On Behalf Of:
`
`Novartis AG and LTS Lohmann Therapie-Systeme AG
`
`By:
`
`Raymond R. Mandra
`ExelonPatchIPR@fchs.com
`(212) 218-2100
`
`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. 2014-00550
`
`U.S. Patent 6,335,031
`
`PATENT OWNERS’ RESPONSE
`PURSUANT TO 37 C.F.R. § 42.220
`
`

`

`TABLE OF CONTENTS
`
`I.
`
`II.
`
`INTRODUCTION ...........................................................................................1
`
`THE RELEVANT LEGAL STANDARDS ....................................................5
`
`a.
`
`b.
`
`c.
`
`d.
`
`The discovery of an unknown problem can constitute a
`non-obvious invention...........................................................................5
`
`Obviousness requires proof of a motivation for a POSA
`to have combined the claim elements ...................................................6
`
`If testing is required to discover the problem solved by
`the claimed invention, then the invention is not obvious......................7
`
`The existence of FDA guidance as to a general course of
`action does not suffice to render obvious a patent that
`solves a specific problem ......................................................................8
`
`III.
`
`THE TRUE STATE OF THE ART.................................................................9
`
`a.
`
`b.
`
`c.
`
`d.
`
`e.
`
`The art taught not to use excipients unless they are
`required..................................................................................................9
`
`The art taught not to use antioxidants unless they are
`required................................................................................................10
`
`The art taught that oxidation is formulation-specific..........................13
`
`The art taught that rivastigmine was chemically stable ......................13
`
`A POSA would not reasonably have predicted that
`rivastigmine would oxidatively degrade based on its
`structure...............................................................................................15
`
`IV.
`
`PETITIONER’S CITED PRIOR ART..........................................................20
`
`a.
`
`b.
`
`c.
`
`d.
`
`Enz.......................................................................................................21
`
`The Handbook .....................................................................................22
`
`Rosin....................................................................................................24
`
`Elmalem...............................................................................................28
`i
`
`

`

`e.
`
`e.
`
`f.
`
`f.
`
`Ebert ....................................................................................................36
`
`Ebert .................................................................................................... 36
`
`Sasaki...................................................................................................40
`
`Sasaki ................................................................................................... 40
`
`V.
`
`V.
`
`CONCLUSION..............................................................................................44
`
`CONCLUSION .............................................................................................. 44
`
`ii
`
`ii
`
`

`

`I.
`
`INTRODUCTION
`
`Novartis AG and LTS Lohmann Therapie-Systeme AG (“Patent Owners”)
`
`respectfully submit this 37 C.F.R. § 42.220 response to the April 2, 2014 petition
`
`of Noven Pharmaceuticals Inc. (“Petitioner”) seeking inter partes review (“IPR”)
`
`of U.S. Patent No. 6,335,031 (“’031 Patent”).
`
`The Board in an October 14, 2014 decision (Paper 10) instituted IPR against
`
`the ’031 Patent on the following Grounds:
`
`Ground
`
`References
`
`Basis
`
`Claims
`
`3
`
`4
`
`5
`
`Enz and the Handbook, optionally in
`view of Rosin and/or Elmalem and/or
`Ebert
`
`§ 103(a)
`
`1, 2, 7, 15, 18
`
`Enz and the Handbook and/or Rosin
`and/or Ebert
`
`§ 103(a)
`
`3, 16
`
`Enz and Sasaki
`
`§ 103(a)
`
`1-3, 7, 14, 16, 18
`
`No challenged claim is obvious on any of these Grounds, for the following
`
`reasons:
`
` The ’031 Patent is directed to and claims pharmaceutical compositions,
`
`particularly transdermal devices, comprising rivastigmine and an
`
`antioxidant. (Ex. 1001 at col. 8, l. 34-col. 10, l. 13.)
`
` The relevant invention date for assessing the alleged obviousness of the
`
`’031 Patent is January 12, 1998. (Ex. 2012 ¶ 23.)
`
`1
`
`

