Paper 77
` Entered: November 30, 2015
`
`Trials@uspto.gov
`Tel: 571-272-7822
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`NOVEN PHARMACEUTICALS, INC.,
`and MYLAN PHARMACEUTICALS INC.
`Petitioner,
`
`v.
`
`NOVARTIS AG and LTS LOHMANN THERAPIE-SYSTEME AG,
`Patent Owner.
`____________
`
`Case IPR2014-005501
`Patent 6,335,031 B1
`_____________
`
`Before FRANCISCO C. PRATS, ERICA A. FRANKLIN, and
`CHRISTOPHER G. PAULRAJ, Administrative Patent Judges.
`
`FRANKLIN, Administrative Patent Judge.
`
`DECISION
`Denying Patent Owner’s Request for Rehearing
`37 C.F.R. § 42.71
`
`
`1 Case IPR2015-00268 has been joined with this proceeding.
`
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`

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`IPR2014-00550
`Patent 6,335,031 B1
`
`
`’031 Patent Claims
`1, 2, 7, 15 and 18
`
`INTRODUCTION
`I.
`Novartis AG and LTS Lohmann Therapie-Systeme AG (collectively,
`“Patent Owner”) request reconsideration of the Final Decision entered on
`September 28, 2015, Paper 69 (“Final Decision” or “Final Dec.”). Paper 71
`(“Rehearing Request” or “Req. Reh’g”).
`In the Final Decision, we addressed the following grounds of
`unpatentability for challenged claims 1–3, 7, 15, 16 and 18 of U.S. Patent
`No. 6,335,031 B1 (Ex. 1001, “the ’031 patent”):
`References
`Basis
`Enz,2 the Handbook,3 Rosin,4
`§ 103(a)
`Elmalem,5 and Ebert6
`Enz, the Handbook, Rosin, and Ebert
`Enz and Sasaki7
`
`§ 103(a)
`§ 103(a)
`
`3 and 16
`1–3, 7, 15, 16 and 18
`
`Petitioner relied on two declarations of Dr. Agis Kydonieus, Ex. 1010;
`Ex. 1031, and two declarations of Dr. Christian Schöneich, Ex. 1011; Ex.
`1032. Patent Owner relied on the declaration of Dr. Alexander M. Klibanov,
`Ex. 2012.
`
`
`
`2 Ex. 1002, UK Patent Application GB 2,203,040 A, published Oct. 12, 1988
`(“Enz”).
`3 Ex. 1003, HANDBOOK OF PHARMACEUTICAL EXCIPIENTS (A. Wade & P.J.
`Weller eds., 2d ed. 1994) (“the Handbook”).
`4 Ex. 1008, US 4,948,807, issued Aug. 14, 1990 (“Rosin”).
`5 Ex. 1009, Antagonism of Morphine-Induced Respiratory Depression by
`Novel Anticholinesterase Agents, 30 NEUROPHARMACOLOGY 1059–64
`(1991) (“Elmalem”).
`6 Ex. 1006, WO 95/24172, published Sept. 14, 1995 (“Ebert”).
`7 Ex. 1005, JP Patent Application 59-184121, published Oct. 19, 1984
`(“Sasaki”).
`
`
`
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`IPR2014-00550
`Patent 6,335,031 B1
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`
`In the Final Decision, we held that Noven Pharmaceuticals, Inc. and
`Mylan Pharmaceuticals Inc. (collectively, Petitioner) had shown by a
`preponderance of the evidence that claims 1–3, 7, 15, 16 and 18 of U.S.
`Patent No. 6, 335,031 B1 (Ex. 1001, “the ’031 patent”) are unpatentable for
`obviousness under 35 U.S.C. § 103(a). Final Dec. 42.
`II. ANALYSIS
` “When rehearing a decision on petition, a panel will review the
`decision for an abuse of discretion.” 37 C.F.R. § 42.71(c). “The burden of
`showing a decision should be modified lies with the party challenging the
`decision. The request must specifically identify all matters the party
`believes the Board misapprehended or overlooked, and the place where each
`matter was previously addressed in a motion, an opposition, or a reply.” 37
`C.F.R. § 42.71(d). For the reasons discussed below, Petitioner’s Rehearing
`Request is denied.
`A.
