UNITED STATES PATENT AND TRADEMARK OFFICE
`___________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
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`NOVEN PHARMACEUTICALS, INC.,
`Petitioner
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`v.
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`NOVARTIS AG AND LTS LOHMANN THERAPIE-SYSTEME AG,
`Patent Owners
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`___________________
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`Inter Partes Review IPR2014-00550
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`U.S. Patent No. 6,335,031
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`DECLARATION OF AGIS KYDONIEUS, PH.D.
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`Page 1 of 49
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`Noven Ex. 1010
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`___________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
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`NOVEN PHARMACEUTICALS, INC.,
`Petitioner
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`v.
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`NOVARTIS AG AND LTS LOHMANN THERAPIE-SYSTEME AG,
`Patent Owners
`
`___________________
`
`
`
`Inter Partes Review IPR2014-00550
`
`U.S. Patent No. 6,335,031
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`
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`DECLARATION OF AGIS KYDONIEUS, PH.D.
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`Page 1 of 49
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`Noven Ex. 1010
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`I, Agis Kydonieus, Ph.D., declare and state as follows:
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`I.
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`QUALIFICATIONS
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`1.
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`I am currently the President of Samos Pharmaceuticals LLC, a company
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`through which I am providing consulting services to pharmaceutical companies in
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`the field of drug delivery. Samos also develops innovative drug delivery
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`technologies for its own use. Currently I am also cofounder and Chief Scientific
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`Officer of InteguRx Therapeutics LLC a company developing transdermal
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`products in the women’s health area. I am also cofounder and President of KAT
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`Transdermals LLC a company developing transdermal products in the CNS area.
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`Additionally I am Senior Scientific Advisor to Agile Therapeutics Inc., a company
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`developing contraceptive transdermal products.
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`2.
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`I received my B.S.Ch.E. in 1959, and my Ph.D. (chemical engineering) in
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`1964, both from the University of Florida in Gainsville. The last 35 years of my
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`career have focused on the development of transdermal drug delivery systems.
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`Prior to assuming my current positions, I served as Vice President of Convatec,
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`previously a subsidiary of Bristol Myers Squibb. Convatec developed a variety of
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`topically applied products, including transdermal drug delivery systems and in
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`association with BMS. I also served as President of Hercon Laboratories, a
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`company focused on transdermal drug delivery systems. I am also a founding
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`member of the Controlled Release Society, a scientific body dedicated to drug
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`delivery science and technology.
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`3.
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`Over the course of my career, I have been awarded 23 US issued patents
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`for inventions concerning the topical and transdermal delivery of drugs and edited
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`ten books pertaining to the delivery of bioactive materials, four of which pertain to
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`topical and transdermal delivery. I have authored over 100 book chapters,
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`scientific publications, abstracts and presentations regarding delivery of bioactive
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`agents including transdermal drug delivery.
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`4.
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`A copy of my curriculum vitae, which sets forth my education and
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`experience in further detail, is attached at Exhibit 1022.
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`5.
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`I have been engaged as an expert on behalf of Petitioner, Noven
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`Pharmaceuticals, Inc. I am being compensated at my customary rates of $300.00-
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`400.00 per hour (depending on the total hours worked per month). My
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`compensation increases to $500.00 per hour for time spent attending depositions,
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`trials, or other legal proceedings. My compensation is not related in any way to the
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`outcome of this proceeding. In the previous four years, I have not testified as an
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`expert in any case, whether at trial or deposition.
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`II.
`6.
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`INFORMATION CONSIDERED
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`In forming the opinions set forth herein, I have relied on my own
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`experiences and knowledge. I have also considered the documents discussed
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`herein, which include the following:
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`U.S. Patent No. (“the ʼ031 patent”) (Ex. 1001)
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`U.S. Patent 4,948,807 (“Rosin”) (Ex. 1008)
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`Neuropharmacology (1991) 30: 1059-1064 (“Elmalem”) (Ex.
