UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________________________________
`
`TWI PHARMACEUTICALS, INC.,
`Petitioner,
`v.
`MERCK SERONO S.A.,
`Patent Owner.
`_________________________________________________
`Case IPR2023-00049
`Patent 7,713,947
`
`Case IPR2023-00050
`Patent 8,377,903
`____________________________________________________
`
`DECLARATION OF ALAIN MUNAFO, Ph.D.
`
`Merck 2053
`TWi v Merck
`IPR2023-00049
`
`
`_______________________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________________________________
`
`TWI PHARMACEUTICALS, INC.,
`Petitioner,
`v.
`MERCK SERONO S.A.,
`Patent Owner.
`_________________________________________________
`Case IPR2023-00049
`Patent 7,713,947
`
`Case IPR2023-00050
`Patent 8,377,903
`____________________________________________________
`
`DECLARATION OF ALAIN MUNAFO, Ph.D.
`
`Merck 2053
`TWi v Merck
`IPR2023-00049
`
`
`
`
`
`
`I, Alain Munafo, Ph.D., declare as follows:
`
`IPR2023-00049, IPR2023-00050
`U.S. Patent Nos. 7,713,947, 8,377,903
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`I.
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`INTRODUCTION
`I am over eighteen years of age, and I am competent to testify as to
`1.
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`the matters set forth herein if I am called upon to do so.
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`2.
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`I submit this Declaration on behalf of Merck Serono S.A. (“Patent
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`Owner”) for consideration by the Patent Trial and Appeal Board in the following
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`Inter Partes Review proceedings: IPR2023-00049 (“’049 IPR”) and IPR2023-
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`00050 (“’050 IPR”). I understand that the ’049 IPR corresponds to Inter Partes
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`Review of U.S. Patent No. 7,713,947 (“the ’947 patent”) (Ex. 1001) and the ’050
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`IPR corresponds to Inter Partes Review of U.S. Patent No. 8,377,903 (“the ’903
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`patent”) (Ex. 1002).
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`3.
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`I am being compensated for my time in preparing this declaration at
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`my usual consulting rate of 450 Swiss Francs per hour. My compensation is in no
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`way contingent on the substance of my testimony or the outcome of this or any
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`other proceeding.
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`4.
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`I am a named co-inventor of both the ’947 patent and the ’903 patent.
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`When U.S. Provisional Application No. 60/638,669 and European Provisional
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`Application No. EP04106909, to which the ’947 patent and the ’903 patent claim
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`priority, were filed on December 22, 2004, and for more than two years before
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`1
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`then, I was working with other co-inventors of the ’947 patent and the ’903 patent
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`to design and develop an oral dosing regimen for cladribine.”
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`5.
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`I am providing this declaration as a co-inventor of the ’947 patent and
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`the ’903 patent and as someone knowledgeable about the relationship and joint
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`research and development agreement between the teams at Serono1 and IVAX.2
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`6.
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`I have reviewed copies of U.S. Pat. No. 7,888,328 (“Bodor ’328”) and
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`PCT Application WO 2004/087101 (“Bodor PCT”) which were provided to me by
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`counsel. I understand Bodor ’328 is numbered Ex. 1029 in both IPRs and the
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`Bodor PCT is numbered Ex. 1007 in both IPRs. Bodor ’328 and the Bodor PCT
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`each name Drs. Bodor and Dandiker as co-inventors.
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`7.
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`Bodor ’328 includes the following disclosure of a regimen for treating
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`multiple sclerosis (MS) using cladribine:
`
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`1 Serono S.A. is a subsidiary of Patent Owner, Merck Serono S.A. I collectively
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`refer to Ares Trading S.A., its parent Serono S.A., and their other affiliates
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`including Serono International S.A. and Serono Inc., between 2002 and 2004, as
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`“Serono” throughout this declaration.
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`2 I understand that IVAX Corporation is an affiliate of IVAX International GmbH.
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`I collectively refer to IVAX Corporation and IVAX International GmbH as
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`“IVAX” throughout this declaration.
