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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`RANBAXY LABORATORIES LTD and RANBAXY INC.,
`Petitioners
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`v.
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`ADAMAS PHARMACEUTICALS, INC.,
`Patent Owner
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`Inter Partes Review No.: 2015-00410
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`U.S. Patent No. 8,362,085
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`DECLARATION OF ARTHUR H. KIBBE, Ph.D.
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`IPR2015-00410
`Petitioners' Ex. 1002
`Page 1
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`I, Arthur H. Kibbe, Ph.D., declare and state as follows:
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`I.
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`1.
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`QUALIFICATIONS
`I am a Tenured Professor in the Department of Pharmaceutical Sciences at
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`Wilkes University Nesbitt School of Pharmacy in Wilkes-Barre, Pennsylvania. I have
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`held this position since 1994. From 1994 to 2012, I was Chair of the Department of
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`Pharmaceutical Sciences at Wilkes University Nesbitt School of Pharmacy.
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`2. My areas of expertise include drug product formulation, pharmacokinetics
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`and biopharmaceutics. I have over 40 years of experience working directly or
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`indirectly with the pharmaceutical industry, the Food and Drug Administration
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`(FDA), professional and trade associations, and academia.
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`3.
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`I received my Bachelor of Science in Pharmacy in 1966 from Columbia
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`University in New York City and received both my Master of Science and Ph.D. in
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`Pharmaceutical Sciences from the University of Florida in 1968 and 1973,
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`respectively. My Ph.D. includes a specialty in Pharmacokinetics and
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`Biopharmaceutics, as well as formulation design and development.
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`4.
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`I am a Fellow of the Academy of Pharmaceutical Research and Science, and
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`a member of Rho Chi Honorary Pharmaceutical Society. Since 2000, I have been a
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`Member of the Food and Drug Administration’s Scientific Advisory Committee, and I
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`served as chairman of the committee from 2001-2004. I have also been a consultant
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`to the Subcommittee on Oversight of the Energy and Commerce Committee of the
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`United States Congress (1990 to 1992). I also have been a member of the FDA’s
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`IPR2015-00410
`Petitioners' Ex. 1002
`Page 2
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`Generic Drug Advisory Committee and was Chairman of a special panel appointed by
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`the FDA Commissioner to investigate Fairness in the Generic Drug Approval
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`Process.
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`5.
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`I was Editor-in-Chief of the Handbook of Pharmaceutical Excipients, 3rd Edition
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`and also a contributing author of several monographs. I was on the Steering
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`Committee of the Handbook of Pharmaceutical Excipients, 2nd, 4th, 5th, and 6th Editions. I
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`continue to serve on the Steering Committee for upcoming editions, and continue to
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`contribute to many of the monographs.
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`6.
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`A copy of my curriculum vitae, which includes a more detailed description
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`of my credentials and a list of my publications, is attached hereto as Appendix A.
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`7.
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`I am being compensated $500 per hour for work performed for this matter.
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`My compensation is not dependent on the outcome of this matter.
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`II.
`8.
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`MATERIALS REVIEWED
`In forming my opinions, I have reviewed, among other things, U.S. Patent
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`No. 8,362,085 (“the ’085 patent,” Ex. 1001) and papers filed in the U.S. Patent and
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`Trademark Office (“PTO”) in connection with prosecution of the application that
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`issued as the ’085 patent and the applications leading to the ’085 patent, which I
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`understand to constitute the prosecution history of the ’085 patent. I have also relied
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`upon my accumulated scientific knowledge and experience. I have further reviewed
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`numerous patents and printed publications. A full list of materials I have considered
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`can be found attached hereto as Appendix B.
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`IPR2015-00410
`Petitioners' Ex. 1002
`Page 3
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`III.
`9.
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`LEGAL STANDARDS
`In this section I describe my understanding of certain legal standards. I have
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`been informed of these legal standards by Petitioners’ attorneys. I am not an
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`attorney, and I am relying only on instructions from Petitioners’ attorneys for these
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`legal standards. I have applied these understandings in my analysis as detailed below.