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`1009)
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`UK Patent No. 2,203,040 (“Enz”) (Ex. 1002)
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`PCT Publication WO 95/24172 (“Ebert”) (Ex. 1006)
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`a certified translation of Japanese Published Application No. JP
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`59-184121 (“Sasaki”) (Ex. 1005)
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`The Handbook of Pharmaceutical Excipients (2nd Ed. 1994, Wade,
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`A. and Weller, P.J., Eds.) (“Handbook”) (Ex. 1003)
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`Declaration of Christian Schöneich, Ph.D. (Ex. 1011)
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`“Safety/Tolerability Trial of SDZ ENA 713 in Patients with
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`Probable Alzheimer’s Disease,” John J. Sramek et al., Life
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`Sciences, Vol. 58, No. 15, pp. 1201-1207 (1996) (“Sramek”) (Ex.
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`1012)
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`
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`“New acetylcholinesterase inhibitor shows promise in largest
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`Alzheimer’s trial to date,” Formulary, Vol. 32, Dec. 1997
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`(“Formulary Article”) (Ex. 1013)
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`ICH Topic Q 1 A, Stability Testing Guidelines: Stability Testing
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`of New Drug Substances and Products (CPMP/ICH/380/95) (Ex.
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`1014)
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`7.
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`I have reviewed the documents referenced above, in view of my own
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`knowledge and experience concerning the development of pharmaceuticals,
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`including transdermal drug delivery systems. It is my opinion that at the time of
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`the alleged invention, a person of ordinary skill in the art would have been aware
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`of the compound rivastigmine (also known as ENA 713), and that it was being
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`developed as a treatment for Alzheimer’s disease. It is my opinion that at the time
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`of the alleged invention, a person of ordinary skill in the art working to develop a
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`pharmaceutical composition comprising rivastigmine, including a transdermal
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`rivastigmine delivery system, would have been motivated to combine rivastigmine
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`with an antioxidant. It is my opinion that the person of ordinary skill in the art
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`would have reasonably expected that an antioxidant would reduce or prevent the
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`oxidative decomposition of rivastigmine in the transdermal device.
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`III. LEGAL STANDARDS
`8.
`I have been instructed by counsel for Noven, and understand, that a patent
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`is not written for the general public, but instead is directed to a “person of ordinary
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`skill” in the field of the patent. I have been informed by counsel for Noven that
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`factors such as the education level of those working in the field, the sophistication
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`of the technology, the types of problems encountered in the art, the prior art
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`solutions to those problems, and the speed at which innovations are made, help
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`establish the level of skill in the art.
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`9.
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`It is my opinion that the subject matter of the ʼ031 patent draws from
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`several disciplines, and as such, the patent is directed to a collaborative team of
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`individuals in which each person would have been able to draw upon the
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`experiences and knowledge of the others. In particular, the person of ordinary skill
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`is a chemist, chemical engineer, polymer chemist, or pharmaceutical chemist
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`working to develop pharmaceutical formulations, including transdermal drug
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`delivery systems. The person of ordinary skill would be familiar with the testing
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`that accompanies the development of any pharmaceutical formulation, including
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`testing for efficacy and stability. The person of ordinary skill would be familiar
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`with excipients typically employed in pharmaceutical formulations, including
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`transdermal devices. The person of ordinary skill would have knowledge of
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`organic chemistry, or would collaborate with a person having knowledge of
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`organic chemistry, and would be able to make predictions about the physical
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`properties of a compound based upon its chemical structure.
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`10.
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`I have been informed by counsel for Noven, and understand, that if a
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`single prior art reference discloses each limitation recited in a claim, the claim is
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`unpatentable as anticipated. I further understand that the prior art reference need
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`not explicitly disclose each limitation, but can do so inherently.
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`11.
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`I have been informed by counsel for Noven, and understand, that if the
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`differences between the claimed subject matter and prior art are such that the
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`claimed subject matter as a whole would have been obvious to a person of ordinary
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`skill, then the patent claim is unpatentable as obvious. I understand that the
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`following factors must be evaluated in determining whether the claimed subject
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`matter is obvious: (1) the scope and content of the prior art; (2) the differences
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`between the claim and the prior art; (3) the level of ordinary skill in the art at the
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`time the patent was filed; and (4) any secondary considerations of nonobviousness.
