`
`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`___________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
`
`
`NOVEN PHARMACEUTICALS, INC.,
`Petitioner
`
`v.
`
`NOVARTIS AG AND LTS LOHMANN THERAPIE-SYSTEME AG,
`Patent Owners
`
`___________________
`
`
`Inter Partes Review No.: 2014-00549
`
`U.S. Patent No. 6,316,023
`
`
`
`
`
`DECLARATION OF AGIS KYDONIEUS, PH.D.
`
`
`
`Noven Ex. 1010
`
`Page 1 of 42
`
`
`
`
`
`I, Agis Kydonieus, Ph.D., declare and state as follows:
`
`I.
`
`QUALIFICATIONS
`
`1.
`
`I am currently the President of Samos Pharmaceuticals LLC, a company
`
`through which I am providing consulting services to pharmaceutical companies in
`
`the field of drug delivery. Samos also develops innovative drug delivery
`
`technologies for its own use. Currently I am also cofounder and Chief Scientific
`
`Officer of InteguRx Therapeutics LLC a company developing transdermal
`
`products in the women’s health area. I am also cofounder and President of KAT
`
`Transdermals LLC a company developing transdermal products in the CNS area.
`
`Additionally I am Senior Scientific Advisor to Agile Therapeutics Inc, a company
`
`developing contraceptive transdermal products.
`
`2.
`
`I received my B.S.Ch.E. in 1959, and my Ph.D. (chemical engineering) in
`
`1964, both from the University of Florida in Gainsville. The last 35 years of my
`
`career have focused on the development of transdermal drug delivery systems.
`
`Prior to assuming my current positions, I served as Vice President of Convatec,
`
`previously a subsidiary of Bristol Myers Squibb. Convatec developed a variety of
`
`topically applied products, including transdermal drug delivery systems and in
`
`association with BMS. I also served as President of Hercon Laboratories, a
`
`company focused on transdermal drug delivery systems. I am also a founding
`
`member of the Controlled Release Society, a scientific body dedicated to drug
`
`
`
`
`
`Noven Ex. 1010
`
`Page 2 of 42
`
`
`
`
`
`delivery science and technology.
`
`3.
`
`Over the course of my career, I have been awarded 23 US issued patents
`
`for inventions concerning the topical and transdermal delivery of drugs and edited
`
`ten books pertaining to the delivery of bioactive materials, four of which pertain to
`
`topical and transdermal delivery. I have authored over 100 book chapters,
`
`scientific publications, abstracts and presentations regarding delivery of bioactive
`
`agents including transdermal drug delivery.
`
`4.
`
`A copy of my curriculum vitae, which sets forth my education and
`
`experience in further detail, is attached at Exhibit 1023.
`
`5.
`
`I have been engaged as an expert on behalf of Petitioner, Noven
`
`Pharmaceuticals, Inc. I am being compensated at my customary rates of $300.00-
`
`400.00 per hour (depending on the total hours worked per month). My
`
`compensation increases to $500.00 per hour for time spent attending depositions,
`
`trials, or other legal proceedings. My compensation is not related in any way to the
`
`outcome of this proceeding. In the previous four years, I have not testified as an
`
`expert in any case, whether at trial or deposition.
`
`II.
`6.
`
`INFORMATION CONSIDERED
`
`In forming the opinions set forth herein, I have relied on my own
`
`experiences and knowledge. I have also considered the documents discussed
`
`herein, which include the following:
`
`
`
`
`
`Noven Ex. 1010
`
`Page 3 of 42
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`U.S. Patent No. 6,316,023 (“the ʼ023 patent”) (Ex. 1001)
`
`U.S. Patent 4,948,807 (“Rosin”) (Ex. 1008)
`
`Neuropharmacology (1991) 30: 1059-1064 (“Elmalem”) (Ex.
`
`1009)
`
`European Patent Application No. 0155,229 (“Kissel”)(Ex. 1007)
`
`UK Patent No. 2,203,040 (“Enz”) (Ex. 1002)
`
`PCT Publication WO 95/24172 (“Ebert”) (Ex. 1006)
`
`a certified translation of Japanese Published Application No. JP
`
`59-184121 (“Sasaki”) (Ex. 1005)
`
`The Handbook of Pharmaceutical Excipients (2nd Ed. 1994, Wade,
`
`A. and Weller, P.J., Eds.) (“Handbook”) (Ex. 1003)
`
`Declaration of Christian Schoneich, Ph.D. (Ex. 1011)
`
`ICH Topic Q 1 A, Stability Testing Guidelines: Stability Testing
`
`of New Drug Substances and Products (CPMP/ICH/380/95) (Ex.