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`10.
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`I understand that in order to receive a patent, an inventor must invent or
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`discover a new and useful process, machine, manufacture, or composition of matter.
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`11.
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`I understand that patent protection may be granted for any new and useful
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`process, machine, manufacture, or composition of matter, or any new and useful
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`improvement thereof.
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`A. The Ordinarily-Skilled Artisan
`12. With respect to the level of ordinary skill in the art at the relevant times
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`applicable to the ’085 patent, I understand that factors such as the education level of
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`those working in the field, the sophistication of the technology, the types of problems
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`encountered in the art, the prior art solutions to those problems, and the speed at
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`which innovations are made may help establish the level of skill in the art. I also
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`understand that one with ordinary skill has the ability to understand the technology
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`and make modest adaptations or advances, with ordinary creativity, and is not an
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`automaton.
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`13.
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`I am advised that patents are addressed to a person who is described as
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`having “ordinary skill in the art,” who sets the standard by which patents are
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`IPR2015-00410
`Petitioners' Ex. 1002
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`interpreted and determines the extent to which they represent an improvement in the
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`art. I have been advised that several factors may be considered in determining the
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`level of “ordinary skill in the art,” including: the education of those who worked in
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`the field of the invention, including the inventor and others; the nature of the
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`challenges typically encountered in the relevant art; and how the prior art has
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`provided solutions to those challenges.
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`14.
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`It is my opinion that a person of ordinary skill in the art for the subject
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`matter of the claims of the ’085 patent would possess a relatively high level of skill.
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`This person would have at least a Master’s degree or Ph.D. degree in the field of
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`pharmaceutical sciences or a related discipline, as well as several years of experience
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`formulating pharmaceutically active compounds in various dosage forms, including
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`immediate and sustained release dosage forms. If such a person were to have a higher
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`degree of experience, that person could have a lower level of formal education. A
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`person of ordinary skill in the art would collaborate with others who have expertise in
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`methods of treating Alzheimer’s disease and dementia. A person of ordinary skill in
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`the art would understand the references referred to herein and have the capability to
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`draw inferences from them.
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`15.
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`I consider myself to have been an expert in the art of the ’085 patent at the
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`time of the alleged inventions claimed therein.
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`16.
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`B.
`Claim Construction
`I understand that the first step in interpreting patent claims is to properly
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`IPR2015-00410
`Petitioners' Ex. 1002
`Page 5
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`construe the claims to determine claim scope and meaning. I understand that claim
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`language is read in light of the whole patent, including the other claims, the
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`specification, and the prosecution history as it would be interpreted by one of
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`ordinary skill in the art. The meaning of a claim term is the ordinary and customary
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`meaning of the term to a person of ordinary skill at the time of the invention unless
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`the patentee provides a special definition of that term.
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`17.
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`I understand that in Inter Partes Review proceedings the claim terms are
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`presumed to take on their ordinary and customary meaning based on the broadest
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`reasonable interpretation of the claim language. It is my opinion that Applicants did
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`not attributed any special meanings to the claim terms in the ’085 patent.
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`C.
`Prior Art
`I understand that a patent or other publication must first qualify as prior art
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`18.
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`before it can be used to invalidate a patent claim. I understand that documents and
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`materials that qualify as prior art can be used to render a claim unpatentable as
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`anticipated under 35 U.S.C. § 102 or as obvious under 35 U.S.C. § 103.
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`19.
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`I understand that the “priority date” of a patent is taken to be the date on
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`which the application leading to the patent is filed. I have been informed by counsel
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`that a patent can have an earlier priority date if earlier applications in the chain leading
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`to the patent show that the inventors possessed the later-claimed subject matter when
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`they filed the earlier applications.
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`20.
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`I further understand that the “critical date” for a patent claiming priority to
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`IPR2015-00410
`Petitioners' Ex. 1002
`Page 6
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`U.S. applications is one year prior to its priority date. It is my understanding that
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`publications prior to the critical date are prior art that can render a patent claim
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`unpatentable regardless of the purported date of invention.