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`12.
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`I have been informed by counsel for Noven, and understand, that
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`secondary considerations of non-obviousness are part of the obviousness inquiry,
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`and that some examples of secondary considerations that tend to show non-
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`obviousness include:
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`(1)
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`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)
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`any failure of others to achieve the results of the invention;
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`(3)
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`any commercial success or lack thereof of the products and processes
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`covered by the invention;
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`(4)
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`any deliberate copying of the invention by others in the field;
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`(5)
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`any taking of licenses under the patent by others;
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`(6)
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`any expression of disbelief or skepticism by those skilled in the art
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`upon learning of the invention;
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`(7)
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`any unexpected results achieved by the invention;
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`(8)
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`any praise of the invention by others skilled in the art; and
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`(9)
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`any lack of contemporaneous and independent invention by others.
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`I understand that the factfinder(s) must determine whether potential evidence of
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`secondary considerations has a nexus to the claimed invention.
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`13.
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`I have been informed by counsel for Noven, and understand, that in the
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`context of these proceedings, a claim will be found unpatentable as obvious if the
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`preponderance of the evidence indicates that the claim would have been obvious. I
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`further understand that in the context of these proceedings, a claim is not presumed
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`to be valid.
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`IV. THE CHALLENGED CLAIMS
`14.
`I have reviewed each of the claims in the ʼ031 patent, and understand that
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`Noven is challenging claims 1-3, 7, 15, 16, and 18 as unpatentable. Claims 1 and
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`15 are independent and are reproduced below:
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`1. A pharmaceutical composition comprising
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`(a) a therapeutically effective amount of (S)-N-ethyl-3-
`{(1-dimethylamino) ethyl}-N-methyl-phenyl carbamate
`in free base or acid addition salt form (Compound A),
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`(b) about 0.01 to about 0.5 percent by weight of an
`antioxidant, based on the weight of the composition, and
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` (c) a diluent or carrier.
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`15. A method of stabilizing (S)-N-ethyl-3-{(1-
`dimethylamino)ethyl}-N-methyl-phenyl-carbamate in
`free base or acid addition salt form (Compound A),
`wherein the method comprises forming a composition by
`combining Compound A with an amount of anti-oxidant
`effective to stabilize Compound A from degradation.
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`V. CLAIM CONSTRUCTION
`15.
`I have been informed by counsel for Noven, and understand, that in the
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`context of the current proceedings, each of the terms in the claims is given its
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`broadest reasonable interpretation in light of the specification. I have reviewed the
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`specification of the ʼ031 patent, and in my opinion there are no special definitions
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`attributed any of the claim terms. As such, I interpret the claim terms under the
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`“broadest reasonable” standard, and in particular to have the following meanings in
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`light of the specification:
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` Pharmaceutical Composition – In my opinion, a pharmaceutical
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`composition is a composition suitable for pharmaceutical use, e.g. for
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`administration to a patient.
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` Antioxidant – In my opinion, an antioxidant is a compound which reduces
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`or prevents the oxidative decomposition of other compound(s).
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` Diluent or carrier – In my opinion, a diluent or carrier is an inactive
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`ingredient(s) that aid(s) in the administration of the drug.
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` Transdermal device – In my opinion, transdermal device means medical
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`device for systemic drug administration through skin.
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` Substrate – In my opinion, substrate means a backing layer providing
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`structural support for the pharmaceutical composition.
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` Adhesive layer – In my opinion, adhesive layers means layer of adhesive.
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` Stabilizing – In my opinion, stabilizing means reducing degradation.
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` Amount of antioxidant effective to stabilize Compound A from
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`degradation – In my opinion, amount of antioxidant effective to stabilize
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`Compound A from degradation means an amount of antioxidant that
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`reduces the oxidative degradation of Compound A.