`
`1014)
`
`
`
`“New acetylcholinesterase inhibitor shows promise in largest
`
`Alzheimer’s trial to date,” Formulary, Vol. 32, Dec. 1997
`
`(“Formulary Article”) (Ex. 1013)
`
`
`
`“Safety/Tolerability Trial of SDZ ENA 713 in Patients with
`
`Probable Alzheimer’s Disease,” John J. Sramek et al., Life
`
`
`
`Noven Ex. 1010
`
`Page 4 of 42
`
`
`
`
`
`Sciences, Vol. 58, No. 15, pp. 1201-1207 (1996) (“Sramek”) (Ex.
`
`1012)
`
`III. SUMMARY OF OPINIONS AND EXPECTED TESTIMONY
`7.
`I have reviewed the documents referenced above, in view of my own
`
`knowledge and experience concerning the development of pharmaceuticals,
`
`including transdermal drug delivery systems. It is my opinion that at the time of
`
`the alleged invention, a person of ordinary skill in the art would have been aware
`
`of the compound rivastigmine (also known as ENA 713), and that it was being
`
`developed as a treatment for Alzheimer’s disease. It is my opinion that at the time
`
`of the alleged invention, a person of ordinary skill in the art working to develop a
`
`pharmaceutical composition comprising rivastigmine, including a transdermal
`
`rivastigmine delivery system, would have been motivated to combine rivastigmine
`
`with an antioxidant. It is my opinion that the person of ordinary skill in the art
`
`would have reasonably expected that an antioxidant would reduce or prevent the
`
`oxidative decomposition of rivastigmine in the transdermal device.
`
`IV. LEGAL STANDARDS
`8.
`I have been instructed by counsel for Noven, and understand, that a patent
`
`is not written for the general public, but instead is directed to a “person of ordinary
`
`skill” in the field of the patent. I have been informed by counsel for Noven that
`
`factors such as the education level of those working in the field, the sophistication
`
`
`
`
`
`Noven Ex. 1010
`
`Page 5 of 42
`
`
`
`
`
`of the technology, the types of problems encountered in the art, the prior art
`
`solutions to those problems, and the speed at which innovations are made, help
`
`establish the level of skill in the art.
`
`9.
`
`It is my opinion that the subject matter of the ʼ023 patent draws from
`
`several disciplines, and as such, the patent is directed to a collaborative team of
`
`individuals in which each person would have been able to draw upon the
`
`experiences and knowledge of the others. In particular, the person of ordinary skill
`
`is a chemist, chemical engineer, polymer chemist, or pharmaceutical chemist
`
`working to develop pharmaceutical formulations, including transdermal drug
`
`delivery systems. The person of ordinary skill would be familiar with the testing
`
`that accompanies the development of any pharmaceutical formulation, including
`
`testing for efficacy and stability. The person of ordinary skill would be familiar
`
`with excipients typically employed in pharmaceutical formulations, including
`
`transdermal devices. The person of ordinary skill would have knowledge of
`
`organic chemistry, or would collaborate with a person having knowledge of
`
`organic chemistry, and would be able to make predictions about the physical
`
`properties of a compound based upon its chemical structure.
`
`10.
`
`I have been informed by counsel for Noven, and understand, that if a
`
`single prior art reference discloses each limitation recited in a claim, the claim is
`
`unpatentable as anticipated. I further understand that the prior art reference need
`
`
`
`
`
`Noven Ex. 1010
`
`Page 6 of 42
`
`
`
`
`
`not explicitly disclose each limitation, but can do so inherently.
`
`11.
`
`I have been informed by counsel for Noven, and understand, that if the
`
`differences between the claimed subject matter and prior art are such that the
`
`claimed subject matter as a whole would have been obvious to a person of ordinary
`
`skill, then the patent claim is unpatentable as obvious. I understand that the
`
`following factors must be evaluated in determining whether the claimed subject
`
`matter is obvious: (1) the scope and content of the prior art; (2) the differences
`
`between the claim and the prior art; (3) the level of ordinary skill in the art at the
`
`time the patent was filed; and (4) any secondary considerations of nonobviousness.
