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`On Behalf Of:
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`Noven Pharmaceuticals, Inc.
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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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`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 No.: 2014-00550
`U.S. Patent No. 6,335,031
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`PETITIONER’S REPLY
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`TABLE OF CONTENTS
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`Page
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`INTRODUCTION ........................................................................................... 1
`I.
`II. OBSERVING RIVASTIGMINE’S OXIDATIVE
`DEGRADATION IS NOT A PATENTABLE INVENTION ........................ 2
`III. A POSA WOULD HAVE REASONABLY EXPECTED
`RIVASTIGMINE TO OXIDATIVELY DEGRADE BASED
`ON ITS CHEMICAL STRUCTURE .............................................................. 4
`A. Dr. Schoneich’s Opinions Are Not “Theoretical”................................. 4
`The Known Susceptibility of Nicotine to Oxidation Would Have
`B.
`Informed the POSA’s Expectation About Rivastigmine ...................... 5
`Testing Would Not Have Been Required for a POSA to Determine
`that Rivastigmine Is Particularly Susceptible to Oxidation .................. 6
`Susceptibility to Oxidation Would Have Been Predicable ................... 7
`D.
`IV. THE PRIOR ART DOES NOT TEACH THAT
`RIVASTIGMINE IS OXIDATIVELY STABLE ........................................... 9
`
`C.
`
`B.
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`V. A POSA WOULD HAVE BEEN MOTIVATED TO
`COMBINE THE TEACHINGS OF THE PRIOR ART TO
`ARRIVE AT THE CLAIMED INVENTION ............................................... 10
`A. A POSA Would Not Draw the Artificial Distinctions Among the Prior
`Art that Patent Owners Assert ............................................................. 11
`Patent Owners Cannot Avoid the Plain Language of Rosin, Elmalem,
`and Sasaki. ...............................................................................................
`
` ................................................................................................... 12
`VI. THE PRIOR ART DID NOT DISCOURAGE THE USE OF
`ANTIOXIDANTS ......................................................................................... 14
`VII. CONCLUSION .............................................................................................. 15
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`i
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`TABLE OF AUTHORITIES
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`Page(s)
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`Cases
`In re Omeprazole Patent Litig.,
`536 F.3d 1361 (Fed Cir. 2008) ............................................................................... 3
`
`Activevideo Networks, Inc. v. Verizon Commc’ns., Inc.,
`694 F.3d 1312 (Fed. Cir. 2012) ............................................................................ 11
`
`Arlington Indus., Inc. v. Bridgeport Fittings, Inc.,
`581 F. App’x. 859 (Fed. Cir. 2014) ........................................................................ 3
`
`Chapman v. Casner,
`315 F. App’x. 294 (Fed. Cir. 2009) ........................................................................ 2
`
`In re Nomiya,
`509 F.2d 566 (C.C.P.A. 1975) ................................................................................ 2
`
`In re Peehs,
`612 F.2d 1287 (C.C.P.A. 1980) .............................................................................. 2
`
`Innogenetics, N.V. v. Abbott Labs.,
`512 F.3d 1363 (Fed. Cir. 2008) ............................................................................ 11
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................. 10
`
`Leo Pharm. Prods. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) ..........................................................................2, 3
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`ii
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`I.
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`Introduction
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`Patent Owners do not challenge the scientific basis for the POSA’s
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`reasonable expectation of rivastigmine’s susceptibility to oxidative degradation,
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`and either mischaracterize the prior art (and Dr. Kydonieus’ explanations thereof)
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`or raise speculative alternative explanations that find no basis in the prior art’s
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`plain-language text. This is nothing more than collateral evidence designed to
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`distract from the teachings of the prior art and the reasonable expectations the
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`POSA would have maintained based on that art.
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`Patent Owners do not challenge that Enz is a proper starting point for this
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`obviousness analysis, and do not dispute that it would have been routine work for
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`the POSA to select an antioxidant that works in a particular formulation. Patent
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`Owners do not assert that any elements of the challenged ’031 patent claims are
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`not found in the prior art, or that any particular feature of dependent claims 2-3, 7,
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`14, 16 or 18 separately supports patentability. Further, Patent Owners have waived
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`any arguments for secondary considerations of non-obviousness by not presenting
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`them in their Response. (Paper 11 at 3 “any arguments for patentability not raised
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`in the response will be deemed waived.”)