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`D. Anticipation
`I have been instructed by counsel on the law regarding anticipation, and
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`21.
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`understand a claim is unpatentable as anticipated under 35 U.S.C. § 102 of the Patent
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`Act if the claimed invention was patented or published anywhere more than one year
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`prior to the priority date of the patent application (i.e., was patented or published
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`before the “critical date”). I understand that a U.S. or foreign patent qualifies as prior
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`art under § 102(b) to a patent claim if the date of issuance of the patent is more than
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`one year before the priority date of the claim. I further understand that a printed
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`publication, such as an article published in a magazine or trade publication or a
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`published U.S. or foreign patent application, also qualifies as prior art under § 102(b)
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`to a patent claim if the publication occurs more than one year before the priority date
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`of the claim.
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`22.
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`I have also been instructed by counsel that in order for a claim to be
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`anticipated, every limitation of the claimed invention must be disclosed in a single
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`prior art reference, either explicitly or inherently.
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`E. Obviousness
`I have been instructed by counsel on the law regarding obviousness, and
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`23.
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`understand that a patent is unpatentable if the differences between the claimed subject
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`IPR2015-00410
`Petitioners' Ex. 1002
`Page 7
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`matter and the prior art are such that the subject matter as a whole would have been
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`obvious at the time the invention was made to a person of ordinary skill in the
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`pertinent art.
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`24.
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`I have been instructed by counsel that the “time of the invention” for the
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`purposes of the ’085 patent is April 6, 2005. I also have been instructed that the
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`“critical date” is April 6, 2004. In my analyses below, I consider the ordinarily skilled
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`artisan’s understanding as of April 6, 2005, but confirm that my opinions remain the
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`same even if applying the April 6, 2004 date.
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`25.
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`I understand that a person of ordinary skill in the art uses the priority date as
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`a reference point from which the prior art and claimed invention should be viewed.
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`This reference point prevents one from using his or her own insight or hindsight in
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`deciding whether a claim is obvious. Thus, “hindsight reconstruction” cannot be used
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`to combine references together to reach a conclusion of obviousness.
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`26.
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`I also understand that an obviousness determination includes the
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`consideration of various factors such as (1) the scope and content of the prior art, (2)
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`the differences between the prior art and the claims, (3) the level of ordinary skill in
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`the pertinent art, and (4) the existence of secondary considerations of non-
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`obviousness.
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`27.
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`I have been informed and understand that the obviousness analysis requires
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`a comparison of the properly construed claim language to the prior art to determine
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`whether the claimed subject matter as a whole would have been obvious. A claimed
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`IPR2015-00410
`Petitioners' Ex. 1002
`Page 8
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`invention can be obvious when, for example, there is some teaching, suggestion, or
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`motivation in the prior art that would have led one of ordinary skill to modify a prior
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`art reference or to combine prior art reference teachings to arrive at the claimed
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`invention. In other words, even if one reference does not show the whole of the
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`invention, if it would have been obvious to a person of ordinary skill in the art at the
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`relevant time to add the missing pieces (for example as a matter of standard
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`engineering practice or application of a well-known principle in the field), then a
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`single reference can render a claim invalid even if it does not show the whole
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`invention. Moreover, a combination of two or more references can render a claim
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`invalid as obvious whether or not there is an explicit suggestion in one of the
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`references to combine the two references, if as a matter of engineering skill or practice
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`in the field it would be known to do so.
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`28. And as stated above, I understand that secondary considerations must be
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`examined to determine whether a claimed invention would have been obvious to one
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`of ordinary skill in the art and that these include:
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`(1) any long-felt and unmet need in the art that was satisfied by the
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`invention of the patent;
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`(2) any failure of others to achieve the results of the invention;
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`(3) any commercial success or lack thereof of the products and processes
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`covered by the invention;
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`(4) any deliberate copying of the invention by others in the field;
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`IPR2015-00410
`Petitioners' Ex. 1002
`Page 9
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`(5) any taking of licenses under the patent by others;
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`(6) any expression of disbelief or skepticism by those skilled in the art upon
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`learning of the invention;
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`(7) any unexpected results achieved by the invention;
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`(8) any praise of the invention by others skilled in the art; and
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`(9) any lack of contemporaneous and independent invention by others.