`
`12.
`
`I have been informed by counsel for Noven, and understand, that
`
`secondary considerations of non-obviousness are part of the obviousness inquiry,
`
`and that some examples of secondary considerations that tend to show non-
`
`obviousness include:
`
`(1)
`
`any long-felt and unmet need in the art that was satisfied by the
`
`invention of the patent;
`
`(2)
`
`any failure of others to achieve the results of the invention;
`
`(3)
`
`any commercial success or lack thereof of the products and processes
`
`covered by the invention;
`
`(4)
`
`any deliberate copying of the invention by others in the field;
`
`(5)
`
`any taking of licenses under the patent by others;
`
`
`
`
`
`Noven Ex. 1010
`
`Page 7 of 42
`
`
`
`
`
`(6)
`
`any expression of disbelief or skepticism by those skilled in the art
`
`upon learning of the invention;
`
`(7)
`
`any unexpected results achieved by the invention;
`
`(8)
`
`any praise of the invention by others skilled in the art; and
`
`(9)
`
`any lack of contemporaneous and independent invention by others.
`
`I understand that the factfinder(s) must determine whether potential evidence of
`
`secondary considerations has a nexus to the claimed invention.
`
`13.
`
`I have been informed by counsel for Noven, and understand, that in the
`
`context of these proceedings, a claim will be found unpatentable as obvious if the
`
`preponderance of the evidence indicates that the claim would have been obvious. I
`
`further understand that in the context of these proceedings, a claim is not presumed
`
`to be valid.
`
`V. THE CHALLENGED CLAIMS
`14.
`I have reviewed each of the claims in the ʼ023 patent, and understand that
`
`Noven is challenging claims 1-2, 4-5, and 7-8 as unpatentable. Claims 1 and 7 are
`
`independent and are reproduced below (spacing added for ease of reading):
`
`1.
`
`A pharmaceutical composition comprising
`
`1 to 40 weight percent of (S)-N-ethyl-3-[(1-dimethylamino)
`ethyl]-N-methylphenyl carbamate in the form of a free base or
`acid addition salt,
`
`0.01 to 0.5 weight percent of an antioxidant, and
`
`
`
`
`Noven Ex. 1010
`
`Page 8 of 42
`
`
`
`
`
`a diluent or carrier,
`
`wherein the weight percents are based on the total weight of the
`pharmaceutical composition.
`
`7. A transdermal device comprising a pharmaceutical composition
`comprising
`
`1 to 40 weight percent of (S)-N-ethyl-3-[(1-dimethylamino)
`ethyl]-N-methylphenyl carbamate in the form of a free base or
`acid addition salt,
`
`0.01 to 0.5 weight percent of an antioxidant, and
`
`a diluent or carrier,
`
`wherein the weight percents are based on the total weight of the
`pharmaceutical composition.
`
`VI. CLAIM CONSTRUCTION
`15.
`I have been informed by counsel for Noven, and understand, that in the
`
`context of the current proceedings, each of the terms in the claims is given its
`
`broadest reasonable interpretation in light of the specification. I have reviewed the
`
`specification of the ʼ023 patent, and in my opinion there are no special definitions
`
`attributed any of the claim terms. As such, I interpret the claim terms under the
`
`“broadest reasonable” standard, and in particular to have the following meanings in
`
`light of the specification:
`
` Pharmaceutical Composition – In my opinion, a pharmaceutical
`
`
`
`
`Noven Ex. 1010
`
`Page 9 of 42
`
`
`
`
`
`composition is a composition suitable for pharmaceutical use, e.g. for
`
`administration to a patient.
`
` Antioxidant – In my opinion, an antioxidant is a compound that reduces
`
`or prevents the oxidative decomposition of other compound(s).
`
` Diluent or carrier – In my opinion, a diluent or carrier is an inactive
`
`ingredient(s) that aid(s) in the administration of the drug.
`
` Transdermal device – In my opinion, transdermal device means medical
`
`device for systemic drug administration through skin.
`
` The claim term “(S)-N-ethyl-3-[(1-dimethylamino) ethyl]-N-
`
`methylphenyl carbamate” refers to rivastigmine, which has the following
`
`chemical structure:
`
`CH3
`
`O
`
`N
`CH3
`
`CH3
`N
`
`CH3
`
`(S)
`
`O
`
`CH3
`rivastigmine
`
`H
`
`
`
`Rivastigmine is the S-enantiomer of a racemic compound known as RA7. (Ex.