`
`2
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`At the present time, it is envisioned that, for the treatment
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`of multiple sclerosis, 10 mg of cladribine in the instant
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`complex cladribine-cyclodextrin complex in the instant
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`solid dosage form would be administered once per day for
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`a period of five to seven days in the first month, repeated
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`for another period of five to seven days in the second
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`month, followed by ten months of no treatment.
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`’049 Ex. 1029, 13:19-25; ’050 Ex. 1029, 13:19-25. The Bodor PCT contains the
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`same language. ’049 Ex. 1007, 23:15-20; ’050 Ex. 1007, 23:15-20.
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`8.
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`Bodor ’328 (and the Bodor PCT) also include a disclosure of an
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`“alternative” regimen for treating multiple sclerosis (MS) using cladribine:
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`Alternatively the patient would be treated with 10 mg of
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`cladribine in the instant complex cladribine-cyclodextrin
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`complex in the instant dosage form once per day for a
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`period of five to seven days per month for a total of six
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`months, followed by eighteen months of no treatment.
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`’049 Ex. 1029, 13:25-30; ’050 Ex. 1029, 13:25-30; ’049 Ex. 1007, 23:20-24; ’050
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`Ex. 1007, 23:20-24.
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`9.
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`The Bodor PCT also includes a reference to two provisional
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`applications apparently filed by IVAX. ’049 Ex. 1007, 23:24-29; ’050 Ex. 1007,
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`3
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`
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`23:24-29. I was not aware of these provisional applications. And I do not know
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`their subject matter.
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`10.
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`In addition to my recollection and my review of Bodor ’328 and the
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`Bodor PCT, I reviewed the materials cited herein, which refreshed my memory
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`about some details of what occurred from 2002 to 2004.
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`II. BACKGROUND
`I was the former Global Head of Quantitative Pharmacology and then
`11.
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`Executive Scientific Director in Translational Medicine at Merck Serono and am
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`currently retired. My whole professional career relates to clinical pharmacology
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`and pharmaceutical experience, including 27 years in the pharmaceutical industry.
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`My work at Serono (including at Merck Serono) focused on clinical pharmacology,
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`pharmacodynamics and pharmacokinetics, and translational aspects thereof. My
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`work supported Merck Serono’s drug development from concept phase in
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`discovery through late-stage clinical development programs, including regulatory
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`submissions. I have also lectured on bioanalytics, clinical pharmacology, and drug
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`development science, in particular at the School of Pharmacy, Lausanne
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`University, and Lausanne University Hospital, Switzerland. A copy of my current
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`CV is attached as Appendix A.
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`12.
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`I received my Pharmacists Diploma from Lausanne University in
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`1980 and a Ph.D. in Pharmacy from Lausanne University in 1985. I completed a
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`4
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`
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`1.5-year postdoctoral fellowship in Pharmacokinetics at UCSF with Professor L.Z.
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`Benet, were I studied the formation and binding of a tolmetin metabolite
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`(acylglucuronide) in humans.
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`13. Throughout my career, my work has focused on my core expertise in
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`clinical pharmacokinetics and pharmacodynamics, and I have participated in
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`multiple drug development projects and initiatives. Following my postdoctoral
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`fellowship, I spent 5 years in the Clinical Pharmacology division of Lausanne
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`University Hospital. Then I joined Serono as associate director in Clinical
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`Pharmacology in 1993, while continuing to lecture at the School of Pharmacy at
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`Lausanne University.
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`14. At Serono, I took successive roles in Serono’s Clinical Pharmacology,
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`Pharmacometrics, Human Pharmacology, and Experimental Medicine groups. In
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`those roles, I provided strategic and scientific input to Serono’s clinical programs
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`and pre-clinical programs, with special emphasis in study design and data
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`interpretation. I worked as a member of several drug development project teams,
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`including cladribine for treating multiple sclerosis, atacicept for treating
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`rheumatoid arthritis, Iturelix (a growth hormone releasing factor), recombinant
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`proteins for reproductive health (FSH, LH, hCG), Interferon-ß-1a, TNF Binding
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`Protein, and Leukemia Inhibitory Factor.