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`IV. SUMMARY OF OPINIONS AND EXPECTED TESTIMONY
`29.
`It is my opinion that claims 1 and 7 of the ’085 patent are anticipated by U.S.
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`Patent No. 8,039,009 (“Rastogi,” Ex. 1007).
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`30.
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`It is further my opinion that the subject matter of each of claims 1–12 of the
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`’085 patent would have been obvious over U.S. Patent 5,382,601 (“Nürnberg,” Ex.
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`1009) in view of Efficacy and Tolerability of Memantine in Patients with Dementia Syndrome
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`(K. Ditzler, 1991, hereinafter “Ditzler,” Ex. 1010), PCT International Publication No.
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`WO 2004/012741 (“the ’741 PCT,” Ex. 1011), and the Namenda 2003 Label, Ex.
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`1014.
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`31.
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`It is further my opinion that the subject matter of each of claims 1–12 would
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`have been obvious from the ’741 PCT in view of Ditzler and the Namenda 2003
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`Label.
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`32.
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`It is further my opinion that the subject matter of each of claims 1–12 would
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`have been obvious over Rastogi in view of Ditzler and the ’741 PCT.
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`IPR2015-00410
`Petitioners' Ex. 1002
`Page 10
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`V. OVERVIEW OF U.S. PATENT NO. 8,362,085
`A.
`Claims 1–12 of the ’085 Patent
`It is my opinion that the challenged claims of the ’085 patent are generally
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`33.
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`directed to a method for treating a patient with a neurological disorder such as
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`Alzheimer’s disease or dementia, that comprises administering a sustained release oral
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`dosage form once daily that contains a certain amount of memantine (either 22.5 to
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`30 mg, 25 to 30 mg, or 28 mg), which produces certain pharmacokinetic (PK)
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`parameters when administered. Ex. 1001 at Abstract.
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`34. While the claims of the ’085 patent refer to a “sustained release oral dosage
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`form,” the specification of the ’085 patent uses the terms “sustained release,”
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`“extended release,” “modified release” and “controlled release” interchangeably. Ex.
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`1001 at col. 2, ll. 39–43 and col. 3, ll. 23–25.
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`35. The claimed PK parameters each relate to the “change in mean plasma
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`concentration of memantine as a function of time,” or “dC/dT.” In different ways,
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`these PK parameters require that, when compared to an “immediate release” (or
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`“IR”) formulation, the initial rate of rise of the concentration of memantine in the
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`blood plasma produced by the claimed sustained release oral dosage form be slower.
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`For example, some claims require that the dC/dT of the claimed sustained release oral
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`dosage form be 50% or less than the dC/dT from time zero to Tmax of an IR
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`formulation containing the same amount of memantine. The specification of the ’085
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`patent indicates that the claimed sustained release oral dosage forms will reduce side
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`Petitioners' Ex. 1002
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`effects and increase patient compliance. Ex. 1001 at col. 7, l. 56–col. 8, l. 5.
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`B.
`Prosecution Background
`36. The ’085 patent was filed on June 28, 2012 with 30 claims directed to a
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`method of treating a neurological disorder. In a preliminary amendment on
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`September 6, 2012 during prosecution, applicants amended claims 1 and 13 to state
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`that the disorder to be treated included Alzheimer’s disease, dementia, Parkinson’s
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`disease, and neuropathic pain, and cancelled claims 3–4, 7–8, 11–12, 15–16, 19–20,
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`and 23–30. Ex. 1027 at 3–4.