`
`1002 at 3.) As a racemate, RA7 is comprised of an equal mixture of rivastigmine
`
`and its enantiomer ent-rivastigmine, or (R)-rivastigmine:
`
`
`
`
`
`Noven Ex. 1010
`
`Page 10 of 42
`
`
`
`
`
`CH3
`
`O
`
`N
`CH3
`
`O
`
`RA7
`
`CH3
`N
`
`CH3
`
`=
`
`CH3
`
`H
`
`CH3
`
`CH3
`
`O
`
`N
`CH3
`
`O
`
`N
`CH3
`
`O
`
`+
`
`O
`
`CH3
`N
`
`CH3
`
`(S)
`
`CH3
`
`H
`
`CH3
`N
`
`CH3
`
`(R)
`
`CH3
`
`H
`
`rivastigmine
`
`ent-rivastigmine
`
`
`
`VII. BACKGROUND AND STATE OF THE ART
`16. There are several ways in which a physiologically active compound may
`
`be administered to a patient, including enterally (i.e., administration through the
`
`digestive system using, for instance, oral, sublingual or rectal administration);
`
`parenterally (e.g., injection or infusion); and topically (e.g., transdermal
`
`administration). Each mode of administration has attributes that make it more or
`
`less desirable depending on the particular drug. For instance, oral administration is
`
`a practical method of administering drugs to most patients. However, if the drug is
`
`not adsorbed from the gastrointestinal system, is destroyed by stomach acid, or
`
`causes nausea, it may not be suitable for oral administration. In such cases, an
`
`injectable dosage form may be an alternative. However, injectable dosage forms
`
`place greater burdens on the patient, as the injection often must be given by a
`
`medical professional, and can cause discomfort and infection at the injection site.
`
`17. The transdermal delivery of a drug avoids the physiochemical difficulties
`
`associated with oral administration, and does not burden the patient with a painful
`
`
`
`
`
`Noven Ex. 1010
`
`Page 11 of 42
`
`
`
`
`
`or time-consuming injection. In addition, transdermal administration avoids
`
`metabolism of the drug by the liver (so called “first-pass metabolism”).
`
`Transdermal delivery systems can provide release for long periods of time, and can
`
`improve patient compliance. Furthermore, in the context of patients with
`
`dementia, transdermal administration offers the additional benefit that it
`
`circumvents difficulties associated with patients unable or unwilling to swallow an
`
`oral dosage form, and allows caregivers to conveniently administer the drug.
`
`18. Generally, a transdermal device consists of at least three separate
`
`domains, a layer which contains the drug substance (i.e., the active ingredient) and
`
`one or more excipients or carriers (i.e., the pharmaceutical composition); an
`
`impermeable backing layer which prevents the drug substance from diffusing in
`
`directions other than into the skin and protects the drug substance during use of the
`
`device; and a removable layer which protects the pharmaceutical composition until
`
`the device is applied to the skin.
`
`19. The use of transdermal drug delivery systems was well-established prior
`
`to the earliest claimed priority date of the ʼ023 patent (which I am advised by
`
`counsel for Noven is January 12, 1998). The first transdermal device approved by
`
`the FDA contained the active pharmaceutical ingredient scopolamine, and was
`
`approved in 1979.
`
`20. For any drug product to be medically (and commercially) successful, it
`
`
`
`
`
`Noven Ex. 1010
`
`Page 12 of 42
`
`
`
`
`
`must meet several criteria. The drug must confer benefits to patients to an extent
`
`sufficient to outweigh negative side effects associated with the drug. The calculus
`
`of an acceptable benefit/side effect ratio is contextual—severe side effects may be
`
`acceptable for a cancer drug, but unacceptable for a drug that is intended to reduce
`
`mild fever.
`
`21. Another critical aspect is the stability of the drug substance and other
`
`excipients in the product. In the context of pharmaceutical products, “stability”
`
`refers to the ability of a product to have the same safety and potency for a specified
`
`period of time after the product is manufactured. The drug substance and
`
`excipients may convert over time to a different chemical compounds (i.e.,
`
`decompose). At best, any conversion simply diminishes potency, while at worst, it
`
`may form toxic compounds. In general, persons of ordinary skill in the art strive to
`
`develop stable pharmaceutical products with a commercially viable shelf life.