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`Patent Owners rely on the purported lack of motivation to add an antioxidant
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`to a rivastigmine pharmaceutical composition. But as Petitioners have shown, the
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`evidence that a POSA would have maintained a reasonable expectation of
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`1
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`rivastigmine’s propensity to oxidatively degrade extinguishes any notion that
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`observing rivastigmine’s degradation is the basis of an invention, and thus claims
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`1-3, 7, 14-16 and 18 of the ’031 patent are unpatentable.
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`II. Observing Rivastigmine’s Oxidative Degradation Is Not A Patentable
`Invention
`The observation of a problem is not per se a patentable invention. (Paper 25
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`at 5.) Rather, the obviousness inquiry must consider whether the POSA would
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`have reasonably expected the problem or what the prior art as a whole would have
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`suggested to the POSA. See, e.g., Chapman v. Casner, 315 F. App’x. 294, 298-
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`299 (Fed. Cir. 2009) (Rader, Cir. J., dissenting, noting that whether a POSA would
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`have expected a problem is part of the obviousness analysis); In re Peehs, 612 F.2d
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`1287, 1290 (C.C.P.A. 1980) (determinative question for obviousness was whether
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`cause of problem would have been recognized by POSA); In re Nomiya, 509 F.2d
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`566, 571-72 (C.C.P.A. 1975) (obviousness inquiry hinged on whether the prior art
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`suggested the existence of the problem solved).
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`Leo Pharm. Prods. v. Rea, 726 F.3d 1346 (Fed. Cir. 2013) is not on point.
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`In that case, the prior art’s failure to recognize the stability issue was attributed to
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`its consistent teaching away from mixing Vitamin D analogs with other drugs in
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`the first place. Id. at 1353-54, 55, 57. Further, the court found that the eventual
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`solution (use of a particular solvent) was not known or predictable. Id. at 1356-57.
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`Finally, the court found the most probative evidence of nonobviousness was
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`2
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`secondary considerations. Id. at 1358-59. See also Arlington Indus., Inc. v.
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`Bridgeport Fittings, Inc., 581 F. App’x. 859, 864 (Fed. Cir. 2014) (distinguishing
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`Leo Pharm. Prods). The Omeprazole case, 536 F.3d 1361 (Fed Cir. 2008), is
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`likewise distinguishable because the prior art taught away from the claimed
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`subcoating approach, and because the court found that other solutions were
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`available that a POSA would have tried first. Id. at 1380.
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`In the present case, the prior art is not alleged to “teach away” from the use
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`of an antioxidant with rivastigmine. (Contra Paper 25 at 20-44.) There is no
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`evidence of secondary considerations supporting nonobviousness. (Ex. 1025 at
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`131:10-13.) And, unlike Omeprazole, the use of an antioxidant is a common
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`solution to address oxidative degradation in pharmaceutical formulations. (Ex.
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`1010 ¶¶ 51, 63, 86; Ex. 1031 ¶¶ 9, 11-12, 84-86, 89, 108, 116-21, 130-33.)
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`Furthermore, the prior art instructed the POSA to consider the structural features of
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`the compound that could give rise to degradative issues (Ex. 2014 at 181-83; Ex.
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`1016 at 91), and Dr. Schöneich demonstrates that the POSA would have identified
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`features in the rivastigmine molecule rendering it “particularly susceptible” to
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`oxidative degradation (a conclusion reinforced by the POSA’s awareness of
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`nicotine and its known propensity to oxidize). (Ex. 1011 ¶¶ 12, 53-59; Ex. 1032 ¶¶
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`7-15, 52-59.) As such, the POSA would not have been surprised to observe
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`oxidative degradation (Ex. 1025 at 81:1-6; Ex. 1032 ¶ 15) and would have
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`3
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`employed the well-known solution of antioxidant use.