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` The claim term “(S)-N-ethyl-3-[(1-dimethylamino)ethyl]-N-methylphenyl
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`carbamate” refers to rivastigmine, which has the following chemical
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`structure:
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`CH3
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`O
`
`N
`CH3
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`CH3
`N
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`CH3
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`(S)
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`O
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`CH3
`rivastigmine
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`H
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`Rivastigmine is the S-enantiomer of a racemic compound known as RA7. (Ex.
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`1002 at 3.) As a racemate, RA7 is comprised of an equal mixture of rivastigmine
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`and its enantiomer ent-rivastigmine, or (R)-rivastigmine:
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`CH3
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`O
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`N
`CH3
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`O
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`RA7
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`CH3
`N
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`CH3
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`=
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`CH3
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`H
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`CH3
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`CH3
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`O
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`N
`CH3
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`O
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`N
`CH3
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`O
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`+
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`O
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`CH3
`N
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`CH3
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`(S)
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`CH3
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`H
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`CH3
`N
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`CH3
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`(R)
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`CH3
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`H
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`rivastigmine
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`ent-rivastigmine
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`VI. BACKGROUND AND STATE OF THE ART
`16. There are several ways in which a physiologically active compound may
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`be administered to a patient, including enterally (i.e., administration through the
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`digestive system using, for instance, oral, sublingual or rectal administration);
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`parenterally (e.g., injection or infusion); and topically (e.g., transdermal
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`administration). Each mode of administration has attributes that make it more or
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`less desirable depending on the particular drug. For instance, oral administration is
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`a practical method of administering drugs to most patients. However, if the drug is
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`not adsorbed from the gastrointestinal system, is destroyed by stomach acid, or
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`causes nausea, it may not be suitable for oral administration. In such cases, an
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`injectable dosage form may be an alternative. However, injectable dosage forms
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`place greater burdens on the patient, as the injection often must be given by a
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`medical professional, and can cause discomfort and infection at the injection site.
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`17. The transdermal delivery of a drug avoids the physiochemical difficulties
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`associated with oral administration, and does not burden the patient with a painful
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`or time-consuming injection. In addition, transdermal administration avoids
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`metabolism of the drug by the liver (so called “first-pass metabolism”).
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`Transdermal delivery systems can provide release for long periods of time, and can
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`improve patient compliance. Furthermore, in the context of patients with
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`dementia, transdermal administration offers the additional benefit that it
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`circumvents difficulties associated with patients unable or unwilling to swallow an
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`oral dosage form, and allows caregivers to conveniently administer the drug.
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`18. Generally, a transdermal device consists of at least three separate
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`domains, a layer which contains the drug substance (i.e., the active ingredient) and
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`one or more excipients or carriers (i.e., the pharmaceutical composition); an
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`impermeable backing layer which prevents the drug substance from diffusing in
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`directions other than into the skin and protects the drug substance during use of the
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`device; and a removable layer which protects the pharmaceutical composition until
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`the device is applied to the skin.
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`19. The use of transdermal drug delivery systems was well-established prior
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`to the earliest claimed priority date of the ʼ031 patent (which I am advised by
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`counsel for Noven is January 12, 1998). The first transdermal device approved by
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`the FDA contained the active pharmaceutical ingredient scopolamine, and was
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`approved in 1979.
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`20. For any drug product to be medically (and commercially) successful, it
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`must meet several criteria. The drug must confer benefits to patients to an extent
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`sufficient to outweigh negative side effects associated with the drug. The calculus
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`of an acceptable benefit/side effect ratio is contextual—severe side effects may be
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`acceptable for a cancer drug, but unacceptable for a drug that is intended to reduce
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`mild fever.
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`21. Another critical aspect is the stability of the drug substance and other
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`excipients in the product. In the context of pharmaceutical products, “stability”
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`refers to the ability of a product to have the same safety and potency for a specified
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`period of time after the product is manufactured. The drug substance and
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`excipients may convert over time to a different chemical compounds (i.e.,
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`decompose). At best, any conversion simply diminishes potency, while at worst, it
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`may form toxic compounds. In general, persons of ordinary skill in the art strive to
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`develop stable pharmaceutical products with a commercially viable shelf life.