`
`22.
`
`Issues of product stability can be especially important in the development
`
`of transdermal devices. This is because, for example, the preparation of
`
`transdermal patches often involves intermediate steps where the drug substance is
`
`in solution, and because the drug substance may remain in solution or suspension
`
`in the finished drug product. This permits the drug to undergo reactions more
`
`readily than in completely solid dosage forms.
`
`23. Stability of the drug substance is one of the first considerations addressed
`
`
`
`
`
`Noven Ex. 1010
`
`Page 13 of 42
`
`
`
`
`
`in early drug product development. The formulator will seek to understand the
`
`mechanisms of degradation of the drug substance, including identifying functional
`
`groups and labile centers, and will consider how the drug substance behaves under
`
`external factors such as pH, temperature, humidity, and light.
`
`24. The pathways by which a drug may degrade depend on the molecular
`
`structure of the drug. For instance, a compound containing an ester functional
`
`group may be susceptible to hydrolysis. A compound containing an oxidizable
`
`functional group may be susceptible to oxidation.
`
`25. The formulator will also consider drug-excipient interactions, and will
`
`take all of this information into account in designing a stable formulation. Indeed,
`
`regulatory guidelines in effect as of January 1998 recommended that applicants
`
`perform stability tests on the drug substance and drug product. This included
`
`stress testing on the drug substance to determine its intrinsic stability and
`
`degradation pathways, as well as formal studies on the drug substance to show that
`
`it will remain within specification during the re-test period if stored under the
`
`recommended storage conditions. (See ICH Topic Q 1 A, Stability Testing
`
`Guidelines: Stability Testing of New Drug Substances and Products
`
`(CPMP/ICH/380/95) (Ex. 1014).)
`
`
`
`
`
`Noven Ex. 1010
`
`Page 14 of 42
`
`
`
`
`
`VIII. SPECIFIC PRIOR ART REFERENCES
`A.
`Sramek and the Formulary Article
`I have reviewed “Safety/Tolerability Trial of SDZ ENA 713 in Patients
`
`26.
`
`with Probable Alzheimer’s Disease,” John J. Sramek et al., Life Sciences, Vol. 58,
`
`No. 15, pp. 1201-1207, 1996 (“Sramek,” Ex. 1012) and “New acetylcholinesterase
`
`inhibitor shows promise in largest Alzheimer’s trial to date,” Formulary, Vol. 32,
`
`Dec. 1997 (the “Formulary Article,” Ex. 1013). Sramek and the Formulary Article
`
`teach that the compound rivastigmine (also known as ENA 713) was being
`
`developed as a treatment for Alzheimer’s disease. (Ex. 1012 at 1; Ex. 1014 at 3.)
`
`27. Rivastigmine was reportedly well-tolerated, with the majority of patients
`
`experiencing only mild-to-moderate adverse events. (Ex. 1012 at 6; Ex. 1013 at 3.)
`
`Rivastigmine was characterized as an improvement over tacrine, a first-generation
`
`acetylcholinesterase inhibitor used to treat Alzheimer’s disease. (Ex. 1012 at 1-2.)
`
`In addition, the Formulary Article noted that rivastigmine was given twice a day,
`
`while donepezil, a newly-approved second generation acetylcholinesterase
`
`inhibitor, was given once a day. (Ex. 1013 at 3.)
`
`B. U.S. Patent 4,948,807 (“Rosin”)
`I have reviewed the Rosin reference. It discloses the compound RA7,
`
`28.
`
`which is racemic rivastigmine. (Ex. 1008 at, e.g., 5:44-45, 14:17-19, 10:10-27.) In
`
`my opinion, a person of ordinary skill would have understood that RA7 was an
`
`especially promising compound both because it was called out as a single species
`
`
`
`
`Noven Ex. 1010
`
`Page 15 of 42
`
`
`
`
`
`in claim 3, and because it had one of the highest therapeutic ratios (efficacy vs.
`
`toxicity) of all the disclosed compounds (Table 3). (Id. at 14:17-19, 10:59-11:17.)