`Federal Circuit Decision in Watson
`Patent Owner asserts that we overlooked the Federal Circuit’s
`decision in Novartis Pharms. Corp. v. Watson Labs, Inc., –– F. App’x ––,
`Nos. 2014-1799 et al., 2015 WL 2403308 at *5–8 (Fed. Cir. May 21, 2015)
`(“Watson”) in two respects. Req. Reh’g 2–7, 9–13. First, according to
`Patent Owner, “the Board erred in overlooking the Federal Circuit’s holding
`in Watson that Elmalem would not have taught a person of ordinary skill in
`the art that rivastigmine is oxidatively unstable or required an antioxidant.”
`Id. at 7.8 Second, Patent Owner asserts that the Board overlooked the
`
`8 Patent Owner asserts also that we “overlooked that district court expert
`credibility determinations should be accorded great deference ‘because the
`court saw the witnesses and heard the testimony.’” Req. Reh’g 6 (quoting
`Celsis In Vitro, Inc. v. CellzDirect, Inc., 664 F.3d 922, 929 (Fed. Cir. 2012)).
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`Federal Circuit’s holding in Watson that “‘susceptibility’ to oxidative
`degradation would not have motivated a person of ordinary skill in the art to
`add an antioxidant to the transdermal formulation in Enz.” Id. at 9–10.
`We have carefully reviewed Patent Owner’s arguments presented in
`the Request for Rehearing, but do not find them persuasive. In particular,
`the Decision squarely addresses the Federal Circuit’s decision in Watson and
`explains why that decision does not control in this proceeding. Final Dec.
`4–5. Specifically, we stated:
`The Federal Circuit’s Watson decision does not control here
`because Noven has presented additional prior art and
`declaratory evidence that was not before the Court in Watson.
`Moreover, in an inter partes review, a petitioner’s burden of
`proving unpatentability is by a preponderance of the evidence
`rather than by clear and convincing evidence, as required in
`district court litigation. Thus, while we have considered the
`Federal Circuit’s decision, we have independently analyzed
`patentability of the challenged claims based on the evidence
`and standards that are applicable to this proceeding.
`
`Id.
`
`Significantly, the Federal Circuit noted that “[t]he district court
`admitted that there ‘does not appear to be an objectively ‘correct’ reading [of
`Elmalem],” rather both arguments regarding whether Elmalem teaches or
`suggests adding an antioxidant to rivastigmine “seem logical and are
`supported by highly qualified experts in the field.” Watson at 992 (quoting
`Novartis Pharm. Corp. v. Par Pharm., Inc., 48 F. Supp. 3d 733, 757 (D. Del.
`2014). Further, the Federal Circuit explained that the district court credited
`
`
`However, the deference a district court receives for expert credibility
`determinations is accorded by the Federal Circuit reviewing an appeal from
`the district court, not by the Board in an inter partes trial proceeding.
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`Novartis’ expert testimony as being more credible than Watson’s expert. Id.
`at 993. Based upon that credibility assessment, the district court found that
`Elmalem’s use of an antioxidant was to reduce variability among samples
`tested, and not a teaching or suggestion that rivastigmine is susceptible to
`oxidative degradation so as to motivate one of skill in the art to combine an
`antioxidant with it. Id. (citing Novartis Pharm. Corp. v. Par Pharm., Inc.,
`48 F. Supp. 3d 733 at 756–57).
`While acknowledging that “the plain language of the Elmalem article
`appears to present a close[] question,” on appeal, the Federal Circuit gave
`“great deference” to the credibility determination of the district court. Id. at
`996. Based upon that deference, the Federal Circuit affirmed the district
`court’s holding that Watson failed to prove by clear and convincing evidence
`that the asserted claims of the ’031 patent would have been obvious. Id. at
`997.
`
`In this proceeding, the Petitioners Noven and Mylan presented
`different evidence than what Watson presented in district court regarding
`what Elmalem would have taught a person of ordinary skill in the art.
`Specifically, the Petitioners relied upon the declaration testimony of Dr.
`Kydonieus and Dr. Schöneich. Patent Owner has not shown that the same
`declaratory evidence was presented in the district court case reviewed by the
`Federal Circuit. In the Decision, we explain our finding that Elmalem’s
`disclosure suggests adding an antioxidant to rivastigmine to prevent
`oxidation was based upon our consideration of the evidence and arguments
`presented to us. Final Dec. 32. In particular, upon considering and
`comparing the testimony of Patent Owner’s expert, Dr. Klibanov, with that
`
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`of Petitioner’s experts, Drs. Kydonieus and Schöneich, we afforded greater
`persuasive weight to the testimony of Petitioner’s experts. See id. at 31–35.