`

` As of 1998, the art taught a person of ordinary skill in the art (“POSA”)
`
`not to include an antioxidant in a pharmaceutical formulation unless one
`
`was required. (Ex. 2012 ¶¶ 37-46.)
`
` As of 1998, the art as a whole did not teach or suggest to the POSA that
`
`rivastigmine underwent oxidative degradation under pharmaceutically
`
`relevant conditions or required an antioxidant. (Ex. 2012 ¶ 47.) To the
`
`contrary, the art as a whole—including Rosin and Elmalem—taught that
`
`rivastigmine was chemically stable and did not require an antioxidant in
`
`any pharmaceutical composition. (Ex. 2012 ¶ 47.)
`
` As of 1998, a POSA would not reasonably have predicted from the
`
`chemical structure of rivastigmine that rivastigmine would oxidatively
`
`degrade under pharmaceutically relevant conditions or require an
`
`antioxidant. (Ex. 2012 ¶¶ 119-160.) To the contrary, Petitioner’s experts
`
`in this IPR admitted at trial in a parallel litigation, Novartis
`
`Pharmaceuticals Corp. v. Noven Pharmaceuticals Inc., 13-cv-527 (D.
`
`Del.), that a POSA would need to conduct testing to determine whether
`
`rivastigmine oxidatively degrades under pharmaceutically relevant
`
`conditions. (Ex. 1025 at 95:24-96:18, 232:6-13, 258:8-13, 283:14-
`
`284:19, Ex. 1029 at 53:10-17.) It is undisputed that no such testing was
`
`reported in the art as of 1998. (Ex. 2012 ¶ 47.)
`
`2
`
`

`

` Because none of Enz, the Handbook, Rosin, Elmalem, Ebert or Sasaki,
`
`alone or in combination, taught or suggested to the POSA that
`
`rivastigmine underwent oxidative degradation under pharmaceutically
`
`relevant conditions, and because a POSA would not reasonably have
`
`predicted from rivastigmine’s structure that rivastigmine would
`
`oxidatively degrade under pharmaceutically relevant conditions, the
`
`problem of rivastigmine’s oxidative degradation under pharmaceutically
`
`relevant conditions was unknown as of 1998. (Ex. 2012 ¶¶ 47, 125.)
`
`Moreover, the art as of 1998 taught a POSA not to include an antioxidant
`
`in a pharmaceutical formulation unless one was required. (Ex. 2012 ¶¶
`
`14-15.) Thus, as of 1998 there was no motivation for a POSA to
`
`combine rivastigmine with an antioxidant in a pharmaceutical
`
`composition. (Ex. 2012 ¶ 15.)
`
` The starting point for each of Petitioner’s Grounds is Example 2 of Enz,
`
`which discloses a rivastigmine transdermal formulation. (Paper 1 at 30,
`
`41-42, 43-44; Ex. 2012 ¶ 50.) Petitioner alleges that Elmalem and/or
`
`Rosin teach that rivastigmine (or the racemate RA7, of which
`
`rivastigmine is the (S)-enantiomer) should be combined with an
`
`antioxidant in Example 2 of Enz. (Paper 1 at 32-33.) That allegation is
`
`wrong. Regardless, the alleged antioxidant teachings of Elmalem and
`
`3
`
`

`

`Rosin are limited to injectable formulations. (Ex. 2012 ¶¶ 65, 109.) And
`
`Petitioner’s IPR experts admitted at trial in Novartis v. Noven, 13-cv-527
`
`(D. Del.), that whether and to what extent a compound degrades in a
`
`particular pharmaceutical formulation depends on the formulation, i.e.,
`
`that degradation is formulation-specific. (Ex. 1025 at 95:24-96:18,
`
`232:6-13, 258:8-13, 283:14-284:19; see also Ex. 1029 at 53:10-17.)
`
`Thus, even if a POSA as of 1998 would have read Elmalem or Rosin to
`
`suggest that an antioxidant may be required in an injectable formulation,
`
`that suggestion would not have led a POSA to expect that rivastigmine
`
`would oxidatively degrade or require an antioxidant in a transdermal
`
`formulation, and would not have motivated a POSA to combine
`
`rivastigmine and an antioxidant in a transdermal formulation, such as
`
`Example 2 of Enz. (Ex. 2012 ¶¶ 16, 50.)
`
`Put simply, the problem of the oxidative degradation of rivastigmine in a
`
`pharmaceutical composition was unknown as of 1998, and a POSA would not
`
`have been motivated to solve a problem that he or she did not know existed.
`
`Because the problem was unknown, the solution provided by the ’031 Patent
`
`would not have been obvious.
`
`4
`
`