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`5
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`15.
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`In 2006, Merck acquired Serono and confirmed me in my role. At
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`Merck Serono, I headed the Modelling and Simulation group for 8 years from 2006
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`to 2014. In 2014, I became Merck Serono’s Global Head of Quantitative
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`Pharmacology. In that role, I oversaw Merck Serono’s deterministic and stochastic
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`modelers (from Quantitative Systems Pharmacology to Pharmacometry), clinical
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`pharmacokineticists, and clinical pharmacologists to drive and support the
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`discovery, development and commercialization of innovative medicines for
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`patients. I held that role until February 2020, when, in anticipation of my
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`retirement, I took the role of Executive Scientific Director, providing strategic and
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`scientific advice to Merck Serono’s Translational Medicine programs. I retired in
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`June 2021.
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`16.
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`I have co-authored over 70 publications in peer-reviewed journals and
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`presented numerous posters and presentations at international conferences. I have
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`been a member of several professional societies. I was a fellow of the American
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`Association of Pharmaceutical Scientists (AAPS), the Population Approach Group
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`in Europe (PAGE), and the American Society for Clinical Pharmacology and
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`Therapeutics (ASCPT). I have also received patents for my work on cladribine
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`regimens for treating multiple sclerosis and the use of TACI-Ig fusion protein for
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`the manufacture of a medicament for treating lupus erythematosus.
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`6
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`III. DEVELOPMENT OF MAVENCLAD BY SERONO
`17. From 2001 through several years after 2004, I was part of a team at
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`Serono that was researching and developing an oral dosing regimen using
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`cladribine to treat multiple sclerosis (“MS”). My team at Serono started
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`investigating whether cladribine could be used to treat multiple sclerosis in 2001.
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`We pursued cladribine as a potential treatment for MS based on its effects on some
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`biomarkers of MS, but it had not been demonstrated whether cladribine could
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`actually be used safely and effectively to treat MS and, if so, what cladribine
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`dosing regimen might be appropriate. Therefore, in 2003 and 2004, we at Serono
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`were investigating whether a safe and effective oral cladribine regimen could be
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`designed through some combination of particular dosages, lengths of dosing
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`periods, and lengths of cladribine-free periods, in addition to otherwise planning
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`and designing Phase III trials to evaluate whether the dosing regimens were safe
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`and effective.
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`18. My team at Serono included my co-inventors of the ’947 patent and
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`the ’903 patent, Drs. Lopez-Bresnahan, Ythier, and De Luca, along with many
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`others.
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`19. Dr. Ythier, who was my supervisor at the time, and I researched and
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`investigated pharmacokinetics of cladribine to be used in treating patients with
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`MS, with the goal of developing dosing regimens that would be safe and effective.
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`7
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`We then used our findings to help design clinical study protocols for Phase III
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`studies of cladribine for treating MS, focusing on what dose and dosing regimen
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`would allow safe, effective treatment.
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`20. Dr. Lopez-Bresnahan and her team worked with us to design the
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`dosing regimen for the Phase III study protocol(s), designing the inclusion and
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`exclusion criteria, study assessments, and discontinuation criteria (in collaboration
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`with statisticians), and planning all necessary elements to ensure the study was safe
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`and statistically meaningful to demonstrate doses were safe and effective. She then
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`directed and helped manage the Phase III trials.
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`21. Dr. De Luca was Serono’s Chief Intellectual Property Counsel. His
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`discussions with various team members during the development of cladribine for
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`treating MS contributed to our development of a proposed dosing regimen.
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`22. The work of our team at Serono ultimately led to the development of
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`the drug Mavenclad® and its unique dosing regimen, which is approved by the
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`FDA, and the authorities in many other countries, to treat MS. Our work also led
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`to patents, including the ’947 patent and the ’903 patent, which claim dosing
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`regimens for treating MS.
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`8
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`IV. COLLABORATION WITH IVAX
` In October, 2002, Serono partnered with IVAX to develop an oral
`23.