`
`Rosin teaches that the “compounds of the present invention” could be made into
`
`pharmaceutical compositions that could be prepared with an antioxidant. (Id. at
`
`8:56, 7:45-50.) Rosin teaches that preferred antioxidants for use with the
`
`compounds of the present invention include sodium metabisulphite and ascorbic
`
`acid. (Id. at 7:51-53.) In my opinion, one of ordinary skill would have readily
`
`understood RA7 was a “compound of the present invention,” as the term was used
`
`by Rosin, for the same reasons that it was a promising drug candidate.
`
`29.
`
`In my opinion, a teaching that the racemic compound RA7 is susceptible
`
`to oxidative degradation is equally applicable to the single enantiomer
`
`rivastigmine. Although the properties of enantiomers and racemates can differ in
`
`certain situations, e.g. in biological activity, in the context of an aqueous solution
`
`or dispersion in a polymer, each enantiomer will typically behave the same.
`
`Therefore, based on the teaching of Rosin that RA7 could be formulated with an
`
`antioxidant, the person of ordinary skill would have understood that rivastigmine
`
`was susceptible to oxidative degradation.
`
`C. Elmalem et al. Neuropharmacology, Vol. 30, pp. 1059-64 (1991)
`(“Elmalem”)
`
`30.
`
`I have reviewed the Elmalem reference, and understand it to teach
`
`compositions of the racemic compound RA7 and an antioxidant. Elmalem
`
`
`
`
`Noven Ex. 1010
`
`Page 16 of 42
`
`
`
`
`
`describes experiments designed to compare three drugs, RA6, RA7, and RA15, to
`
`physostigmine with respect to the drugs’ ability to counteract morphine-induced
`
`respiratory depression in rabbits. (Ex. 1009 at 1.) Elmalem describes two different
`
`aqueous solutions of RA7 with sodium metabisulfite, a common antioxidant. (Ex.
`
`1009 at 2.) Elmalem explicitly teaches that the sodium metabisulfite was added in
`
`order to “prevent oxidation.” (Id.) Because the aqueous solution disclosed by
`
`Elmalem contained nothing except RA7, antioxidant, and saline, the only
`
`reasonable conclusion is that the antioxidant was added to stabilize RA7. Again,
`
`based on Elmalem, the person of ordinary skill in the art could have predicted that
`
`rivastigmine was susceptible to oxidative degradation.
`
`31.
`
`It is also my opinion that, apart from the teachings of Elmalem and Rosin,
`
`the person of ordinary skill would have expected that rivastigmine was susceptible
`
`to oxidative degradation based on its chemical structure. I have reviewed, and
`
`agree with, the Declaration of Christian Schöneich, Ph.D. (Ex. 1011), wherein he
`
`discusses the general chemistry principles that would have led one of ordinary skill
`
`in the art to reasonably expect that rivastigmine would be susceptible to oxidative
`
`degradation.
`
`D. GB 2203040 (“Enz”)
`I have reviewed the Enz reference, and understand it to disclose that the (-
`
`32.
`
`) enantiomer of the racemic compound RA7 is useful to treat cognitive diseases,
`
`
`
`
`
`Noven Ex. 1010
`
`Page 17 of 42
`
`
`
`
`
`including Alzheimer’s disease. (Ex. 1002 at 10.) Enz also teaches that the (-)
`
`enantiomer is superior to both the racemic mixture and the (+) enantiomer,
`
`including for one reason because it “exhibits a particularly marked and selective
`
`inhibition of the acetylcholinesterase.” (Id. at 2, 6.)
`
`33. Enz teaches the (-) enantiomer can be obtained by converting the racemic
`
`RA7 into the diastereomeric tartrate salts, followed by selective crystallization of
`
`the (-) enantiomer. (Id. at 3, 11.) I understand that it has been shown that the
`
`compound designated as rivastigmine, the (-) enantiomer, has the (S) absolute
`
`configuration. (Ex. 1002 at 2-3.)
`
`34. Enz teaches that rivastigmine, either as the free base or acid addition salt,
`
`may advantageously be administered transdermally. (Id. at 14-19.) Enz teaches
`
`that the pharmacokinetic profile from transdermal administration is superior to that
`
`of either oral or subcutaneous administration. (Id. at 15-16.)