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`22.
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`Issues of product stability can be especially important in the development
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`of transdermal devices. This is because, for example, the preparation of
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`transdermal patches often involves intermediate steps where the drug substance is
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`in solution, and because the drug substance may remain in solution in the finished
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`drug product. This permits the drug to undergo reactions more readily.
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`23. Stability of the drug substance is one of the first considerations addressed
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`in early drug product development. The formulator will seek to understand the
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`mechanisms of degradation of the drug substance, including identifying functional
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`groups and labile centers, and will consider how the drug substance behaves under
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`external factors such as pH, temperature, humidity, and light.
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`24. The pathways by which a drug may degrade depend on the molecular
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`structure of the drug. For instance, a compound containing an ester functional
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`group may be susceptible to hydrolysis. A compound containing an oxidizable
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`functional group may be susceptible to oxidation.
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`25. The formulator will also consider drug-excipient interactions, and will
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`take all of this information into account in designing a stable formulation. Indeed,
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`regulatory guidelines in effect as of January 1998 recommended that applicants
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`perform stability tests on the drug substance and drug product. This included
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`stress testing on the drug substance to determine its intrinsic stability and
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`degradation pathways, as well as formal studies on the drug substance to show that
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`it will remain within specification during the re-test period if stored under the
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`recommended storage conditions. (See ICH Topic Q 1 A, Stability Testing
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`Guidelines: Stability Testing of New Drug Substances and Products
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`(CPMP/ICH/380/95) (Ex. 1014).)
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`VII. SPECIFIC PRIOR ART REFERENCES
`A.
`Sramek and the Formulary Article
`26.
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`I have reviewed “Safety/Tolerability Trial of SDZ ENA 713 in Patients
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`with Probable Alzheimer’s Disease,” John J. Sramek et al., Life Sciences, Vol. 58,
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`No. 15, pp. 1201-1207, 1996 (“Sramek,” Ex. 1012) and “New acetylcholinesterase
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`inhibitor shows promise in largest Alzheimer’s trial to date,” Formulary, Vol. 32,
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`Dec. 1997 (the “Formulary Article,” Ex. 1013). Sramek and the Formulary Article
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`teach that the compound rivastigmine (also known as ENA 713) was being
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`developed as a treatment for Alzheimer’s disease. (Ex. 1012 at 1; Ex. 1014 at 3.)
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`27. Rivastigmine was reportedly well-tolerated, with the majority of patients
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`experiencing only mild-to-moderate adverse events. (Ex. 1012 at 6; Ex. 1013 at 3.)
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`Rivastigmine was characterized as an improvement over tacrine, a first-generation
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`acetylcholinesterase inhibitor used to treat Alzheimer’s disease. (Ex. 1012 at 1-2.)
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`In addition, the Formulary Article noted that rivastigmine was given twice a day,
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`while donepezil, a newly-approved second generation acetylcholinesterase
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`inhibitor, was given once a day. (Ex. 1013 at 3.)
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`B. U.S. Patent 4,948,807 (“Rosin”)
`28.
`I have reviewed the Rosin reference. It discloses the compound RA7,
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`which is racemic rivastigmine. (Ex. 1008 at, e.g., 5:44–45, 14:17–19, 10: 9–27.)
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`In my opinion, a person of ordinary skill would have understood that RA7 was an
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`especially promising compound both because it was called out as a single species
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`in claim 3, and because it had one of the highest therapeutic ratios (efficacy vs.
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`toxicity) of all the disclosed compounds (Table 3). (Id. at 14:17–19, 10:59 –
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`11:17.) Rosin teaches that the “compounds of the present invention” could be
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`made into pharmaceutical compositions that could be prepared with an antioxidant.
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`(Id. at 8:56, 7:45–50.) Rosin teaches that preferred antioxidants for use with the
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`compounds of the present invention include sodium metabisulphite and ascorbic
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`acid. (Id. at 7:51–53.) In my opinion, one of ordinary skill would have readily
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`understood RA7 was a “compound of the present invention,” as the term was used
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`by Rosin, for the same reasons that it was a promising drug candidate.