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`formulation of cladribine. Ex. 2048.3 I refer to this agreement between Serono
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`and IVAX, which is titled “Product Development and License Agreement,” as the
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`“Joint Research Agreement.” Id. The Joint Research Agreement defined the
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`respective roles of Serono and IVAX as follows.
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`24.
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`IVAX agreed to “develop an oral dosage formulation of [cladribine]
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`in tablet or capsule form suitable for use in clinical trials and commercial sale.”
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`Id., 19-20 (emphasis added). IVAX also agreed to conduct Phase I trials of its
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`cladribine formulation, which the Joint Research Agreement described as “a
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`pharmacokinetic study,” and to furnish Serono with its results and “all data,
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`information and documentation reasonably required to enable [Serono] to carry out
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`the clinical trials necessary for health authority approvals.” Id., 20-21.
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`25. Serono agreed to “conduct clinical trials,” to determine “the dose,
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`safety, and/or efficacy” of cladribine’s oral tablets or capsules. Id., 2, 17-18.
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`Serono also agreed to “assume all responsibilities and costs associated with
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`statistics and data management, regulatory affairs, clinical quality assurance, safety
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`3 All citations to Patent Owner’s Exhibits are in reference to Patent Owner’s
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`exhibits filed contemporaneously in IPR2023-00049 and IPR2023-00050.
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`studies toxicology and the clinical development of the [final product].” Id., 20-21.
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`Further, Serono agreed to “obtain necessary health authority approvals, and market
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`the final product in the United States and all [major European countries].” Id., 17-
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`18, 22.
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`26. After signing the Joint Research Agreement, IVAX and Serono each
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`performed their respective roles in developing cladribine for treating MS, as
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`agreed. E.g., Ex. 2050; Ex. 2049. IVAX developed an oral dosage formulation of
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`cladribine—solid tablets containing what they called a “complex cladribine-
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`cyclodextrin complex”—and performed Phase I pharmacokinetic (“PK”) studies
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`using a single dose of their formulation. E.g., ’049 Ex. 1007, 33:24-25; ’050 Ex.
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`1007, 33:24-25 (“This study was a 2 center, open-label, randomized, 4-way
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`crossover single dose study using twelve patients with MS.”). Drs. Bodor and
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`Dandiker were both part of the IVAX team who collaborated with my team at
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`Serono. Using IVAX’s oral dosage formulation, my team at Serono developed a
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`dosing regimen for treating MS and performed several Phase I trials, as well as
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`Phase III clinical trials using this regimen, that ultimately led to regulatory
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`approval of MAVENCLAD® (tablets comprising IVAX’s formulation dosed
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`according to our regimen) for treating MS.
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`10
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`27. Confidential communication between the Serono team and the IVAX
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`team took place both at meetings (both in person and by telephone), where formal
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`presentations were made, and by e-mail.
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`28. The IVAX and Serono teams met or corresponded regularly to discuss
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`project progress and various issues. For example, the teams from Serono and
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`IVAX met in Amsterdam on August 27, 2003 to discuss the development of
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`cladribine for treating MS. Ex. 2050. The minutes of that meeting show that Dr.
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`Steve Marcus and Dr. Yogesh Dandiker of IVAX attended the meeting. Dr.
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`Marcus presented on “Phase I studies” for the “cyclodextrin formulation” of
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`cladribine. Id., 2-3. Dr. Dandiker, a co-inventor of Bodor ’328, and D. Emma
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`(also of IVAX) presented on “Formulation progress” for soft gel, hard gel, and
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`tablet formulations of cladribine. Id., 3-4. Dr. Lopez-Bresnahan from my team at
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`Serono, one of the co-inventors of the ’947 patent and the ’903 patent, presented
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`on “Phase III [study] design,” including doses and regimens for treating MS with
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`cladribine. Id., 4-5. I was present at that meeting and confirm that the minutes
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`accurately reflect the work Drs. Marcus, Dandiker, Emma, and Lopez-Bresnahan
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`discussed.