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`37. On the day after the application was filed, a declaration by one of the
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`inventors, Dr. Gregory T. Went (“the Went declaration,” Ex. 1003), was submitted in
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`support of patentability. In the Went declaration, Dr. Went discussed basic
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`pharmacokinetic properties of memantine, as well as the results of several
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`experiments conducted comparing the pharmacokinetics and side effects of
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`immediate release memantine formulations of memantine with several sustained
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`release memantine formulations (referred to in the declaration as “extended release”
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`formulations). Dr. Went drew two conclusions in his declaration: (i) that there would
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`not have been a motivation to make a sustained release memantine dosage form
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`containing more than 20 mg of memantine, and (ii) that the sustained release
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`memantine formulation produced unexpected results. Ex. 1003 at ¶¶ 4, 6, 7, 13, 16.
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`38. Regarding motivation, Dr. Went concluded that one of ordinary skill in the
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`art would not have been motivated to make a sustained release formulation containing
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`IPR2015-00410
`Petitioners' Ex. 1002
`Page 12
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`22.5 to 30 mg of memantine for three reasons. First, Dr. Went stated that one of
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`ordinary skill would not have been motivated to make such a formulation because,
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`due to memantine’s relatively long half-life, immediate release formulations of
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`memantine already have a long duration of activity. Id. at ¶ 4. Second, Dr. Went
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`stated that the side effects of immediate release memantine formulations were
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`observed before memantine had reached its peak plasma concentration, and thus
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`reducing the peak plasma concentration by making a sustained release formulation
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`would not have been expected to reduce side effects. Id. at ¶ 6. Third, Dr. Went
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`stated that immediate release memantine was not well tolerated at doses higher than
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`20 mg/day. Id. at ¶ 7.
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`39. Regarding unexpected results, Dr. Went concluded that it was unexpected to
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`have a decrease in memantine-related side effects in the ER memantine formulations
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`having a dC/dT value less than 50% of the dC/dT of IR memantine formulation. Id.
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`at ¶ 13.
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`40. The examiner issued a Notice of Allowance to the Applicants on September
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`24, 2012 (Ex. 1004). While the applicants had argued (and Dr. Went had declared)
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`that there was both a lack of motivation to develop the claimed subject matter and
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`that there had been unexpected the results, the examiner only relied on the
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`unexpected results component in the allowance, stating:
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`The declaration demonstrates the unexpected results of the
`claimed method of treating a patient with Alzheimer’s
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`IPR2015-00410
`Petitioners' Ex. 1002
`Page 13
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`disease, dementia, Parkinson’s disease and neuropathic pain
`to reduce side effects that could not have been predicted by
`specifically reducing the plasma concentration as a function
`of time (dC/dT) of memantine to be less than 50% of than
`[sic] of an immediate release dosage form.
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`Ex. 1004 at 2.
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`C.
`Priority Date for the Claims of the ’085 Patent
`41. The application leading to the ’085 patent was filed on June 28, 2012. The
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`’085 patent claims priority to U.S. Patent Application No. 12/840,132, filed on July
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`20, 2010, which is a continuation of U.S. Patent Application 12/512,701, filed on July
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`30, 2009, currently U.S. Patent 8,168,209, which is a division of U.S. Patent
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`Application No. 11/285,905, filed on November 22, 2005, now U.S. Patent 7,619,007.
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`The ’701 application is also a continuation-in-part of application No. 11/399,879,
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`filed on April 6, 2006, currently U.S. Patent No. 8,058,291, and a continuation-in-part
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`of U.S. Patent Application No. 11/285,905.
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`42. The ’085 patent also claims priority to U.S. Provisional Application Nos.
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`60/630,885 (“the ’885 provisional application,” Ex. 1005), 60/701, 857 (“the ’857
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`provisional application”), 60/635,365 (“the ’365 provisional application,” Ex. 1006),
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`and 60/669,290 (“the ’290 provisional application”), filed on November 23, 2004, July
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`22, 2005, December 10, 2004, and April 6, 2005, respectively.
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`43.