`

`II.
`
`THE RELEVANT LEGAL STANDARDS
`
`a.
`
`The discovery of an unknown problem
`can constitute a non-obvious invention
`
`“As an initial matter, an invention can often be the recognition of a problem
`
`itself.” Leo Pharm. Prods., Ltd. v. Rea, 726 F.3d 1346, 1353 (Fed. Cir.
`
`2013) (patent non-obvious where the inventors “recognized and solved . . . a
`
`problem that the prior art did not recognize and . . . was not solved for over a
`
`decade”). If the problem was not previously known or reasonably suggested in the
`
`art, an invention that solves that problem is non-obvious. E.g., Eibel Process Co.
`
`v. Minn. & Ont. Paper Co., 261 U.S. 45, 67-68 (1923); In re Omeprazole Patent
`
`Litig., 536 F.3d 1361, 1380-81 (Fed. Cir. 2008) (patent non-obvious where the
`
`prior art did not “suggest any need to stabilize omeprazole,” and a POSA thus
`
`“would not have seen a reason to insert [the claimed stabilizing] subcoating in the
`
`prior art formulation”). Indeed, where the prior art fails to recognize the problem,
`
`“ordinary artisans would not have thought to try at all” to solve the problem, and
`
`thus, the invention cannot be “obvious to try.” Leo, 726 F.3d at 1356-57.
`
`Importantly, however, the invention itself cannot be used “to define the problem
`
`that the invention solves” because this represents a form of impermissible
`
`hindsight. Mintz v. Dietz & Watson, Inc., 679 F.3d 1372, 1377 (Fed. Cir. 2012).
`
`As of 1998, the problem of rivastigmine’s oxidative degradation in a
`
`pharmaceutical composition was not known or reasonably suggested in the art.
`
`5
`
`

`

`(Ex. 2012 ¶ 47.) Accordingly, the solution to that problem, which is provided by
`
`the invention of the ’031 Patent, would not have been obvious or even “obvious to
`
`try.”
`
`b.
`
`Obviousness requires proof of a motivation
`for a POSA to have combined the claim elements
`
`“Obviousness requires more than a mere showing that the prior art includes
`
`separate references covering each separate limitation in a claim under
`
`examination.” Unigene Labs, Inc. v. Apotex, Inc., 655 F.3d 1352, 1360 (Fed. Cir.
`
`2011). Rather, Watson must prove “a reason that would have prompted a [POSA]
`
`to combine the elements in the way the claimed new invention does.” KSR Int’l
`
`Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007); Unigene, 655 F.3d at 1360-61.
`
`Whether explicit or implicit, “some kind of motivation must be shown from some
`
`source . . . [to] understand why a [POSA] would have thought of either combining
`
`two or more references or modifying one to achieve the patented method.”
`
`Innogenetics, N.V. v. Abbott Labs., 512 F.3d 1363, 1374 (Fed. Cir. 2008)
`
`(affirming district court’s preclusion of defendant’s expert’s “vague and
`
`conclusory obviousness testimony which did not offer any motivation for one
`
`skilled in the art to combine the particular references he cites”); see also
`
`ActiveVideo Networks, Inc. v. Verizon Commc’ns, Inc., 694 F.3d 1312, 1328 (Fed.
`
`Cir. 2012) (judgment of nonobviousness affirmed where expert’s testimony on
`
`motivation to combine prior art was “generic” and “fail[ed] to explain why a
`
`6
`
`

`

`[POSA] would have combined elements from specific references in the way the
`
`claimed invention does”).
`
`Petitioner has failed to show any motivation from any source that would
`
`have led a POSA as of 1998 to achieve the claimed subject matter of the ’031
`
`Patent. In the absence of such motivation, the invention of the ’031 Patent would
`
`not have been obvious.
`
`c.
`
`If testing is required to discover the problem solved
`by the claimed invention, then the invention is not obvious
`
`Where the discovery of the problem that is solved by the claimed invention
`
`would have required testing, then the invention would not be obvious. In Leo, the
`
`Federal Circuit reversed the Board’s determination in an inter partes
`
`reexamination that a patent directed to stable compositions of vitamin D was
`
`obvious. 726 F.3d at 1348. The Federal Circuit reasoned that:
`
`[B]ecause neither [of the prior art references] Dikstein nor
`
`Serup recognized or disclosed the stability problem, the record
`
`shows no reason for one of ordinary skill in the art to attempt to
`
`improve upon either Dikstein or Serup using Turi. The
`
`ordinary artisan would first have needed to recognize the
`
`problem, i.e., that the formulations disclosed in Dikstein and
`
`Serup were not storage stable. To discover this problem, the
`
`ordinary artisan would have needed to spend several months
`
`7
`
`