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`III. A POSA Would Have Reasonably Expected Rivastigmine To
`Oxidatively Degrade Based On Its Chemical Structure
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`A POSA would have expected rivastigmine to be particularly susceptible to
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`oxidative degradation from an examination of its chemical structure during
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`preformulation. (Ex. 1031 ¶¶ 7-8, 24-31, 35, 44, 93; Ex. 1032 ¶¶ 22-26.) Upon
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`examination of the structure, a POSA would have immediately recognized the
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`presence of three structural features in rivastigmine that cause a specific carbon-
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`hydrogen bond in the molecule to be “especially weak” and therefore “particularly
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`susceptible” to oxidation: the carbon-hydrogen bond is immediately adjacent to
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`each of (i) an aromatic ring (i.e., the carbon-hydrogen bond is at a benzylic
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`position); (ii) a tertiary amine; and (iii) an additional carbon substituent (–CH3),
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`making the carbon a tertiary carbon. (Ex. 1011 ¶¶ 19-35, 53-59; Ex. 1032 ¶¶ 7-15.)
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`Importantly, Dr. Klibanov does not dispute the technical conclusions that these
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`particular structural features of rivastigmine result in a weakened C-H bond and
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`that the molecule was susceptible to oxidative degradation on this basis. (See Ex.
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`1032 ¶ 14.)
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`A. Dr. Schoneich’s Opinions Are Not “Theoretical”
`Dr. Schöneich’s opinions are not “theoretical” as Patent Owners argue
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`(Paper 25 at 16), but rather are based on well-known chemical principles,
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`confirmed by standard textbooks, that determine if a particular bond in a molecule
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`4
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`will be weak and therefore susceptible to oxidation. (Ex. 1011 ¶¶ 19-35; Ex. 1032
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`¶¶ 7-15, 20; Ex. 1007 at 680, 693.) The POSA was instructed by the prior art to
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`consider chemical structure in identifying modes of degradation, and was informed
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`that “[b]enzylic, allylic, and tertiary positions are especially susceptible to
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`oxidation.” (Ex. 1007 at 693; Ex. 1032 ¶¶ 11, 22-25.)
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`Patent Owners’ attempts to redefine “susceptible” by cherry-picking from
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`Dr. Schöneich’s testimony are misleading and their statement that “essentially all
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`organic compounds can undergo oxidative degradation under sufficiently harsh
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`conditions (e.g., burning)” misses the point. (Paper 25 at 16.) A POSA would
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`have been concerned with susceptibility to degradation under pharmaceutically
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`relevant conditions and not “sufficiently harsh conditions (e.g., burning).”
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`(Ex. 1032 ¶ 18.) Moreover, Dr. Schöneich testified that “susceptibility” means
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`“likelihood” as he in fact stated that a POSA would have understood that
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`rivastigmine, due to the presence of three adjacent functional groups, would be
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`“particularly susceptible” and “prone to oxidation” because it contains an
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`“especially weak,” and “readily-cleaved C-H bond.” (See, e.g., Ex. 1025 at 48:2-
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`49:13; Ex. 1011 ¶¶ 12, 55; Ex. 1032 ¶ 19.)
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`B.
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`The Known Susceptibility of Nicotine to Oxidation Would Have
`Informed the POSA’s Expectation About Rivastigmine
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`The relevant structural similarities between nicotine and rivastigmine, and
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`nicotine’s known susceptibility to oxidative degradation, would have reinforced
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`5
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`the POSA’s expectation that rivastigmine is particularly susceptible to oxidation.
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`(Ex. 1011 ¶¶ 48-49, 56-59; Ex. 1032 ¶¶ 52-59.) It is undisputed that nicotine was
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`known to undergo oxidative degradation under pharmaceutically relevant
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`conditions including in transdermal formulations. (Ex. 1011 ¶¶ 48-49; Ex. 1032 ¶¶
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`56, 59; Ex. 1021 at 90-91; Ex. 1026 at 563:3-11.) Dr. Klibanov fails to state why
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`any of the differences he identified between rivastigmine and nicotine would be
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`considered important to a POSA or change Dr. Schöneich’s conclusion. (Ex. 1032
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`¶¶ 52-56.) Moreover, Dr. Klibanov testified that rivastigmine and nicotine do in
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`fact share all the relevant features that a POSA would identify as causing
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`rivastigmine to be particularly susceptible to oxidation. (Ex. 1026 at 539:15-
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`541:23; Ex. 1032 ¶ 56.)