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`It is my opinion that the earliest priority date to which the ’085 patent is
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`even potentially entitled is April 6, 2005, the filing date of the ’290 provisional
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`application, because the contents of ’885 and ’365 provisional applications do not
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`disclose all of the limitations of the claims of the ’085 patent. Specifically, in my
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`opinion, the ’885 and ’365 provisional applications do not disclose to one skilled in
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`the art at least four limitations required by the claims: (1) a sustained release oral
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`dosage form that provides a dC/dT that is “less than about 50% of the dC/dT
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`provided by the same quantity of an immediate release form of memantine,
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`determined in a time period between 0-Tmax of the immediate release form of
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`memantine” (Ex. 1001 at claims 1–6), (2) a sustained release oral dosage form that
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`provides a dC/dT that is “less than about 50% of the dC/dT provided by the same
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`quantity of an immediate release form of memantine, determined in a time period
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`between 0 hours and 6 hours of administration of memantine” (id. at claims 7–12), (3)
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`a sustained release oral dosage form that provides a dC/dT that is “2.1 ng/mL/hr or
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`less, determined in a time period of 0 to 4 hours” (id. at claims 1–12), or (4) a
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`sustained release oral dosage form that provides a dC/dT that is 2.1 ng/mL/hr or less
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`“determined in a time period of 2 to 4 hours” (id. at claims 2, 4, 6, 8, 10 and 12).
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`44. The ’885 provisional application is generally directed to “methods and
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`compositions for administering an NMDA receptor antagonist (e.g., memantine) to a
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`subject.” Ex. 1005 at Abstract; see also p. 3, ll. 13–17. The ’885 provisional application
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`also describes sustained release compositions. Id. at p. 3, ll. 18–23; p. 4, ll. 25–29; p.
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`6, l. 10–p. 10, l. 27. The ’885 provisional application provides no specific
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`pharmacokinetics of a sustained release memantine composition. Moreover, the
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`dC/dT parameters recited in the claims of the ’085 patent are not mentioned in the
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`’885 provisional application and cannot be calculated from the disclosure of the ’885
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`provisional application.
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`45. The ’365 provisional application is directed to methods for treating tuberous
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`sclerosis complex with an adamantine derivative, including memantine. Ex. 1006 at
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`3–4, 8–9. The ’365 provisional application makes only one mention of a sustained
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`release oral dosage form, stating: “[t]he formulations can be administered in either a
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`local or systemic manner or in a depot or sustained release fashion.” Ex 1006 at 12.
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`The ’365 provisional does not provide any pharmacokinetic parameters for such
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`formulations.
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`46.
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`It is my opinion that the ’885 and ’365 provisional applications would not
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`convey to a person of ordinary skill in the art that the inventors were in possession of
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`the subject matter claimed in the ’085 patent at the time these provisional applications
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`were filed. Accordingly, it is my opinion that the ’085 patent claims are not entitled to
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`claim priority to either of these provisional applications, and the earliest priority date
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`to which the claims of the ’085 patent are even possibly entitled is April 6, 2005.
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`VI. PATENTS AND PRINTED PUBLICATIONS RELIED ON
`47.
`I rely on the following patents and publications in my review:
`
`A. Rastogi – U.S. Patent No. 8,039,009 (Ex. 1007)
`48. U.S. Patent No. 8,039,009, titled “Modified Release Formulations of
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`IPR2015-00410
`Petitioners' Ex. 1002
`Page 16
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`Memantine Oral Dosage Forms” (“Rastogi,” Ex. 1007) was filed on June 16, 2005.
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`Rastogi claims priority to Provisional Application No. 60/581,242 (“’242 Provisional,”
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`Ex. 1008) filed on June 17, 2004, which is prior to the earliest filing date of the ’085
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`patent. Accordingly, I am instructed that subject matter disclosed in both Rastogi and
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`the provisional application is prior art to the ’085 patent under 35 U.S.C. § 102(e).
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`49. Rastogi generally discloses the use of pharmaceutical compositions
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`containing memantine or an acceptable salt of memantine, given in once-daily,
`
`sustained release formulations for the treatment of Alzheimer’s disease. Ex. 1007 at
`
`col. 2, l. 65–col. 3, l. 7; col. 3, ll. 17–31; col. 5, l. 66–col. 6, l. 6; col. 9, ll. 44–51; col. 10,
`
`l. 18–21; Ex. 1008 at p. 5, ll. 26–31; p. 6, ll. 8–12; p. 9, ll. 17–21; p. 14, ll. 5–9; p. 14, l.
