Sawai (IPR2019-00789), Ex. 1004, p. 020
`
`
`
`produce substantial efficacy. Indeed, a person of ordinary skill in the art would
`
`have expected the effects on brain lesions with 480 mg/day to be closer to those
`
`with 360 mg/day than those with 720 mg/day. A person of ordinary skill in the art
`
`would not have expected the results reported in the DEFINE and CONFIRM
`
`publications.”); 45 (“It is stunning and unexpected to see, in two large
`
`independent studies, that increasing an ineffective dose (360 mg/day) by a small
`
`amount (120 mg/day) produces a strong therapeutic effect, and that a further,
`
`larger dose
`
`increase (to 720 mg/day) produces virtually no additional
`
`therapeutic benefit.”) (emphasis added). Dr. Thisted is not a medical doctor and
`
`has no expertise in PK/PD, and he made no statement that he relied on a medical
`
`treatment or PK/PD expert to support such strong characterizations.
`
`36.
`
`In my experience as a biostatistician, it is inappropriate to offer
`
`opinions such as these, that are clearly outside the expertise of even the most
`
`experienced statisticians.
`
`I would not feel comfortable opining on, for example,
`
`whether a skilled artisan would have expected therapeutic efficacy, the details of a
`
`drug’s predicted or actual dose-response curve, or whether observed therapeutic
`
`efficacy of 480 mg/day dimethyl fumarate was “stunning.” Id. ¶ 23, 33, 44, 45. I
`
`have reviewed Dr. Thisted’s qualifications, as outlined by him in his previous
`
`report (id. ¶¶ 2–11), and I do not see any experience that would render Dr. Thisted
`
`21
`
`Sawai (IPR2019-00789), Ex. 1004, p. 021
`
`
`
`qualified to give the sweeping therapeutic efficacy opinions that he gave to support
`
`Biogen’s case.
`
`22
`
`Sawai (IPR2019-00789), Ex. 1004, p. 022
`
`
`
`I declare that all statements made herein on my own knowledge are true and
`
`that all statements made on information and belief are believed to be true, and
`
`further, that these statements were made with the knowledge that willful false
`
`statements and the like so made are punishable by fine or imprisonment, or both,
`
`under Section 1001 of Title 18 of the United States Code.
`
`Dated: July 13, 2018
`
`23
`
`Sawai (IPR2019-00789), Ex. 1004, p. 023
`
`
`
`EXHIBIT A
`EXHIBIT A
`
`Sawai (IPR2019-00789), Ex. 1004, p. 024
`
`Sawai (IPR2019-00789), Ex. 1004, p. 024
`
`
`
`CURRICULUM VITÆ
`(updated April14, 2017)
`
`Ian W. McKeague
`Department of Biostatistics
`Columbia University
`722 West 168th Street, 6th Floor
`New York, NY 10032-2603
`
`EDUCATION
`Statistics
`Ph.D.
`1977–1980
`University of North Carolina at Chapel Hill
`Mathematics
`1975–1976 M.Math.
`University of Cambridge
`1972–1975 B.A. (1st class hons.), M.A. Mathematics
`University of Cambridge
`Ph.D. thesis: Covariance Operators and their Applications in Probability and Information Theory.
`Advisor: C. R. Baker.
`
`PROFESSIONAL EXPERIENCE
`2004–present
`Professor of Biostatistics, Columbia University
`2000–2004
`Ralph A. Bradley Professor of Statistics, Florida State University
`1996–1999
`Chairman, Department of Statistics, Florida State University
`1991–2000
`Professor, Department of Statistics, Florida State University
`1986–1991
`Associate Professor, Dept. of Statistics, Florida State University
`1980–1986
`Assistant Professor, Dept. of Statistics, Florida State University
`Nov–Dec 1991
`Visiting MSRI, University of California, Berkeley
`Visiting Universit´e Joseph Fourier, Grenoble, France
`Feb–May 1992
`June–July 2001 Visiting Universit´e Joseph Fourier, Grenoble, France
`May–June 1985 Visiting University of Padua, Italy
`
`RESEARCH INTERESTS
`Post-selection inference, functional data analysis, empirical likelihood, non-standard asymptotics, statistical methods
`for tr
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