`Thus, to the extent that Patent Owner asserts that the Board
`overlooked its burden under In re Baxter International, Inc., 678 F.3d 1357,
`1365 (Fed. Cir. 2012)(“Baxter”) to not arrive at a different conclusion than
`the Federal Circuit, Req. Reh’g 1, the argument is misplaced as the evidence
`and arguments presented in this proceeding differed from that considered by
`the court system in that litigation. See Baxter at 1365–66 (acknowledging
`burden of proof and record evidence considered by the Board was different
`than in court system and affirming the Board’s different result, i.e., that the
`challenged claims were not patentable). As in Baxter, our expert credibility
`determination is not comparable to that of the district court, as we only
`considered the persuasive testimony of two experts “that had not been raised
`in the prior district court proceeding.” id. at 1365. Thus, the Federal
`Circuit’s deference to and affirmance of the credibility determinations of the
`district court do not control the outcome in this proceeding.
`Regarding Patent Owner’s assertion that, in Watson, the Federal
`Circuit “held that ‘susceptibility’ to oxidative degradation would not have
`motivated a person of ordinary skill in the art to add an antioxidant to the
`transdermal formulation in Enz,” Req. Reh’g 9–10, we disagree with that
`characterization. To the contrary, the Federal Circuit stated, “here Watson
`failed to prove that a rivastigmine formulation was known to be susceptible
`to oxidative degradation.” Watson at 996 (emphasis added). Additionally,
`the Federal Circuit explained that it gave considerable deference to the
`district court’s finding that the prior art did not teach or suggest that
`rivastigmine was known to be susceptible to oxidative degradation, and that
`
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`“without an appreciation for rivastigmine’s susceptibility to oxidative
`degradation, one of skill in the art would not have been motivated … to add
`an antioxidant to a rivastigmine formulation.” Id. at 997. Moreover, we are
`not persuaded by Patent Owner’s argument that we overlooked the Federal
`Circuit’s affirmance of the district court’s finding that the evidence did not
`teach or suggest rivastigmine’s susceptibility to oxidative degradation
`because, as discussed above, the courts did not consider the same declaratory
`evidence presented in this proceeding.
`Further, to the extent that Patent Owner asserts that we overlooked the
`Federal Circuit decision in Watson regarding the ground based upon the
`combined teachings of Enz and Sasaki, Req. Reh’g 14–15, we remain
`unpersuaded as the district court case reviewed by the Federal Circuit
`decision in Watson did not consider the combination of Enz and Sasaki.
`See Final Dec. 4–5 (explaining, among other differences, that in this
`proceeding “Noven presented additional prior art that was not before the
`Court in Watson”).
`B.
`Chemical Stability of Rivastigmine
`Patent Owner asserts that the Board overlooked Patent Owner’s
`evidence “that the Elmalem authors did not believe or reasonably expect
`rivastigmine to be oxidatively unstable or require an antioxidant.” Req.
`Reh’g 7. In the Patent Owner Response, Patent Owner asserted that a person
`of ordinary skill in the art reading Elmalem would not have reasonably
`expected that rivastigmine would oxidatively degrade under
`pharmaceutically relevant conditions or require an antioxidant in any
`pharmaceutical formulation because two journal articles, Enz 1991 and
`Weinstock 1994, describing rivastigmine as showing “greater chemical
`
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`stability” than physostigmine, did not describe adding an antioxidant to
`rivastigmine. PO Resp. 36 (citing Ex. 2026 and Ex. 2027). In the rehearing
`request, Patent Owner asserts that because Weinstock 1994 was written by
`two of the Elmalem authors and they did not add an antioxidant to
`rivastigmine, it is apparent that they did not believe or reasonably expect
`rivastigmine to be oxidatively unstable or require an antioxidant. Req.
`Reh’g 7–8.
`As indicated in the Decision, we considered each of Patent Owner’s
`arguments, including those asserting an interpretation of Elmalem based
`upon the alleged teachings of Enz 1991 and Weinstock 1994. See
`Final Dec. 26 (referring to Patent Owner’s Response at pages including
`those addressing Enz 1991 and Weinstock 1994). To the extent we might
`not have explained specifically why Patent Owner’s arguments based upon
`Enz 1991 and Weinstock 1994 are not persuasive, we do so here.