`
`30–p. 15, l.1.
`
`50. The specification discloses that the prior art teaches the administration of
`
`NMDA receptor antagonists in a modified-release form. Ex. 1007 at col. 1, ll. 14–15;
`
`col. 6 , ll. 49–53; col. 12, ll. 37–39; Ex. 1008 at p. 3, ll. 6–7; p. 10, ll. 17–19; p. 16, 10–
`
`14. Rastogi states that there is motivation for seeking a once-daily, modified release
`
`formulation for the treatment of Alzheimer’s disease:
`
`Currently, a dosing regimen of memantine of twice a day is
`employed using immediate release tablets. This may be
`undesirable because patient compliance decreases as the
`frequency of taking a drug increases. Moreover
`administration of an immediate-release tablet can lead to
`greater frequency of adverse events due to a faster rate of
`
`-16-
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`IPR2015-00410
`Petitioners' Ex. 1002
`Page 17
`
`
`
`absorption. . . .There is therefore an existing and continual
`need for a once a day modified release formulation
`containing memantine. . . .
`
`Ex. 1007 at col. 2, l. 65–col. 3, l. 7; Ex. 1008 at p. 5, ll. 26–31.
`
`51. Rastogi describes “6-hour release” and “12-hour release” formulations (also
`
`referred to as “6 hour dissolution” and “12 hour dissolution”). For the 12-hour
`
`release formulations, about 70 to 80% of the active ingredient (memantine
`
`hydrochloride) is released after about 12 hours following entry into the use
`
`environment. Ex. 1007 at col 3, ll. 32–35; Ex. 1008 at p. 6, ll. 10–15. Example 1
`
`describes 12-hour release formulations made using a polymeric matrix, each of which
`
`includes at least one component that sustains the release of memantine. Ex. 1007 at
`
`Table 1; col. 12, ll. 37–43; Ex. 1008 at p. 16, Table 1; p. 16, ll. 10–14.
`
`52. Rastogi also discloses memantine hydrochloride forms containing about 10
`
`mg to about 80 mg per tablet. Ex. 1007 at col. 3, ll. 35–55; Ex. 1008 at p. 6, ll. 16–26.
`
`53. Rastogi further discloses a crossover pharmacokinetic study in Example 2.
`
`In that study, each subject received a different one of the three treatment regimens on
`
`study days 1, 22, and 43, allowing a 21-day washout period in between each treatment.
`
`Ex. 1007 at col. 15, ll. 33–45; Ex. 1008 at p. 18, l. 25–p. 19, l. 3. In this way, each
`
`subject received each of the three treatment regimens one time (one on day 1, a
`
`different one on day 22, and a third one on day 43). The treatments were: Treatment
`
`A (or “IR Formulation”), consisting of two tablets of 10 mg of an immediate release
`
`-17-
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`IPR2015-00410
`Petitioners' Ex. 1002
`Page 18
`
`
`
`formulation, one given at 8 a.m. and one given at noon; Treatment B (or “MR
`
`Formulation I”), consisting of 20 mg of a modified release formulation with a six hour
`
`dissolution administered at 8 a.m.; and Treatment C (or “MR Formulation II”),
`
`consisting of a second modified release formulation with 20 mg and a twelve hour
`
`dissolution administered at 8 a.m. Ex. 1007 at col. 15, ll. 33–45; Ex. 1008 at p. 18, l.
`
`25–p. 19, l. 3.
`
`54. The mean plasma concentrations of memantine during the first 24 hours
`
`post-dosage for each treatment are presented in Figure 7 of Rastogi. Ex. 1007 at col.