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`29.
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`In my opinion, a teaching that the racemic compound RA7 is susceptible
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`to oxidative degradation is equally applicable to the single enantiomer
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`rivastigmine. Although the properties of enantiomers and racemates can differ in
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`certain situations, e.g. in biological activity, in the context of an aqueous solution
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`or dispersion in a polymer, each enantiomer will typically behave the same.
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`Therefore, based on the teaching of Rosin that RA7 could be formulated with an
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`antioxidant, the person of ordinary skill would have understood that rivastigmine
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`was susceptible to oxidative degradation.
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`C. Elmalem et al. Neuropharmacology, Vol. 30, pp. 1059-64 (1991)
`(“Elmalem”)
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`30.
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`I have reviewed the Elmalem reference, and understand it to teach
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`compositions of the racemic compound RA7 and an antioxidant. Elmalem
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`describes experiments designed to compare three drugs, RA6, RA7, and RA15, to
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`physostigmine with respect to the drugs’ ability to counteract morphine-induced
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`respiratory depression in rabbits. (Ex. 1009 at 1.) Elmalem describes two different
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`aqueous solutions of RA7 with sodium metabisulfite, a common antioxidant. (Ex.
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`1009 at 2.) Elmalem explicitly teaches that the sodium metabisulfite was added in
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`order to “prevent oxidation.” (Id.) Because the aqueous solution disclosed by
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`Elmalem contained nothing except RA7, antioxidant, and saline, the only
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`reasonable conclusion is that the antioxidant was added to stabilize RA7. Again,
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`based on Elmalem, the person of ordinary skill in the art could have predicted that
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`rivastigmine was susceptible to oxidative degradation.
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`31.
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`It is also my opinion that, apart from the teachings of Elmalem and Rosin,
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`the person of ordinary skill would have expected that rivastigmine was susceptible
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`to oxidative degradation based on its chemical structure. I have reviewed, and
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`agree with, the Declaration of Christian Schöneich, Ph.D. (Ex. 1011), wherein he
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`discusses the general chemistry principles that would have led one of ordinary skill
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`in the art to reasonably expect that rivastigmine would be susceptible to oxidative
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`degradation.
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`D. GB 2203040 (“Enz”)
`32.
`I have reviewed the Enz reference, and understand it to disclose that the (-
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`) enantiomer of the racemic compound RA7 is useful to treat cognitive diseases,
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`Page 17 of 49
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`including Alzheimer’s disease. (Ex. 1002 at 10.) Enz also teaches that the (-)
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`enantiomer is superior to both the racemic mixture and the (+) enantiomer, for one
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`reason because it “exhibits a particularly marked and selective inhibition of the
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`acetylcholinesterase.” (Id. at 3, 6.)
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`33. Enz teaches the (-) enantiomer can be obtained by converting the racemic
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`RA7 into the diastereomeric tartrate salts, followed by selective crystallization of
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`the (-) enantiomer. (Id. at 3, 11.) I understand that the compound designated as
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`rivastigmine, the (-) enantiomer, has been shown to have the (S) absolute
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`configuration. (Ex. 1018 at 4.)
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`34. Enz teaches that rivastigmine, either as the free base or acid addition salt,
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`may advantageously be administered transdermally. (Id. at 14-19.) Enz teaches
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`that the pharmacokinetic profile from transdermal administration is superior to that
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`of either oral or subcutaneous administration. (Id. at 15-16.)