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`29. As another example, on December 17, 2003, Isabelle Emery of
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`Serono emailed a draft Regulatory Briefing Document to the team at Serono,
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`including me, and the team at IVAX, including Dr. Dandiker, the co-inventor of
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`11
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`Bodor ’328, and Dr. Marcus. Ex. 2049, 1. The Regulatory Briefing Document,
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`which I contributed to, contained a “Proposed Phase 3 Study” designed and
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`developed by Serono inventors. Id., 47-51. This email asked various members of
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`the Serono and IVAX teams to review portions of the Briefing Document. Id., 1-3.
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`In particular, Dr. Dandiker of IVAX was asked to review the section on
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`“Chemistry, Manufacturing, and Controls,” which addressed the formulation of
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`cladribine, how it was to be manufactured, and the quality control processes to be
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`used. Id. I was asked to review the section on “Pharmacokinetics and
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`Pharmacodynamics.” Id. And Dr. Lopez-Bresnahan from my team at Serono was
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`asked to review the entire document, including the section on the “Clinical
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`Development Plan,” which included the dosage and regimens to be administered to
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`patients. Id. This distribution of tasks reflected the distribution of responsibilities
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`as per the Joint Research Agreement.
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`V. COMMUNICATIONS BETWEEN SERONO AND IVAX
`In the Joint Research Agreement, Serono and IVAX agreed to
`30.
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`confidentially share information and communicate frequently about the ongoing
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`development of cladribine for treating MS. Ex. 2048, 18, 22. IVAX agreed to
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`furnish Serono with the results of its Phase I pharmacokinetic trials of an oral
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`dosage formulation of cladribine and “all data, information and documentation
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`reasonably required to enable [Serono] to carry out the clinical trials necessary for
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`12
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`health authority approvals.” Id., 20-21. Serono agreed to “keep [IVAX] generally
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`informed as to [Serono’s] progress in these efforts” (that is, in determining dosage
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`regimens, planning, designing, and conducting Phase III trials, obtaining regulatory
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`approval, and marketing and selling the final product). Id., 22. The parties
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`mutually agreed that information they shared would be kept confidential and would
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`“not be disclosed to third parties and [would] be made available only to recipient’s
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`employees or independent contractors who agree in writing to equivalent
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`conditions and who have a need to know the information for the purposes specified
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`under [the agreement].” Id., 30.
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`31. To facilitate this communication, the Joint Research Agreement
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`established a “Joint Development Committee…comprising at least two
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`representatives from each” of Serono and IVAX. Id., 18. This Joint Development
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`Committee was required to meet “as often as necessary,” and at least “within sixty
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`(60) days…” Id. This Joint Development Committee did meet regularly through
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`2003 and 2004. E.g., Ex. 2050. For example, as I will describe in more detail
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`below, our teams met in Amsterdam on August 27, 2003 to discuss our respective
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`progress of Phase I trials, formulation work, and planning for Phase III trials. Ex.
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`2050. I was present at that meeting in Amsterdam, which also included Dr.
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`Dandiker of IVAX, co-inventor of Bodor ’328, and several other members of the
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`IVAX team, including Dr. Marcus. Id.
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`32.
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`In addition to formal meetings of the Joint Development Committee,
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`my team at Serono and the team at IVAX exchanged numerous emails and
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`documents. These emails included, for example, informal discussions and drafts of
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`regulatory documents. Recipients included Dr. Dandiker, Dr. Marcus, and several
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`other members of the IVAX team. For example, as I discuss in more detail both
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`above and below, on December 17, 2003, Isabelle Emery of Serono emailed a draft
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`Regulatory Briefing Document to my team at Serono and the IVAX team to ask
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`members of both teams to review the draft. Ex. 2049.
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`VI. SERONO TEAM’S DEVELOPMENT OF THE REGIMEN
`DISCLOSED IN THE BODOR PCT
`33. Ultimately, I and my team at Serono, and not anyone at IVAX, were
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`the first and only people to design and develop the regimen for treating MS which
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`is disclosed in Bodor ’328 (and the Bodor PCT to which it claims priority). The
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`IVAX team did not contribute to the design or development of that dosing regimen
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`or the unique weight-based regimen that we later claimed in the ’947 patent and
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`the ’903 patent.