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`C. Testing Would Not Have Been Required for a POSA to Determine
`that Rivastigmine Is Particularly Susceptible to Oxidation
`Contrary to Patent Owners’ assertion (Paper 25 at, e.g., 16, 19), testing
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`would not have been required for a POSA to determine that rivastigmine is
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`particularly susceptible to oxidative degradation under pharmaceutically relevant
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`conditions. Patent Owners mischaracterize the testimony of Dr. Kydonieus and
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`Schöneich in an attempt to avoid this conclusion. (Paper 25 at 2.) That oxidation
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`is formulation dependent does not support Patent Owners’ contentions that testing
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`is required to identify the problem or that a POSA cannot apply observations from
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`a different dosage form. (Paper 25 at, e.g., 5, 13, 19.) A POSA would have known
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`6
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`that oxidation depends upon the presence of initiators and can be prevented by
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`excluding initiators (which can be difficult), eliminating oxygen, or adding an
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`antioxidant. (Ex. 1032 ¶ 26.) No matter the formulation, susceptibility to
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`oxidation is an inherent property of the drug based on the chemical structure. (Id.)
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`Testing may be used to determine to what extent oxidation occurs in a
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`particular formulation after the expectation is identified. (Ex. 1031 ¶ 25.)
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`Examination of the chemical structure was a routine “fundamental process” in
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`preformulation analysis that allowed a POSA to identify susceptibility to oxidative
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`degradation. (Ex. 1025 at 74:1-16; see also Ex. 1032 ¶¶ 22-25, Ex. 2020 at 110,
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`Ex. 2014 at 181, Ex. 1031 ¶¶ 28-37.) Once identified, a POSA would not have
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`been surprised when actually observing the expected degradation. (Ex. 1031 ¶¶ 10,
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`25, 92; Ex. 1032 ¶ 15; Ex. 1025 at 81:1-6.)
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`Patent Owners’ statement that the inventors of the ’031 patent required
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`“exhaustive testing” to determine that rivastigmine undergoes oxidative
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`degradation (Paper 25 at 19) is
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`. (Ex. 1031 ¶ 130-31; Ex. 1033 at N0272229.)
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`Susceptibility to Oxidation Would Have Been Predicable
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`D.
`Patent Owners’ attempts to cast oxidation reactions as a nascent field of
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`7
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`chemistry is of course contradicted by the prior art’s textbook teachings on the
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`subject. (Ex. 1032 ¶¶ 7-15; Ex. 2014 at 181-83; Ex. 1016 at 91; Ex. 1007 at 683;
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`Ex. 1025 at 65:4-67:23.) Patent Owners’ attempts to impute unpredictability from
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`notions of “complexity” fail because they only address the reaction mechanism of
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`oxidation and not the susceptibility of the molecule itself to undergo the reaction.
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`(Contra Paper 25 at 18-19; Ex. 1032 ¶¶ 30-36.) All of the art relied on by Patent
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`Owners explicitly relates to the mechanisms of oxidation and not to the
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`susceptibility of a drug to oxidation. (Ex. 2012 ¶ 121; Ex. 2014 at 183; Ex. 1015 at
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`82; Ex. 1032 ¶ 33.) As Dr. Schöneich explained, susceptibility to oxidation is
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`independent from the mechanisms of oxidation reactions, so these arguments have
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`no merit. (Ex. 1032 ¶¶ 32-36.)
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`Dr. Klibanov’s argument that degradation reactions are unpredictable
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`because “the structure of the molecule as a whole (and not just the presence of
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`certain functional groups) determines the stability” (Ex. 2012 ¶ 120; see also Paper
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`25 at 18) is incorrect. The ability to predict reactivity based on functional group
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`properties is a foundation of organic chemistry. (Ex. 1032 ¶¶ 22-25.) A POSA
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`would have understood that the presence of particular functional groups in a
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`molecule has consequences. (Ex. 1031 ¶ 28-29; Ex. 1032 ¶¶ 7-13, 24-25.) Dr.
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`Klibanov contradicts his “whole molecule” notion, when he applies standard
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`functional group chemistry in his declaration. (Ex. 1032 ¶¶ 27-29.)