`

`running storage stability tests. Only after recognizing the
`
`existence of the problem would an artisan then turn to the prior
`
`art and attempt to develop a new formulation for storage
`
`stability. If these discoveries and advances were routine and
`
`relatively easy, the record would undoubtedly have shown that
`
`some ordinary artisan would have achieved this invention
`
`within months of Dikstein or Serup. Instead this invention does
`
`not appear for more than a decade.
`
`Id. at 1356 (internal citations omitted).
`
`As in Leo, Petitioner’s prior art in this IPR does not recognize or disclose the
`
`stability problem addressed by the invention of the ’031 Patent. (Ex. 2012 ¶ 47.)
`
`As in Leo, a POSA would need to have conducted stability tests to discover the
`
`problem, and only after recognizing the existent of the problem would a POSA
`
`have attempted to address it. (Ex. 2012 ¶ 34.) And, as in Leo, the invention of the
`
`’031 Patent did not appear until a decade after the 1988 publication of Petitioner’s
`
`primary art reference, Enz.
`
`d.
`
`The existence of FDA guidance as to
`a general course of action does not suffice to
`render obvious a patent that solves a specific problem
`
`The existence of FDA guidance teaching a general course of action does not
`
`suffice to render obvious a patent that solves a specific problem. See In re
`
`8
`
`

`

`Cyclobenzaprine Hydrochloride Extended-Release Patent Litig., 676 F.3d 1063,
`
`1073-74 (Fed. Cir. 2012) (FDA guidance concerning extended-release
`
`formulations did not render obvious patent directed to specific pharmacokinetic
`
`characteristics of a specific extended-release formulation where such guidance
`
`provided “only general guidance as to the particular form of the claimed invention
`
`or how to achieve it.”) Additionally, 35 U.S.C. § 103(a) does not require an
`
`inventor to devise a new way to discover an invention for the invention to be
`
`patentable. 35 U.S.C. § 103(a) (“Patentability shall not be negatived by the
`
`manner in which the invention was made.”).
`
`Petitioner contends that FDA guidelines generally teaching drug makers to
`
`test the stability of drugs and drug formulations would have led a POSA to the
`
`specific invention claimed by the ’031 Patent (e.g., in Paper 1 at 34). Under
`
`Eurand and 35 U.S.C. § 103(a), that contention is not proof of obviousness.
`
`III. THE TRUE STATE OF THE ART
`
`a.
`
`The art taught not to use excipients unless they are required
`
`The ’031 Patent is directed to pharmaceutical compositions—particularly
`
`transdermal devices—comprising the anticholinesterase inhibitor compound
`
`rivastigmine and an antioxidant. (Ex. 1001 at col. 8, l. 34-col. 10, l. 13.) The
`
`relevant art thus is pharmaceutical formulation. The parties agree that the relevant
`
`9
`
`

`

`date for assessing the alleged obviousness of the ’031 Patent is January 12, 1998.
`
`(Ex. 2012 ¶ 23.)
`
`Pharmaceutical formulation involves combining an active pharmaceutical
`
`ingredient (“API”) with excipients to arrive at a dosage form, such as a transdermal
`
`device, that can be effectively administered to a patient. (Ex. 2012 ¶ 36.) As of
`
`1998, the art taught that not all excipients are compatible with all APIs or with all
`
`other excipients, and that—due to the complex interaction among APIs, excipients
`
`and other factors such as pH, light and humidity—determining whether and which
`
`excipients would be compatible with a particular API could not reasonably have
`
`been predicted in advance of testing.
`
`(Ex. 2012 ¶¶ 37-39, 43; Ex. 2014 at 196-
`
`204; Ex. 2017 at 1507.) Given the potential for excipient incompatibility, a
`
`common-sense principle that a POSA would have known and followed as of 1998
`
`was not to add an excipient to a pharmaceutical formulation unless it was required.
`
`(Ex. 2012 ¶¶ 38-39; Ex. 2018 at col. 4, ll. 24-32.)
`
`b.
`
`The art taught not to use antioxidants unless they are required
`
`Antioxidants are agents that reduce the oxidative degradation of other
`
`compounds, including APIs. (Ex. 2012 ¶ 27.) With respect to the use of
`
`antioxidants as excipients in pharmaceutical formulations, the art expressly taught
`
`a POSA that antioxidants “should only be used once it has been shown that their
`
`use cannot be avoided, even if the manufacturing process is optimized to minimise
`
`10
`
`