`As we discussed with respect to Rosin and Elmalem, a description that
`a compound shows “greater chemical stability” than another compound, is
`not necessarily a teaching that either compound is oxidatively stable. See
`Fin. Dec. 31–32. Indeed, as with Rosin and Elmalem, Enz 1991and
`Weinstock 1994 do not address oxidative stability. Dr. Kydonieus’
`explanation regarding the “greater chemical stability” description in Rosin is
`applicable here also, i.e., that to a person of ordinary skill in the art, the
`comparative statement “at best means that RA7 is more stable than an
`unstable compound.” Fin. Dec. 32 (quoting Ex. 1031 ¶ 48).
`
`Moreover, Dr. Kydonieus addressed Enz 1991 and Weinstock 1994,
`explaining how Patent Owner’s declarant, Dr. Klibanov, mischaracterized
`those publications as suggesting that rivastigmine is oxidatively stable. Ex.
`
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`1031 ¶¶ 68–70. In particular, Dr. Kydonieus noted that Enz 1991 described
`rivastigmine by stating the “drug appears to have greater chemical stability
`and longer duration of action than does physostigmine” based upon
`administration to human volunteers, suggesting that Enz 1991 is referring to
`the duration of action of rivastigmine in the body. Id. at 68–69 (quoting Ex.
`2026, 272). Similarly, Dr. Kydonieus noted that Weinstock 1994 states, “In
`animals and human subjects [rivastigmine] showed superior chemical
`stability, oral bioavailability and a longer duration of action than
`physostigmine,” suggesting that Weinstock 1994 is referring to in vivo
`activity of rivastigmine rather than oxidative stability in a pharmaceutical
`formulation. Id. at 70 (quoting Ex. 2027, 219).
`
`Therefore, for reasons similar to those provided in the Final Decision
`regarding the relative chemical stability of rivastigmine disclosed by Rosin
`and Elmalem, we were not persuaded by Patent Owner’s arguments
`regarding similar statements in Enz 1991 and Weinstock 1994. Thus, Patent
`Owner has not established that we overlooked its argument.
`C. Other Compounds Not Reported To Include an Antioxidant
`Patent Owner asserts that “the Board overlooked Patent Owner’s
`evidence of multiple compounds with the same structural features as
`rivastigmine that were not reported in the prior art to be oxidatively unstable
`or to contain an antioxidant in their commercial formulations.” Req. Reh’g
`8 (citing PO Resp. 18; Ex 2012 ¶¶ 133–137). According to Patent Owner,
`we neither mentioned those exemplary compounds in our Final Decision,
`nor offered any reason why a person of ordinary skill in the art would ignore
`them. Id.
`
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`We disagree. As indicated in the Final Decision, we considered
`Patent Owner’s argument. See Final Dec. 12 (referring to Patent Owner’s
`Response at pages including those addressing exemplary compounds sharing
`structural features with rivastigmine). To begin, we note that Patent Owner
`did not mention by name any of the “multiple exemplary compounds” in the
`Patent Owner’s Response. See PO Resp. 18 (referring to examples of
`compounds having features similar to rivastigmine, without identifying those
`examples). Instead, Patent Owner referred to the sections of Dr. Klibanov’s
`declaration that address those examples. Id. (citing Ex. 2012 ¶¶ 133–137).
`Patent Owner relies on those same sections of Dr. Klibanov’s declaration
`elsewhere in the Patent Owner’s Response also. See., e.g., PO Resp. 42.
`In the Final Decision, we address specifically each of the examples
`Dr. Kydonieus described in those sections of his declaration. See Final Dec.
`19–20. Significantly, we explained that merely identifying examples of
`drugs having structural similarities to rivastigmine that were “not reported to
`contain antioxidants in their commercial transdermal formulations,” Ex.
`2012 ¶ 133, was insufficient to establish that the compounds were not
`susceptible to oxidative degradation in pharmaceutically relevant conditions.
`Final Dec. 20–21. We explained further that neither Patent Owner nor Dr.
`Klibanov identified any statement in the Physician’s Desk Reference upon
`which Dr. Klibanov relied in support of his assertions, or elsewhere,
`describing the oxidative stability or shelf-life of any of the asserted
`exemplary compounds. Id. at 19–20.