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`34.
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`In particular, Dr. Lopez-Bresnahan and I, with the support of Drs.
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`Ythier and De Luca, designed a regimen for treating MS by administering oral
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`cladribine 10 mg tablets daily for 5-7 days per month for 2 months followed by a
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`10-month cladribine free period. This occurred before February 2004 (when, I am
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`informed by counsel, the first provisional application containing this disclosure,
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`14
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`U.S. Application No. 60/541,247, was filed by IVAX, naming only Dr. Bodor as
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`an inventor). Our development of the regimen in 2003 is documented, for
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`example, in the minutes of the August 2003 Amsterdam meeting, Ex. 2050, as well
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`as in the December 2003 Regulatory Briefing Document, Ex. 2049.
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`A. August 2003 Presentation
`35. By August 2003, I and my team at Serono had designed dosing
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`regimens where cladribine was administered orally for periods of five consecutive
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`days in a month, repeated each month until the target effective dose was reached.
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`Ex. 2050, 4-5. One particular regimen we had developed involved two months of
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`treatment: five consecutive days in the first month, then five consecutive days in
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`the second month.
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`36. My colleague Dr. Lopez-Bresnahan presented one such regimen at a
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`meeting in August 2003, which I described above. Id. The minutes of that
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`meeting show that Dr. Lopez-Bresnahan presented a “Phase III [study] design,”
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`including two regimens for treating MS with oral cladribine. Id. The minutes
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`identify the two regimens as “treatment arms” for the proposed study: one with a
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`“cumulative dose approximating 0.7 mg/kg” and one with a cumulative dose
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`approximating “2.1 mg/kg.” Id., 4. Certain other Serono documents refer to the
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`“0.7 mg/kg” dose as the “low” dose and to the “2.1 mg/kg” dose as the “high”
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`dose. E.g., Ex. 2049, 48.
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`37. The minutes also state that in both arms the doses would be delivered
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`as “5 days” per month for a number of months. Ex. 2050, 4-5. The low dose arm
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`would be delivered by a regimen of:
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`“5 days × 2 months.”
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`Id.4 She also stated that each dose would be delivered using one of IVAX’s oral
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`formulations, the development of which had been discussed earlier at that meeting.
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`38. As Dr. Lopez-Bresnahan described at the August 2003 meeting, the
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`two months of treatment (or, for the high dose arm, six months of treatment) were
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`followed by the remainder of the “[d]uration of treatment” which was “24
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`months.” Id. For patients in the low dose arm, who would receive cladribine
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`during 5-days in each of 2 months, the period without treatment would have been a
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`“cladribine-free period” of 22-months. For patients in the high dose arm, who
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`would receive six months of cladribine, the period without treatment would have
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`been a “cladribine-free period” of 18-months.
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`4 The minutes of the August 2003 Meeting describe this regimen as a “cumulative
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`dose approximating 0.7 mg/kg ([0].35 mg/kg × 5 days × 2 months).” Ex.2050, 4.
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`0.35 mg/kg is half the approximate cumulative dose, so this means 0.35 mg/kg per
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`month for 2 months, delivered over 5 consecutive days each month.
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`16
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`IPR2023-00049, IPR2023-00050
`U.S. Patent Nos. 7,713,947, 8,377,903
`
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`B. December 2003 Briefing Document
`39. By December 2003, I and my team at Serono had refined the dosing
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`regimens for the planned Phase III trial to use 10 mg solid tablets and have a
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`retreatment period 12 months after the first treatment period. Ex. 2049. Thus, in
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`the regimen my team at Serono had developed by December 2003, a two-month
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`initial treatment period would be followed by a ten-month cladribine-free period.
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`40. For example, on December 17, 2003, Isabelle Emery of Serono
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`circulated via email a draft Briefing Document to my team at Serono and to the
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`IVAX team, including Dr. Dandiker and Dr. Marcus, which I described above. Id.