`

`the potential for oxidation, for example by manufacturing and filling products
`
`under an inert headspace gas.” (Ex. 2012 ¶ 40; Ex. 2019 at 1, 3.) The art also
`
`taught that antioxidants can react chemically with the drugs they were intended to
`
`stabilize and bring about an unexpected increase (rather than a decrease) in the
`
`oxidative degradation of an API. (Ex. 2012 at ¶¶ 41-42; Ex. 2020 at 118; Ex. 2021
`
`at 97; Ex. 2022 at 680-684; Ex. 2023 at 1.) The art further taught that, as of 1998,
`
`alternatives to antioxidants were available to potentially reduce the oxidative
`
`degradation of APIs in pharmaceutical formulations, including in transdermal
`
`devices. (Ex. 2012 ¶¶ 44-45; Ex. 2017 at 1507; Ex. 2020 at 119; Ex. 2024 at col.
`
`5, ll. 26-28, col. 6, ll. 25-34, col. 8, ll. 4-8; Ex. 2025 at col. 2, ll. 37-52, col. 3, ll.
`
`10-19.) Indeed, of the 15 transdermal devices that were commercially available in
`
`the United States in 1998, none were reported to contain an antioxidant. (Ex. 2012
`
`¶ 46; Ex. 2022 at 486-488, 640-644, 680-684, 842-845, 878-880, 880-883, 884-
`
`888, 890-891, 1336-1340, 1365-1367, 1439-1442, 1553-1554, 1568-1569, 2541-
`
`2542, 2634-2636.) Given those teachings, a POSA as of 1998 would not have
`
`been motivated to modify or improve an existing pharmaceutical formulation by
`
`adding an antioxidant unless an antioxidant was required. (Ex. 2012 ¶¶ 38-46, 56.)
`
`Patent Owners expect Petitioner to contend in reply that, as of 1998, it was
`
`routine to add antioxidants to pharmaceutical formulations early in the testing or
`
`development of such formulations—regardless of whether oxidative degradation
`
`11
`
`

`

`was known to occur or an antioxidant was known to be required. That is not true.
`
`Pharmaceutical formulation development is complex and unpredictable, and the
`
`testing done during pharmaceutical formulation development is data-driven and
`
`conducted in response to specific problems that arise. (Ex. 2012 ¶ 26; Ex. 1014 at
`
`1.) That reality is reflected in Dr. Kydonieus’s cross-examination in this IPR,
`
`wherein he admitted that there “can be 100 different problems that can come up in
`
`pharmaceutical development” (Ex. 1029 at 36:23-37:13; see also id. at 38:17-
`
`39:11); that there is no single stability testing protocol that must be followed in
`
`every case (id. at 96:16-100:13); and that the testing to be conducted in each case
`
`is negotiated by the drug maker and the FDA (id.). It is also reflected in the fact
`
`that of the 15 transdermal devices commercially available in the United States in
`
`1998, none were reported to contain an antioxidant. (Ex. 2012 ¶ 46; Ex. 2022 at
`
`486-488, 640-644, 680-684, 842-845, 878-880, 880-883, 884-888, 890-891, 1336-
`
`1340, 1365-1367, 1439-1442, 1553-1554, 1568-1569, 2541-2542, 2634-2636.)
`
`It
`
`is further reflected in the fact that the inventors of the ’031 Patent themselves did
`
`not add an antioxidant to their rivastigmine test formulations until after they
`
`discovered that rivastigmine degraded in those formulations.1 (Ex. 2012 ¶¶ 161-
`
`167; Ex. 2015 at LTS0042714; Ex. 2032; Ex. 2053.)
`
`1 Although an inventor’s efforts are not relevant to obviousness, they can be
`
`12
`
`

`

`c.
`
`The art taught that oxidation is formulation-specific
`
`As of 1998, a POSA would have understood that whether a drug compound
`
`oxidatively degrades depends on the pharmaceutical formulation in which the
`
`compound is contained. (Ex. 2012 ¶ 49.) Petitioner’s IPR experts Drs. Agis
`
`Kydonieus and Christian Schöneich agree: both admitted at the December 1-3,
`
`2014 trial in a parallel litigation, Novartis v. Noven, 13-cv-527 (D. Del.), that
`
`whether a compound will oxidatively degrade in a particular environment or
`
`pharmaceutical formulation, such as in a transdermal device, cannot be predicted in
`
`advance of testing. (Ex. 1025 at 95:24-96:18, 232:6-13, 258:8-13, 283:14-284:19;
`
`see also Ex. 1029 at 53:10-17.) A POSA thus would not consider a teaching or
`
`suggestion that a compound undergoes oxidative degradation in one formulation to
`
`be a teaching or suggestion that the compound will undergo oxidative degradation
`
`in a different formulation. (Ex. 2012 ¶ 16, 49-50.)
`
`d.
`
`The art taught that rivastigmine was chemically stable
`
`Drs. Kydonieus and Schöneich admitted that a POSA would need to conduct
`
`testing to determine whether rivastigmine oxidatively degrades under
`
`pharmaceutically relevant conditions. (Ex. 2012 ¶ 49; Ex. 1025 at 95:24-96:18,
`
`relevant to non-obviousness. E.g., Neupak, Inc. v. Ideal Mfg. & Sales Corp., 41 F.
`
`App’x 435, 440 (Fed. Cir. 2002).
`
`13
`
`