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`8
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`Patent Owners’ reliance on commercial formulations lacking an antioxidant
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`does not support the proposition that examination of chemical structure lacks
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`predictive value. (Ex. 1032 ¶¶ 41-51.) Dr. Klibanov confirmed that one cannot
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`draw any conclusions regarding the drug’s susceptibility to oxidation from the fact
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`that it is formulated without a “reported” antioxidant because a POSA could take
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`other known steps to prevent oxidation. (Ex. 1032 ¶ 42; Ex. 1026 at 551:9-553:6;
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`see Ex. 2012 ¶ 45 (air-tight packaging as a counter-measure.) Dr. Schöneich
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`agreed. (Ex. 1025 at 91:8-92:2.) Moreover, Patent Owners’ assertion that certain
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`pharmaceutical compounds “were not reported to undergo oxidation” has no basis
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`in fact. (Paper 25 at 18, 20.) Patent Owners cite the Physician’s Desk Reference
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`(PDR), which provides prescribing information on approved drugs, and would not
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`be expected to report whether or not drugs undergo oxidation. (Ex. 1031 ¶ 32.)
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`IV. The Prior Art Does Not Teach that Rivastigmine is Oxidatively Stable
`Contrary to Patent Owners’ assertion (Paper 25 at 13-15), the prior art does
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`not teach that rivastigmine (or its racemate, RA7) is oxidatively stable. A POSA
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`would not have considered the prior art statements that rivastigmine was more
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`stable than physostigmine to mean that rivastigmine (or RA7) was stable because
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`physostigmine was known to be a particularly unstable drug. (Ex. 1031 ¶¶ 47-48.)
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`Physostigmine was known to be “chemically unstable” with a “relatively short
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`half-life (20-40 mins).” (Ex. 1008 at 1:30-37; Ex. 1026 at 379:16-380:5, 424:6-
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`9
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`425:23.) Indeed, Dr. Klibanov testified that physostigmine was known to be a
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`“particularly labile compound.” (Ex. 1026 at 425:6-8.)
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`A POSA would not understand the prior art statements that rivastigmine (or
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`RA7) has “greater chemical stability” than physostigmine to encompass oxidation.
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`(Contra Paper 25, e.g., at 15, 25-26, 28.) A POSA would have recognized that
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`physostigmine does not have the structural features that render rivastigmine
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`susceptible to oxidation. (Ex. 1032 ¶¶ 65-67.) For that reason, any improved
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`stability of rivastigmine over physostigmine would not change the POSA’s
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`understanding that rivastigmine is particularly susceptible to oxidation. (Id.)
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`V. A POSA Would Have Been Motivated To Combine The Teachings of
`The Prior Art To Arrive At The Claimed Invention
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`There was ample motivation for a POSA to combine the prior art in the
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`manner asserted by Petitioner. Patent Owners assertion that the prior art does not
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`explicitly state that rivastigmine undergoes oxidative degradation (Paper 25 at, e.g.,
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`3, 15), even if true, is not the end of the obviousness inquiry because it excludes
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`the other knowledge a POSA would have. Motivation to add an antioxidant to a
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`rivastigmine formulation need not be explicit in the prior art. KSR Int’l Co. v.
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`Teleflex Inc., 550 U.S. 398, 419 (2007). Motivation can come from the knowledge
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`and common sense possessed by the ordinarily skilled artisan.1 Id. at 402-3. A
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`1 Innogenetics is not applicable because, unlike here, that defendant “did not offer
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`10
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`POSA would have had knowledge of chemistry, including knowledge of bond-
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`strengths and structural features that cause certain bonds to be particularly weak
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`and therefore susceptible to oxidation. (Ex. 1011 ¶¶ 14-31; Ex. 1032 ¶¶ 5, 7-15.)
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`Therefore, even if the prior art does not expressly disclose rivastigmine’s oxidative
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`behavior, the POSA’s knowledge of chemistry and formulation principles from
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`other prior art provides the expectation of rivastigmine’s susceptibility to oxidative
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`degradation, which is itself a motivation to combine the prior art asserted by
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`Petitioners. (Ex. 1032 ¶¶ 24-25; Ex. 1031 ¶¶ 8-9, 24-30, 93.)
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`A. A POSA Would Not Draw the Artificial Distinctions Among the
`Prior Art that Patent Owners Assert
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`Patent Owners’ attempt to manufacture artificial, non-substantive
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`differences among the prior art fails. (Ex. 1031 ¶¶ 92-110; contra Paper 25 at 13,
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`27, 35-36, 37-39 and Ex. 2012 ¶¶ 13, 60, 69, 74, 78, 168-74.) A POSA would
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`
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`any motivation [for a POSA] to combine the particular references,” and there was a
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`“complete absence of any proof” that a POSA would find the method obvious
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`based on prior art or the knowledge possessed by a POSA. Innogenetics, N.V. v.