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`35. Enz discloses the preparation of a transdermal composition containing
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`rivastigmine tartrate. (Id. at 17-20; “Compound A” is rivastigmine tartrate.) In my
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`opinion, one of ordinary skill would have recognized that the composition
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`described by Enz was not a finished, marketable product, but rather that Enz
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`describes a rudimentary laboratory sample. For instance, the transdermal
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`composition lacks a removable release liner and pouch to protect the composition
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`prior to use. Enz also lacks any in vivo human test data associated with the
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`Page 18 of 49
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`example transdermal composition. As such, an ordinarily-skilled artisan would
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`have viewed the composition disclosed by Enz as a starting point for further
`
`development, rather than a finished product. Indeed, Enz specifically cites several
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`other documents for additional information regarding transdermal delivery
`
`systems. (Ex. 1002 at 17, citing to, e.g., Remington’s Pharmaceutical Sciences,
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`GB 2098865, and EP 155,229). Enz does not disclose any stability testing for the
`
`rivastigmine patch, including data on susceptibility to oxidation, nor does it
`
`suggest that the patch would be stable over a period of a few years.
`
`E.
`36.
`
`PCT Publication WO 95/24172 (“Ebert”)
`
`I have read PCT Publication WO 95/24172, entitled “Drug-containing
`
`adhesive composite transdermal delivery device,” to Charles D. Ebert and others,
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`published on September 14, 1995. (“Ebert,” Ex. 1006.) I understand Ebert to
`
`disclose a transdermal drug delivery device for nicotine and other drugs. (Ex. 1006
`
`at 3.) Ebert teaches that conventional methods of preparing transdermal devices
`
`containing drugs such as nicotine are problematic for a variety of reasons. For
`
`example, Ebert teaches that because nicotine is volatile, it can evaporate if a drying
`
`step is employed, leading to reduced and uneven concentrations of the drug
`
`throughout the composition. (Id. at 5.)
`
`37. To solve this problem, Ebert describes the preparation of a
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`transdermal device that avoids the use of drying. (Id. at 7.) Specifically, the drug,
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`in gel form, is extruded onto one or two adhesive layers, one of which has an
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`impermeable backing layer and the other of which has a peelable layer. The layers
`
`are then laminated together to produce the transdermal drug delivery system. (Id.
`
`at 7-8.) A schematic of the device is reproduced below:
`
`14 = drug impermeable backing layer
`18 = drug containing composite
`19 = distal adhesive layer
`20 = proximal adhesive layer
`21 = gelled drug layer
`22 = drug impermeable release layer
`
`(Id. at 1.)
`
`38. Ebert teaches that nicotine was known to oxidize readily in the
`
`presence of light and air, and that to minimize oxidation, the transdermal device
`
`should be kept in the dark and under an inert atmosphere. (Id. at 21.) Ebert also
`
`teaches that oxidation may be further reduced by adding an antioxidant to the
`
`active gel, and that the most preferred antioxidant is butylated hydroxytoluene
`
`(BHT) in a range of 0.05-0.2% by weight. (Id.) Ebert teaches that other
`
`antioxidants such as butylated hydroxyanisole (BHA), sodium metabisulfite,
`
`EDTA, and α-tocopherol are also useful. (Id.)
`
`39. Although the exemplified device is described with respect to nicotine (id.
`
`at 1), Ebert explicitly teaches that the device is suitable for any chemical or
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`
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`biological material that may be delivered transdermally. (Id. at 10-11 and 15.)
`
`F.
`40.
`
`JP 59-184121 (“Sasaki”)
`
`I have reviewed a translation of the Sasaki reference. (Ex. 1005.) I
`
`understand Sasaki to disclose, broadly, that antioxidants may be advantageously
`
`added to transdermal compositions containing a variety of active pharmaceutical
`
`ingredients. Sasaki teaches that in transdermal formulations containing a drug—
`
`especially drugs that contain a phenolic hydroxyl group or amino group—in an
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`acrylic adhesive, the drug tends to degrade during storage, even where the patch is
`
`sealed and shielded from light with aluminum laminate packaging. (Id. at 1.)
`
`Sasaki teaches that the decomposition may be inhibited by addition of tocopherol
`
`antioxidants. (Id. at 2.) Sasaki teaches using an amount of tocopherol of 0.005–
`
`5% by weight relative to the acrylic adhesive of the patch, and a preferred amount
`
`of 0.05–1 wt%. (Id.)
`
`41.