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`This document included a description of our plan for Phase III trials of cladribine
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`for treating MS, which was developed by the Serono team, including Drs. Ythier,
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`Lopez-Bresnahan, De Luca, and me. Id., 47-51.
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`41. Similar to Dr. Lopez-Bresnahan’s August 2003 presentation, the study
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`treatment plan in the December 2003 Briefing Document included three arms,
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`which would receive a cumulative dose of 2.1 mg/kg, a cumulative dose of 0.7
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`mg/kg, or just placebo. Id., 47. This Briefing Document refers to these as the
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`“high,” “low,” and “placebo” doses. Id. It further discloses that patients in the
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`high or low dose arm will receive 10 mg solid tablets for “5-day consecutive
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`dosing” each month for a predetermined number of months, as discussed in more
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`detail below. Id., 13-18, 49.
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`17
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`42.
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`IPR2023-00049, IPR2023-00050
`U.S. Patent Nos. 7,713,947, 8,377,903
`
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` The December 2003 Briefing Document also described the design of
`
`the study in more detail, including the proposed dosing regimen and the “double-
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`blind” protocol. Id., 47-49. Double-blind study design, which avoids bias by
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`concealing from both the patients and the treating physicians which arm each
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`patient is in, is an important aspect of clinical studies like this proposed Phase III
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`trial. The longest active treatment duration in the study would be the high dose
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`arm. The December 2003 Briefing Document teaches that the high dose arm
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`would receive six months of active treatment:
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`“5-day[s] [/ month] × 6 [months]” = 2.1 mg/kg
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`Id., 49. This is the treatment schedule we described in the minutes of the August
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`2003 presentation, which describes the same high dose arm as:
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`5 days × 6 months
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`Ex. 2050, 4. As a result, a double-blind study design required 6 months of
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`“treatment” for every patient.
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`43. The planned high and low doses would have been delivered as either a
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`10 mg cladribine tablet or a placebo, as appropriate, to obtain the correct total dose.
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`Specifically, in the “Assignment to treatment groups” section of “Table 5.1-1:
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`Synopsis of the Proposed Phase 3 Study,” under “Blinding,” it states that “all
`
`patients receive [the] same number of tabs (i.e., low dose patients receive placebo
`
`to fill out high dose cycles, any decrease in active treatment dose is replaced with
`
`18
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`
`
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`placebo…).” Ex. 2049, 49. This Briefing Document summarizes the regimen as
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`IPR2023-00049, IPR2023-00050
`U.S. Patent Nos. 7,713,947, 8,377,903
`
`
`“6 cycles (high/low/placebo)” followed by 6 months of no treatment and then “6
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`cycles (low/low/placebo)” after 12 months. Id., 47-48.
`
`44. Thus, I and my team at Serono communicated that patients in the
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`“low” dose treatment arm (0.7 mg/kg) would receive two months of cladribine
`
`followed by 4 months of placebo. 0.7 mg/kg is exactly one-third of the 2.1 mg/kg
`
`“high” dose. Thus, at the same rate of treatment, a patient in the low dose arm
`
`would receive a 0.7 mg/kg dose in exactly one-third of the time:
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`0.7 mg/kg = 2.1 kg/mg / 3
`
`
`
`
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`= (5 days/month × 6 months) / 3
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`= 5 days/month × 2 months
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`This is the treatment schedule we described in the minutes of the August 2003
`
`presentation, which describes the same low dose arm as:
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`5 days × 2 months
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`Ex. 2050, 4.
`
`45. The December 2003 Briefing Document explained patients would
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`receive additional treatment 12 months after the first treatment began. Ex. 2049,
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`47-51. Although the Briefing Document describes this as “6 cycles” of “repeat
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`treatment … at 12-18 months …” Id., 48, 49 (patients “will receive blinded re-
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`treatment at 12-18 months”), it is clear from the context of the document that this
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`19
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`IPR2023-00049, IPR2023-00050
`U.S. Patent Nos. 7,713,947, 8,377,903
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`meant repeat treatment 12 months after the initial treatment, during months 13-18.