`We also explained that it was problematic that Dr. Klibanov did not
`discuss in his declaration whether the commercial formulations comprising
`those exemplary compounds addressed drug stability by some means other
`
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`than adding an antioxidant. Id. at 20. As we stated in the Final Decision,
`Indeed, in his deposition testimony, Dr. Klibanov
`acknowledged that conclusions regarding a drug’s susceptibility
`to oxidation cannot be made based upon its formulation being
`reported not to include an antioxidant, because other means of
`preventing oxidation may have been employed. Ex. 1026,
`247:9–249:6; Pet. Reply 9; Ex. 1032 ¶ 42.
`
`Final Dec. 20. Thus, Patent Owner has not established that we overlooked
`its argument.
`
`D. The European Agency Guidelines
`Patent Owner asserts that we overlooked its evidence that a person of
`ordinary skill in the art would not add an antioxidant unless one was needed.
`Req. Reh’g 13. In particular, Patent Owner refers to a publication by The
`European Agency for the Evaluation of Medicinal Products providing
`guidance on the inclusion of antioxidants and antimicrobial preservatives in
`medicinal products (“EMEA guidelines”). Id. (citing Ex. 2019, 3).
`As indicated in the Final Decision, we considered this argument by
`Patent Owner. See Final Dec. 12 (referring to Patent Owner’s Response at
`pages including those addressing the EMEA guidelines). To the extent we
`might not have explained specifically why the argument was unpersuasive,
`we do so here. In the Patent Owner Response, Patent Owner asserted that
`the art expressly taught that antioxidants “should only be used once it has
`been shown that their use cannot be avoided.” PO Resp. 10. In support of
`that contention, Patent Owner relied on the declaration of Dr. Klibanov and
`the EMEA guidelines. Id. at 9-10. According to Dr. Klibanov, the EMEA is
`the European equivalent of the United States Food and Drug Administration.
`Ex. 2012 ¶ 40. Dr. Klibanov did not provide testimony that the EMEA
`
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`“guidelines” represent anything more than just that. In other words, Patent
`Owner did not establish that the EMEA guidelines represented a restriction,
`rule or regulation for drug formulation in Europe, or that an approach that
`differed from those set forth in the guidance would not be approved by the
`agency, if, in fact, the agency is responsible for approving drugs.
`Moreover, as Dr. Kydonieus explained, the EMEA guidelines are
`directed toward justifying the use of an antioxidant. Ex. 1031 ¶ 93. The
`EMEA guideline states, “Antioxidants should not be used to disguise poorly
`formulated products or inadequate packaging. The need to include an
`antioxidant should be explained and fully justified.” Ex. 2019, 2. Thus, we
`understand the guidance as a whole to be directed to avoiding the use of an
`antioxidant to cure inadequate formulation or packaging techniques, rather
`than categorically avoiding the addition of an antioxidant to prevent
`oxidative degradation in compounds with known susceptibility to such
`degradation.
`As discussed in the Final Decision, based on our consideration of the
`record as a whole, we found that Petitioner established that a person of
`ordinary skill in the art would have predicted that the transdermal
`formulation disclosed by Enz was susceptible to oxidative degradation and
`would have been motivated to add an antioxidant with a reasonable
`expectation of successfully avoiding that predicted degradation. See, e.g., 17
`(addressing the combination of Enz and Sasaki) and 38 (addressing the
`combination of Enz, the Handbook, Rosin, Elmalem, and Ebert).
`Thus, Patent Owner has not established that we overlooked its
`argument or evidence.
`
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`III. CONCLUSION
`We have considered Patent Owner’s request, but find no point of law
`or fact which we overlooked or misapprehended in arriving at our Final
`Decision.
`
`ORDER
`In consideration of the foregoing, it is hereby:
`ORDERED that the Patent Owner’s request for rehearing is denied.
`
`PETITIONER:
`
`Steven J. Lee
`Michael K. Levy
`Christopher J. Couslon
`KENYON & KENYON LLP
`slee@kenyon.com
`mlevy@kenyon.com
`ccoulsson@kenyon.com
`
`Joseph Reisman
`Jay Deshmukh
`William R. Zimmerman
`KNOBBE, MARTENS, OLSON & BEAR, LLP
`2jmr@knobbe.com
`2jrd@knobbe.com
`
`
`
`PATENT OWNER:
`
`Raymond R. Mandra
`Nicholas N. Kallas
`FITZPATRICK, CELLA, HARPER & SCINTO
`rmandra@fchs.com
`ExelonPatchIPR@fchs.com
`
`
`
`13