`
`In my opinion, one of ordinary skill would have understood Sasaki to be
`
`presenting a solution for the problem of oxidative decomposition initiated by
`
`acrylate-type polymers. The person of ordinary skill would have known that
`
`acrylate-type polymers were typically produced using a free-radical process, and
`
`that such a process often resulted in some amount of radical-containing species in
`
`the final polymer product. The person of ordinary skill would have understood
`
`that, over time, the free radicals could come into contact with the drug substance
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`dispersed in the acrylate polymer, and could abstract a hydrogen atom or electron
`
`from the drug compound, leading to decomposition. The person of ordinary skill
`
`would have understood that tocopherol would react with the free radicals in the
`
`acrylate more rapidly than the drug, and thus prevent the oxidation and
`
`decomposition of the drug substance.
`
`G. Handbook of Pharmaceutical Excipients (“Handbook”)
`42.
`I reviewed the Handbook of Pharmaceutical Excipients (2nd Ed. 1994,
`
`Wade, A. and Weller, P.J., Eds.) (“Handbook,” excerpts of which are marked as
`
`Ex. 1003). The Handbook is a reference textbook that lists inactive ingredients and
`
`their physical and chemical properties. Persons of ordinary skill in the art
`
`routinely consult the Handbook to determine what excipients have been previously
`
`approved for use in pharmaceuticals and food products, and in what amounts.
`
`43. The Handbook provides information on antioxidants (including ascorbic
`
`acid, butylated hydroxytoluene (BHT), α-tocopherol, and ascorbyl palmitate)
`
`suitable for use in products intended for human use, and the concentrations at
`
`which they are commonly employed:
`
`Antioxidant
`
`Concentration Typically Used in
`
`Citation in the
`
`Pharmaceutical Products
`
`Handbook (Ex. 1003)
`
`Ascorbic acid
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`In aqueous formulations, 0.01-0.1 %
`
`p. 8
`
`w/v
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`
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`Page 22 of 49
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`BHT
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`In IV injections, 0.0009-0.002 % w/v
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`pp. 19-20
`
`In topical formulations, 0.0075-0.1 %
`
`w/w
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`α-tocopherol
`
`0.001 to 0.05 wt%
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`Not provided
`
`pp. 5-6
`
`pp. 12-13
`
`Ascorbyl
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`palmitate
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`BHA
`
`In IV injections, 0.0002-0.0005 % w/v
`
`pp. 17-18
`
`In topical formulations, 0.005-0.02 %
`
`w/w
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`Propyl gallate
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`≤0.1% % w/v
`
`pp. 21-23
`
`
`VIII. GROUNDS OF UNPATENTABILITY
`(1). Ground 1: Claim 15 is Unpatentable as Anticipated by
`Elmalem
`
`44.
`
`Independent claim 15 is directed to a method of stabilizing Compound A
`
`comprising forming a composition by combining Compound A with an amount of
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`antioxidant effective to stabilize Compound A from degradation. Elmalem meets
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`every limitation of this claim.
`
`45.
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`In Elmalem, two solutions of RA7 with an equal weight of antioxidant
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`were reported: one comprising 1 mg/kg RA7 and 1 mg/kg sodium metabisulphite
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`Page 23 of 49
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`in sterile saline, and the other comprising 2 mg/kg RA7 and 2 mg/kg sodium
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`metabisulphite in sterile saline. (Ex. 1009 at 2.) Elmalem explicitly states that the
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`sodium metabisulphite was added to prevent oxidation of the drug: “All drugs
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`were made up freshly in sterile saline, which included an equal weight of sodium
`
`metabisulphite, to prevent oxidation.” (Id.) (emphasis added).
`
`46. RA7 is comprised of an equal mixture of rivastigmine and its enantiomer
`
`ent-rivastigmine, or (R)-rivastigmine. Accordingly, in the compositions reported
`
`in Elmalem, the ratio of rivastigmine to antioxidant on a wt/wt basis was 0.5:1, or
`
`67% antioxidant. This amount of antioxidant was sufficient to stabilize the
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`rivastigmine. Elmalem taught that this amount of
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