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`For example, if retreatment were to occur during each of months 12-18, that would
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`result in 7 cycles of retreatment, not the described “6 cycles.” Further, the Briefing
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`Document discloses that 3 phases, each with 6 cycles of treatment, added up to a
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`“36 month” duration. Id., 47-49. This shows that each phase would take 12
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`months—6 months of treatment and/or placebo (depending on which arm a patient
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`was in) followed by 6 months with no treatment—so the treatment in the second
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`phase would begin in month 13.
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`46. Therefore, patients in the “low” dose treatment arm would receive
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`treatment in months 1 and 2, placebos in months 3-6, and 6 months with no pills.
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`Id., 49. This would result in a 10-month “cladribine-free” period. This is
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`illustrated in the following figure, which I prepared:
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`
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`20
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`47.
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`IPR2023-00049, IPR2023-00050
`U.S. Patent Nos. 7,713,947, 8,377,903
`
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`In December 2003, we at Serono were also considering administering
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`cladribine to patients for 6 or 7 days per month, including in the low dose arm.
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`The December 2003 Briefing Document and the “Study Treatment” section were
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`in a draft stage. The Serono inventors discussed (e.g., during joint meetings that
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`IVAX attended) that certain parameters in the study protocol, such as the number
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`of days of cladribine dosing each month, might need minor adjustment, e.g., to 6 or
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`7 days per month.
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`48.
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`I and my team at Serono envisioned additional details of the proposed
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`Phase III trials, including additional details about the proposed dosing regimen,
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`that are not reflected in Bodor ’328, the Bodor PCT, or the ’247 provisional.
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`While the December 2003 Briefing Document includes the dosing regimens
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`disclosed in Bodor ’328, the Bodor PCT, and the ’247 provisional, the same is not
`
`true in reverse—Bodor ’328, the Bodor PCT and the ’247 provisional do not
`
`include all the details in our December 2003 Briefing Document. Thus, Bodor
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`’328 does not disclose the full scope of what my team at Serono envisioned or
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`communicated in 2003.
`
`49. After December 2003, I and my team at Serono continued our
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`development of regimens to treat MS using cladribine. Serono ultimately prepared
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`and submitted requests for regulatory approval of cladribine for treating MS. My
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`team at Serono, and not the team at IVAX, planned and conducted Phase III trials
`
`21
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`that studied different dosing regimens of cladribine for treating MS. IVAX
`
`IPR2023-00049, IPR2023-00050
`U.S. Patent Nos. 7,713,947, 8,377,903
`
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`provided its oral formulation but did not otherwise contribute to the design of the
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`dosing regimen. And my team at Serono, and not the team at IVAX, got
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`regulatory approval to market the resulting drug—Mavenclad®.
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`VII. THE SERONO TEAM COMMUNICATED ITS REGIMEN TO THE
`IVAX TEAM
`50. After I and my team at Serono designed both of the regimens
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`disclosed in Bodor ’328—the 2-month regimen which I understand Petitioner cites
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`and the 6-month “alternative” regimen—we confidentially communicated them to
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`the joint project team, including IVAX, for example at the August 2003 meeting
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`and in the December 2003 Regulatory Briefing Document, discussed above, well
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`before February 2004. The team at IVAX who received our communications
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`included at least Dr. Dandiker, one of the named inventors of Bodor ’328, and Dr.
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`Marcus.
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`51. For example, the August 27, 2003 presentation that I discussed above
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`was presented by my colleague Dr. Lopez-Bresnahan to members of the IVAX
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`team, including to Dr. Dandiker and Dr. Marcus, and communicated the then-
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`proposed dosing regimen of daily oral cladribine tablets for 5 days per month for
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`2-months followed by a 22-month cladribine-free period developed by my team at
`
`Serono. Ex. 2050, 4-5. It also communicated to the IVAX team my team at
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`Serono’s alternative dosing regimen of daily oral cl
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