`
`17, l. 41–42; Ex. 1008 at p. 21, l. 19–20. For example, the curve for the second
`
`modified release formulation (Treatment C) represents the mean plasma
`
`concentration levels for the subjects who received Treatment C on day 1, the subjects
`
`who received Treatment C on day 22, and the subjects who received Treatment C on
`
`day 43.
`
`B. Nürnberg – U.S. Patent No. 5,382,601 (Ex. 1009)
`55. U.S. Patent 5,382,601, titled “Memantine-Containing Solid Pharmaceutical
`
`Dosage Forms Having an Extended Two-Stage Release Profile and Production
`
`Thereof,” (“Nürnberg,” Ex. 1009) issued on January 17, 1995, which is more than one
`
`year prior to the earliest filing date of the ’085 patent. Accordingly, I am informed by
`
`counsel that Nürnberg is prior art under 35 U.S.C. § 102(b).
`
`56. Nürnberg is directed to an extended two-phase release solid oral dosage
`
`form that provides extended release of a pharmaceutical active ingredients. Ex. 1009
`-18-
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`IPR2015-00410
`Petitioners' Ex. 1002
`Page 19
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`
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`at col. 1, ll. 9–23; col. 1, ll. 25–31; col. 2, ll. 56–66; col. 4, ll. 3–15. These
`
`pharmaceutical active ingredients include “agents influencing the dementia syndrome
`
`such as memantine,” and that the “[m]ost preferred is memantine.” Id. at col. 5, ll.
`
`49–50; col. 5, l. 63; see also col. 1, ll. 9–23.
`
`57. The specification describes an extended release tablet with a matrix-
`
`controlled release system that is comprised of varying amounts of a water-insoluble
`
`salt of casein and a water-soluble salt of casein. Id. at col. 2, ll. 56–63. The water-
`
`insoluble salt of casein provides extended release of the active ingredient. Id. at col. 6,
`
`ll. 34–46. Some of the disclosed embodiments include only a water-insoluble salt of
`
`casein, and they thus have slower release. Id. at col. 9, ll. 35–48. Nürnberg teaches
`
`that varying the proportions of the water-insoluble salt of casein and the water-soluble
`
`salt of casein “permits the selection of a highly desirable individual release profile,
`
`depending on the active substance and the type of indication to be achieved.” Id. at
`
`col. 9, ll. 49-56.
`
`58. Nürnberg states that “[t]he amount of active substance present can be varied
`
`widely depending on the indication to be treated and the type of dosage form desired,
`
`for example, from 0.01 to 90%, based on the total weight of the pharmaceutical
`
`composition.” Id. at col. 4, ll. 22–26. Example 1 describes an extended-release tablet
`
`containing 20 mg of memantine. Id. at col. 7, ll. 17–35.
`
`59. Nürnberg explains that an extended-release profile is advantageous because
`
`(1) it slows the increase of drug in the blood plasma and thereby reduces undesirable
`-19-
`
`IPR2015-00410
`Petitioners' Ex. 1002
`Page 20
`
`
`
`side effects, and (2) it allows for longer intervals between dosing and thereby increases
`
`patient compliance:
`
` [T]he value of the extended-two-stage release is seen as a
`slower increase of drug concentration into the blood, thus
`reducing undesirable side effects. This is particularly true
`for gastric side effects because, according to FIGS. 1-4,
`only about 40-50% of the drug content is released in the
`stomach. Beyond this, a reliable slow release, generally
`prolongs intervals between application or dosing and thus
`improves patient compliance considerably.
`
`Id. at col. 11, 1. 68–col. 12, 1. 8.
`
`C. Ditzler (Ex. 1010)
`60. Efficacy and Tolerability of Memantine in Patients with Dementia Syndrome, an article
`
`authored by K. Ditzler, was published in 1991. I am instructed that Ditzler is thus
`
`prior art to the ’085 patent under 35 U.S.C. § 102(b).
`
`61. Ditzler describes a double-blind randomized clinical study on the efficacy
`
`and tolerability of memantine hydrochloride in the treatment of dementia patients.
`
`Ex. 1010 at 4. In this study, the patients received 10 mg/day of
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