`
`35. Enz discloses the preparation of a transdermal composition containing
`
`rivastigmine tartrate. (Id. at 17-20; “Compound A” is rivastigmine tartrate.) In my
`
`opinion, one of ordinary skill would have recognized that the composition
`
`described by Enz was not a finished, marketable product, but rather that Enz
`
`describes a rudimentary laboratory sample. For instance, the transdermal
`
`composition lacks a removable release liner and pouch to protect the composition
`
`prior to use. Enz also lacks any in vivo human test data associated with the
`
`
`
`
`
`Noven Ex. 1010
`
`Page 18 of 42
`
`
`
`
`
`example transdermal composition. As such, an ordinarily-skilled artisan would
`
`have viewed the composition disclosed by Enz as a starting point for further
`
`development, rather than a finished product. Indeed, Enz specifically cites several
`
`other documents for additional information regarding transdermal delivery
`
`systems. (Ex. 1002 at 17, citing to, e.g., Remington’s Pharmaceutical Sciences,
`
`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,
`
`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
`
`transdermal device that avoids the use of drying. (Id. at 7.) Specifically, the drug,
`
`
`
`
`
`Noven Ex. 1010
`
`Page 19 of 42
`
`
`
`
`
`in gel form, is extruded onto one or two adhesive layers, one of which has an
`
`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
`
`
`
`
`
`Noven Ex. 1010
`
`Page 20 of 42
`
`
`
`
`
`biological material that may be delivered transdermally. (Id. at 10-11 and 15.)
`
`JP 59-184121 (“Sasaki”)
`
`F.
`I have reviewed a translation of the Sasaki reference. (Ex. 1005.) I
`
`40.
`
`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
`
`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
`
`
`
`
`
`Noven Ex. 1010
`
`Page 21 of 42
`
`
`
`
`
`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”)
`I reviewed the Handbook of Pharmaceutical Excipients (2nd Ed. 1994,
`
`42.
`
`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
`
`In aqueous formulations, 0.01-0.1 %
`
`p. 8
`
`
`
`
`
`Noven Ex. 1010
`
`Page 22 of 42
`
`
`
`
`
`w/v
`
`BHT
`
`In IV injections, 0.0009-0.002 % w/v
`
`pp. 19-20
`
`In topical formulations, 0.0075-0.1 %
`
`w/w
`
`α-tocopherol
`
`0.001 to 0.05 wt%
`
`pp. 5-6
`
`pp. 12-13
`
`Not provided
`
`Ascorbyl
`
`palmitate
`
`BHA
`
`In IV injections, 0.0002-0.0005 % w/v
`
`pp. 17-18
`
`In topical formulations, 0.005-0.02 %
`
`w/w
`
`Propyl gallate
`
`≤0.1% % w/v
`
`pp. 21-23
`
`H. European Patent Application 0 155 229 (“Kissel”)
`44.
`I have reviewed European Patent Application 0 155 229, titled
`
`“Pharmaceutical Compositions,” published on September 18, 1985 to Kissel et al.
`
`(“Kissel,” Ex. 1007).
`
`45. Enz (Ex. 1002) cites Kissel for additional information regarding the
`
`construction of transdermal dosage forms. (Ex. 1002 at 17.) Kissel describes
`
`pharmaceutical compositions for transdermal administration. For example, Figures
`
`1 and 2 are cross-sections through the layers of representative transdermal devices.
`
`
`
`
`
`Noven Ex. 1010
`
`Page 23 of 42
`
`
`
`
`
`(Ex. 1007 at 17:7-27.) Layer (e) (shown in Figure 2) is a protective peel-off layer,
`
`which, upon use, is peeled off so that the device can be stuck to skin. (Id. at 17:24-
`
`27.) Peel-off layers are, and were at the time of the alleged invention, common
`
`components of transdermal systems.
`
`IX. GROUNDS OF UNPATENTABILITY
`(1). There was motivation to modify existing rivastigmine
`treatments
`46. Enz teaches that compared to its racemate, rivastigmine exhibits
`
`particularly marked and selective acetylcholinesterase inhibition (Ex. 1002 at 3),
`
`that it can be prepared using known techniques (id.), and that it can be formulated
`
`into pharmaceutical compositions (id. at 11). In particular, Enz exemplifies a
`
`transdermal device that contains 20% rivastigmine tartrate, together with polymers
`
`and a plasticizer. (Id. at 20.) Enz also teaches that transdermal administration of
`
`rivastigmine is particularly advantageous,