`

`232:6-13, 258:8-13, 283:14-284:19; see also Ex. 1029 at 53:10-17.) It is
`
`undisputed that no such testing was reported in the art as of 1998. (Ex. 2012 ¶ 47.)
`
`To the contrary, the art as a whole as of 1998—including Rosin and
`
`Elmalem—repeatedly and expressly taught that RA7 and rivastigmine showed
`
`“greater chemical stability” than the prior art acetylcholinesterase inhibitor,
`
`physostigmine.2 (Ex. 2012 ¶¶ 47-48; Ex. 1008 at col. 1, ll. 32-34, col. 3, ll. 37-39,
`
`col. 11, ll. 21-29; Ex. 1009 at 1059; Ex. 2026 at 272; Ex. 2027 at 219-220.) Well
`
`before 1998, and as early as 1991, extensive testing had shown that physostigmine
`
`underwent hydrolytic degradation in aqueous solution to form the therapeutically
`
`inactive compound eseroline, which in turn underwent oxidative degradation to
`
`form the colored byproduct rubreserine and other byproducts. (Ex. 2012 ¶¶ 78-86;
`
`Ex. 2033 at 616; Ex. 2035 at 1266; Ex. 2038 at 456; Ex. 2039 at 125.) Thus, the
`
`art as of 1991—including Rosin—taught that physostigmine should be prepared in
`
`aqueous solution with an antioxidant to address the oxidative degradation of
`
`eseroline, and that physostigmine should not be used if it is more than slightly
`
`discolored. (Ex. 2012 ¶¶ 78-86; Ex. 1008 at col. 1, ll. 29-34; Ex. 2040 at 624; Ex.
`
`2041 at 1079.) In contrast to physostigmine, the art as of 1998 did not teach that
`
`2 As of 1998, a POSA would have understood RA7 and rivastigmine (the (S)-
`
`enantiomer of RA7) to have the same oxidative stability. (Ex. 2012 ¶ 96 and fn. 8.)
`
`14
`
`

`

`RA7 or rivastigmine suffered from any form of chemical stability or required an
`
`antioxidant in any pharmaceutical formulation. (Ex. 2012 ¶¶ 47, 78, 86-96.)
`
`Petitioner contends that a teaching that RA7 or rivastigmine showed “greater
`
`chemical stability” than physostigmine is not a teaching that rivastigmine is stable
`
`to oxidation. (Paper 1 at 32-33, fn. 5.) Patent Owners disagree. The term
`
`“chemical stability” encompasses hydrolysis and oxidation, and while
`
`physostigmine was known to hydrolyze in aqueous formulations, it was not known
`
`to oxidize in any pharmaceutical formulation. (Ex. 2012 ¶ 48; Ex. 2037 at col. 8,
`
`ll. 50-65.) Accordingly, a POSA would understand a teaching that RA7 or
`
`rivastigmine showed “greater chemical stability” than physostigmine to be both a
`
`teaching that rivastigmine is more stable than physostigmine to hydrolysis and a
`
`teaching that rivastigmine, like physostigmine, is stable to oxidation under
`
`pharmaceutically relevant conditions. (Ex. 2012 ¶ 48.)
`
`e.
`
`A POSA would not reasonably have predicted that
`rivastigmine would oxidatively degrade based on its structure
`
`As there is no pre-1998 patent or printed publication that teaches or suggests
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`that rivastigmine underwent oxidative degradation, Petitioner has been forced to
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`rely on the hindsight-driven 2014 opinion of Dr. Schöneich that a POSA would
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`have been able to predict that rivastigmine would be “susceptible” to oxidative
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`degradation based on the presence of certain functional groups in rivastigmine’s
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`chemical structure.
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`15
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`