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`Abbott Labs., 512 F.3d 1363, 1374 (Fed. Cir. 2008). Likewise, in Activevideo,
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`unlike here, the defendant Verizon offered only generic motivation, such as “to
`
`build something better.” Activevideo Networks, Inc. v. Verizon Commc’ns., Inc.,
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`694 F.3d 1312, 1328 (Fed. Cir. 2012).
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`11
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`have understood that the susceptibility to oxidative degradation is a property
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`inherent to rivastigmine, and therefore a POSA would not have been dissuaded
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`from combining prior art based on alleged differences in the mode of drug
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`administration or manufacturing method disclosed in prior art references. (Ex.
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`1031 ¶¶ 8-10, 54, 92-110.)
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`In any case, Patent Owners mischaracterize the prior art. Patent Owners
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`assert that Enz (Ex. 1002) applies only to transdermal-type drug administration by
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`limiting their analysis to Example 2, (Ex. 1031 ¶¶97-100; contra Paper 25 at 21, 27,
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`36), but a POSA would have considered Enz as a whole, and understood that it
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`applies to all conventional forms of administration of rivastigmine. (Ex. 1031 ¶¶
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`97-100.) Similarly, Rosin (Ex. 1008) is applicable to all conventional routes of
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`administration, including transdermal delivery. (Id. at ¶¶ 61-64, 123.) Further,
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`neither Enz nor Ebert would have been understood by a POSA to be limited to a
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`particular method of manufacture. (Ex. 1031 ¶ 109-110.)
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`Contrary to Patent Owners’ assertion, a POSA would have considered the
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`disclosures of Rosin and Elmalem to be relevant to rivastigmine, because RA7 and
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`rivastigmine behave the same with respect to oxidative degradation. (Ex. 1031 ¶¶
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`104-105; contra Paper 25 at 3 and Ex. 2012 ¶¶ 104-05.)
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`B.
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`Patent Owners Cannot Avoid the Plain Language of Rosin,
`Elmalem, and Sasaki.
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`Rosin would have motivated a POSA to add an antioxidant to a rivastigmine
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`12
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`transdermal composition such as that of Example 2 of Enz (Ex. 1002). Patent
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`Owners seek to avoid the plain language of Rosin by improperly focusing on the
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`genus of formula I. (Paper 25 at 24.) Rosin, however, discloses RA7 as one of a
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`handful of compounds of the present invention that are “most preferred,” utilized
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`in the examples, and recited in the claims. (Ex. 1008 at 7:51-53, 10:9-11:16,
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`12:56-57, 14:11-30, in particular 14:17-19; Ex. 1031 ¶¶ 38-39.) Rosin specifically
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`highlights antioxidants for use with these select compounds, stating “[p]referred
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`antioxidants for use with compounds of the present invention include sodium
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`metabisulphite and ascorbic acid,” (Ex. 1008 at 7:51-53.)
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`These same “most preferred” RA-series compounds are employed in a later
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`paper (Elmalem, Ex. 1009) by the same research group, and the same “preferred”
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`antioxidant, sodium metabisulfite, was added to “to prevent oxidation” of drugs
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`including RA6, RA7, and RA15. (Ex. 1031 ¶¶ 41-43, 55-60; Ex. 1009 at 1060.)
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`Dr. Klibanov constructs a convoluted, nine page argument in an attempt to
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`avoid the plain-language of Elmalem. (Paper 25 at 28-36; Ex. 1031 ¶¶ 61-78.)
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`While Dr. Klibanov also quibbles with the amount of antioxidant disclosed in
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`Elmalem, he ignores the fact that the amount of antioxidant is within the standard
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`range disclosed in the Handbook. (Ex. 2012 ¶ 110; Ex. 1031 ¶¶ 75-78.)
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`A POSA would understand Sasaki to disclose the tendency of amine
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`containing compounds to oxidatively degrade in a transdermal composition when
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`13
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`acrylic adhesives are employed and the use of antioxidants to prevent the
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`degradation. Sasaki discloses more than “just two amine-containing compounds
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`in a single formulation” as Patent Owners declare. (Ex. 2012 ¶ 153.) Sasaki
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`discloses classes of amine compounds including ethanolamine- and ethylene
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`diamine-based antihistamines. In addition, Sasaki lists three exemplary
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`compounds, which contain a tertiary amine, like rivastigmine. Further, Sasaki
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`discloses a three-month stability study conducted on two amine compounds, in
`
`formulations with and without antioxidants, in an acrylic adhesive formulation (the
`
`same type of adhesive used in example 2 of Enz). (Ex. 1031 ¶¶ 80-82; Ex. 1005 at
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`3.)
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`VI. The Prior Art Did Not Discourage The Use of Antioxidants
`A POSA would have employed antioxidants with a reasonable expectation
`
`of success, and the prior art as a whole did not teach away from or discourage their
`
`use. Oxidation was known to be a prime cause of instability. (Ex. 2017 at 1507.)
`
`Antioxidants were one of a small, finite group of known solutions for preventing or
`
`mitigating oxidative degradation of pharmaceutical active agents in a composition,
`
`(Ex. 1016 at 84, 92-93; Ex. 1025 at 147:3-48:10; Ex. 1010 ¶¶ 28, 30, 38, 40, 42-43,
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`51, 63, 86; Ex. 1031 ¶¶ 11-12, 84-86, 115-23, 130), including in transdermal
`
`formulations. (Ex. 1010 ¶¶ 38, 40.) Other means to prevent oxidation, such as
`
`removal of oxygen or the use of air-tight packaging, were understood to be
`
`
`
`14
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`
`
`
`
`sometimes difficult to employ successfully in practice. (Ex. 1031 ¶ 90 n. 21; Ex.
`
`1005 at 1.) The EMEA Guidelines (Ex. 2019), when viewed in total, suggests that
`
`antioxidant use should be justified, not, as Patent Owners suggest, that they are a
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`last resort. (Ex. 1031at 93; Ex. 2019 at page 2/4; contra Ex. 2012 ¶ 40; contra
`
`Paper 25 at 10-11.)
`
`There is no credible evidence that a POSA would have refrained from
`
`employing an antioxidant and would have harbored anything other than a
`
`reasonable expectation of success in employing one with rivastigmine. (Ex. 1031
`
`¶¶ 43, 92-93, 115-23.) It was known that numerous antioxidants were classified by
`
`the FDA as Generally Recognized as Safe (GRAS). (Ex. 1031 ¶84; see generally
`
`Ex. 1003.) Contrary to Patent Owners’ assertion (Ex. 2012 ¶ 38; Paper 25 at 10), a
`
`POSA would have maintained more than a reasonable expectation that an
`
`antioxidant compatible with rivastigmine could be identified. (Ex. 1031 ¶ 12.)
`
`Various antioxidants were known to be compatible with rivastigmine. (Ex. 1031
`
`¶¶ 76, 121-23.) A POSA would have readily identified an antioxidant that worked
`
`for a particular rivastigmine formulation using well-known methods. (Ex. 1031 ¶¶
`
`12, 116-120, 130; Ex. 1025 at 147:3-148:10, 188:21-189:11.)
`
`VII. Conclusion
`The challenged claims of the ’031 patent are unpatentable as obvious for the
`
`reasons stated above.
`
`
`
`
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`15
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`
`
`Dated: March 31, 2015
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`
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`
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`Respectfully submitted,
`
`/Michael K. Levy/
`Steven J. Lee (Reg. No. 31,272)
`Michael K. Levy (Reg. No. 40,699)
`KENYON & KENYON LLP
`One Broadway
`New York, NY 10004-1007
`Tel: 212-425-7200
`Fax: 212-425-5288
`
`Counsel for Petitioner Noven Pharmaceuticals,
`Inc.
`
`
`
`16
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`
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`CERTIFICATE OF SERVICE
`
` I
`
` also certify pursuant to 37 C.F.R. §42.6(e) that a copy the foregoing
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`Petitioner’s Reply was served electronically on March 31, 2015 to counsel for
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`Patent Owners at the following email address: ExelonPatchIPR@fchs.com.
`
`
`
`
`
`Dated: March 31, 2015
`
`/Christopher J. Coulson/
`
`
`
`Christopher J. Coulson (Reg. No. 61,771)
`
`
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`KENYON & KENYON LLP
`
`One Broadway
`
`New York, NY 10004-1007
`
`Tel: 212-425-7200
`
`Fax: 212-425-5288
`
`Counsel for Petitioner Noven Pharmaceuticals,
`Inc.
`
`1
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`
`
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