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`Patent Owners disagree with Dr. Schöneich’s opinion for at least three
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`reasons.
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`First, Dr. Schöneich’s opinion concerning “susceptibility” is irrelevant to the
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`alleged obviousness of the ’031 Patent. (Ex. 2012 ¶¶ 123-125, 128.) Although Dr.
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`Schöneich has failed to define the term “susceptible” in this IPR, in the Novartis v.
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`Noven trial, 13-cv-527 (D. Del.), he testified that “susceptible” means that there is
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`“the potential for oxidative degradation at [a] site” in the molecule (Ex. 1025 at
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`94:2-15), and that “whether rivastigmine is susceptible to degradation that can be
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`deduced from the structure, [but] whether it actually happens, that needs to be
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`shown experimentally and the extent to [which] it happens needs to be shown
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`experimentally.” (Id. at 96:10-18, emphasis added.) The term “susceptible” as
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`used by Dr. Schöneich and Petitioner thus refers only to the theoretical potential of
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`a compound to oxidatively degrade. But a POSA as of 1998 would have known
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`that essentially all organic compounds can undergo oxidative degradation under
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`sufficiently harsh conditions (e.g., burning). (Ex. 2012 ¶ 123.) That a POSA
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`would have known of such “susceptibility” thus is irrelevant to the problem solved
`
`by the ’031 Patent: the actual oxidative degradation of rivastigmine in a
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`pharmaceutical formulation under pharmaceutically relevant conditions. (Ex. 2012
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`¶¶ 123-125, 128; Ex. 1015 at 82.)
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`16
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`

`

`Second, Dr. Schöneich opines that rivastigmine is “susceptible” to oxidative
`
`degradation due to the presence of certain functional groups in its structure:
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`namely, a benzylic C-H bond and an adjacent tertiary amine. (Ex. 1011 ¶ 12.) Dr.
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`Schöniech cites dextromethorphan and nicotine as examples of compounds that
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`have these functional groups and are “susceptible” to oxidative degradation. (Ex.
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`1011 ¶¶ 47-48.) In fact, neither example supports Dr. Schöniech’s opinions.
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` Dextromethorphan was taught expressly in the art to be “very stable,”
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`“[s]table under all normal conditions of storage,” and to show
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`“[e]xcellent stability” under pharmaceutically relevant conditions. (Ex.
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`2012 ¶¶ 139-143; Ex. 2050 at 433; Ex. 2051 at 621-622; Ex. 2022 at 672,
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`974-975, 1413-1414, 1560, 1569-1570, 1572-1576, 1612-1613, 1623-
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`1624, 1825, 1832-1833, 1948, 2233-2234, 2786, 2885-2886.)
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` Nicotine does not have a benzylic C-H bond, and the C-H bond and
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`adjacent “tertiary amine” on which Dr. Schoneich relies in fact form part
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`of an N-substituted pyrrolidine. (Ex. 2012 ¶¶ 144-145.) Moreover, none
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`of the nicotine transdermal devices commercially available as of 1998
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`were reported to contain an antioxidant. (Ex. 2012 ¶¶ 150-151; Ex. 2022
`
`at 884-888, 1439-1442, 1568-1569.) The prior art knowledge of
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`nicotine’s “susceptibility” to oxidative degradation thus would not have
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`motivated the POSA as of 1998 to add an antioxidant to rivastigmine,
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`17
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`

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`when that same knowledge did not even lead to the addition of an
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`antioxidant to nicotine. (Ex. 2012 ¶¶ 150-151.)
`
`Additionally, the art both before and after 1998 was replete with examples of
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`pharmaceutical compounds having benzylic C-H bonds and adjacent tertiary
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`amines that were not reported to undergo oxidative degradation or to contain an
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`antioxidant in their commercial formulations. (Ex. 2012 ¶¶ 133-137; Ex. 2022 at
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`890-891, 1336-1340, 1878-1881, 1992-1993, 2007-2008, 2015, 2035-2038, 2042-
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`2043, 2872-2874; Ex. 2048 at 2864-2873; Ex. 2049 at 903-910.) Those examples
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`further show that the presence of certain functional groups, such as a benzylic C-H
`
`bond and an adjacent tertiary amine, does not determine the chemical stability of a
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`compound, and that it is the structure of the compound as a whole that matters.
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`(Ex. 2012 ¶¶ 132-137 and fn. 16.)
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`Third, the art as of 1998 was clear that oxidation reactions were complex,
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`poorly understood and unpredictable. (Ex. 2012 ¶¶ 121, 125; Ex. 2014 at 183; Ex.
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`1015 at 82.) That fact is illustrated by Dr. Schöneich’s own declaration, which
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`hypothesizes five alternate oxidation reaction pathways for rivastigmine, but does
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`not cite any documentary evidence to show that any of them in fact occurs. (Ex.
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`2012 ¶ 121; Ex. 1011 at Appendix A.)
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`Patent Owners expect Petitioner to contend in reply that, while the exact
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`reaction by which the oxidation of rivastigmine occurs was not predictable, the
`
`18
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`

`

`“susceptibility” of rivastigmine to oxidation was predictable because
`
`“susceptibility” is intrinsic to the structure of a compound. But, as noted above,
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`“susceptibility” is irrelevant to the problem solved by the ’031 Patent. (Ex. 2012
`
`¶¶ 122-125, 128.) Moreover, Petitioner’s other IPR expert Dr. Kydonieus observes
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`that, as of 1998, FDA guidelines taught that testing was required to determine the
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`“intrinsic stability and degradation pathways” of a drug compound. (Ex. 1010 ¶
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`25 (emphasis added).) If a POSA as of 1998 could have predicted a drug
`
`compound’s intrinsic stability and degradation pathways, testing would not have
`
`been required. (Ex. 2012 ¶¶ 26, 35; Ex. 1014 at 1.) Indeed, even the inventors of
`
`the ’031 Patent, who had at least the skill level of a POSA and years of experience
`
`with rivastigmine, did not predict in advance of testing that rivastigmine would
`
`undergo oxidative degradation. (Ex. 2012 ¶ 161-167; Ex. 2015 at LTS0042714;
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`Ex. 2032; Ex. 2053.) As reported in the ’031 Patent, the inventors had to conduct
`
`“exhaustive testing” to determine that the degradation of rivastigmine was
`
`oxidative in nature and required the addition of an antioxidant to fix. (Ex. 2012 ¶¶
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`166; Ex. 2015 at LTS0042714, 721-724; Ex. 1001 at col. 1, ll. 22-28.)
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`In sum, Dr. Schöneich’s irrelevant, hindsight-driven theories that
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`rivastigmine’s “susceptibility” to oxidative degradation would have been predicted
`
`by a POSA in 1998 are squarely contradicted by reality. Dr. Schöneich admits that
`
`a POSA would have had to test to determine whether rivastigmine actually
`
`19
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`

`

`undergoes oxidative degradation in a pharmaceutical formulation. (Ex. 1025 at
`
`95:24-96:18.) As of 1998, many drug compounds containing a benzylic C-H bond
`
`and an adjacent tertiary amine, like rivastigmine, were not reported to undergo
`
`oxidative degradation or to contain an antioxidant in their commercial
`
`formulations. (Ex. 2012 ¶¶ 133-137.) And as of 1998, the art taught that oxidation
`
`reactions were complex, poorly understood, and unpredictable. (Ex. 2012 ¶ 130;
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`Ex. 1015 at 82; Ex. 2014 at 183.)
`
`IV. PETITIONER’S CITED PRIOR ART
`
`Petitioner’s Grounds 3-5 allege that the challenged claims of the ’031 Patent
`
`are obvious over Enz in view of various combinations of the Handbook, Rosin,
`
`Elmalem, Ebert and/or Sasaki. For the purposes of Patent Owners’ response, the
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`specific differences among Grounds 3-5 and the challenged claims are immaterial.
`
`As explained in further detail below, none of Enz, the Handbook, Rosin, Elmalem,
`
`Ebert and/or Sasaki teaches or suggests that rivastigmine oxidatively degrades
`
`under pharmaceutically relevant conditions or requires an antioxidant.
`
`Accordingly, because the problem of rivastigmine’s oxidative degradation was
`
`unknown in the art, a POSA would not have been motivated to combine Enz with
`
`the Handbook, Rosin, Elmalem, Ebert and/or Sasaki—or any other art—to solve
`
`that problem.
`
`20
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`

`

`a.
`
`Enz
`
`Enz’s United States counterpart, U.S. Patent 5,602,176 (“’176 Patent”)
`
`contains all of the disclosures on which Petitioner here relies. (Ex. 2012 ¶ 53.)
`
`The ’176 Patent was considered by the examiner during prosecution of the ’031
`
`Patent.
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`(Ex. 2012 ¶ 53; Ex. 2029 at N0001063.) The examiner did not reject any
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`claim of the ’031 Patent over the ’176 Patent.3 (Ex. 2012 ¶ 53; Ex. 2029.)
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`Enz discloses rivastigmine and pharmaceutical compositions thereof and
`
`teaches that such compositions can be made in a “conventional manner.” Ex. 2012
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`¶ 54; Ex. 1002 at 10, 16, 19.) Example 2 of Enz discloses a transdermal
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`formulation containing “e.g.” rivastigmine hydrogen tartrate. (Ex. 2012 ¶ 55; Ex.
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`1002 at 19.) Petitioner relies on Examp