Paper No. ___
`Date Filed: May 13, 2016
`
`Filed On Behalf Of:
`Novartis AG
`
`By:
`Nicholas N. Kallas
`NKallas@fchs.com
`ZortressAfinitorIPR@fchs.com
`(212) 218-2100
`
`
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
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`
`
`PAR PHARMACEUTICAL, INC.,
`
`Petitioner,
`
`v.
`
`NOVARTIS AG,
`
`Patent Owner.
`
`
`Case IPR2016-00084
`Patent No. 5,665,772
`
`
`
`
`
`PATENT OWNER NOVARTIS’S REQUEST
`FOR REHEARING UNDER 37 C.F.R. § 42.71(c) AND (d)
`
`
`
`
`
`
`Date Filed: May 13, 2016
`
`Filed On Behalf Of:
`Novartis AG
`
`By:
`Nicholas N. Kallas
`NKallas@fchs.com
`ZortressAfinitorIPR@fchs.com
`(212) 218-2100
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`PAR PHARMACEUTICAL, INC.,
`
`Petitioner,
`
`v.
`
`NOVARTIS AG,
`
`Patent Owner.
`
`
`Case IPR2016-00084
`Patent No. 5,665,772
`
`
`
`
`
`PATENT OWNER NOVARTIS’S REQUEST
`FOR REHEARING UNDER 37 C.F.R. § 42.71(c) AND (d)
`
`
`
`
`
`
`
`
`
`
`
`IPR2016-00084
` U.S. Patent No. 5,665,772
`
`TABLE OF CONTENTS
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`INTRODUCTION AND STATEMENT OF RELIEF
`REQUESTED .................................................................................................. 1
`
`
`
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`I.
`
`II.
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`BASIS FOR RELIEF REQUESTED .............................................................. 2
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`A.
`
`B.
`
`C.
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`Background ........................................................................................... 2
`
`The Board’s Decision Overlooked Novartis’s Arguments
`On Lemke .............................................................................................. 3
`
`The Board’s Decision Overlooked Novartis’s Arguments
`On Yalkowsky ....................................................................................... 7
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`III. CONCLUSION .............................................................................................. 10
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`IPR2016-00084
` U.S. Patent No. 5,665,772
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`INTRODUCTION AND
`STATEMENT OF RELIEF REQUESTED
`
`Pursuant to 37 C.F.R. § 42.71(c) and (d), Patent Owner Novartis AG
`
`
`I.
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`
`
`(“Novartis”) respectfully requests reconsideration of the Board’s April 29,
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`2016 decision instituting inter partes review of the challenged claims of U.S.
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`Patent No. 5,665,772 (“the ’772 patent”), Paper 8 (“Dec.”), on Grounds 1 and
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`2 set forth in the Petition of Par Pharmaceutical, Inc. (“Par”), Paper 2 (“Pet.”).
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`Novartis requests rehearing because the Board overlooked or
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`misapprehended the arguments presented at pages 22–23 and 26 of Novartis’s
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`Preliminary Response, Paper 7 (“Prelim. Resp.”) regarding Lemke (Ex.
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`1008), and at pages 23–26 regarding Yalkowsky (Ex. 1007), either of which
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`provides an independent basis to deny institution. The Board’s decision to
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`institute this review does not specifically reference Novartis’s arguments
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`regarding the Lemke and Yalkowsky references, or cite any of pages 22–26 of
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`the Preliminary Response. The decision identifies only some of Novartis’s
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`arguments and states that it has “considered these and other arguments raised
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`by Novartis” (Dec. 15), but not that it considered all of Novartis’s preliminary
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`response arguments.
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`At pages 22–23 and 26 of its Preliminary Response, Novartis explained
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`that the chemical difference between everolimus and rapamycin at C40 does
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`IPR2016-00084
` U.S. Patent No. 5,665,772
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`not involve the addition of any of the water-solubilizing groups upon which
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`Par based its challenge. Par’s argument with respect to Lemke is thus based
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`on a fundamental scientific error that is fatal to its case. At pages 23–26 of its
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`Preliminary Response, Novartis explained that Yalkowsky’s teachings about
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`the internal entropy of flexible chains, upon which Par relies, apply only to
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`chains of more than five atoms—not shorter chains like everolimus’ C40
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`substituent. Thus, Par’s suggestion to rely on Yalkowsky is contradicted by
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`the reference itself. Novartis should not be put to the burden and expense of
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`defending a case that Par has no reasonable likelihood of winning. See 35
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`U.S.C. § 314(a).
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`II. BASIS FOR RELIEF REQUESTED
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`A. Background
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`As the Board’s decision explains, Par alleges that one of ordinary skill
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`in the art, as of October 9, 1992, would have selected rapamycin as a lead
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`compound, and would have had a motivation to increase its water solubility.
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`Dec. 10–11. In particular, Par alleges that the person of ordinary skill would
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`have chemically modified rapamycin at C40 by introducing a flexible
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`substituent (based only on the teachings of Yalkowsky (Ex. 1007)), that adds
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`an alcohol, amine or carboxylic acid functional group (based only on the
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`teachings of Lemke (Ex. 1008)). Dec. 11–12 (citing Pet. 44–47).
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`IPR2016-00084
` U.S. Patent No. 5,665,772
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`B.
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`The Board’s Decision Overlooked
`Novartis’s Arguments On Lemke
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`In instituting trial on Grounds 1 and 2, the Board overlooked the
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`argument presented at pages 22–23 and 26 of Novartis’s Preliminary
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`Response. There, Novartis explained that Par mischaracterizes the chemical
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`difference between rapamycin and everolimus to justify relying on Lemke.
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`Prelim. Resp. 22–23.
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`In particular, Novartis explained that Par cites Lemke for the
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`proposition that it would have been obvious to consider the addition of water-
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`solubilizing substituents to rapamycin. Id. (citing Pet. 33–34). According to
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`Par, Table 16-1 of Lemke (Ex. 1008 at 116, reproduced at Pet. 24; see also
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`infra n.2) discloses the favorable water-solubilizing effects of adding
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`hydroxyl, amino, and carboxylate groups. Prelim. Resp. 22 (citing Pet. 33–
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`34; Ex. 1003 at ¶ 84). However in focusing on the portions of Lemke’s Table
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`16-1 relevant to alcohol (hydroxyl), amino and carboxylate groups, Par failed
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`to address the evidence in Table 16-1 that is actually relevant to the
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`challenged claims—the entry pertaining to ether groups.
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`IPR2016-00084
` U.S. Patent No. 5,665,772
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`As Novartis explained, the chemical difference between rapamycin and
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`everolimus at C40 is not a hydroxyl, amino, or carboxylate group. Prelim.
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`Resp. 22; compare Dec. 3 (structure of rapamycin) with Pet. 12 (structure of
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`everolimus).1 That is, everolimus does not have an additional hydroxyl,
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`amino or carboxylate group as compared to rapamycin. Prelim. Resp. 22.
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`Both everolimus and rapamycin have a C40 substituent that includes a
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`hydroxyl group so they do not differ in this respect. Therefore, one of
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`ordinary skill who was following Lemke’s disclosure would have been
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`encouraged to add another hydroxyl group, or an amino or carboxylate group
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`at rapamycin’s C40 position, which would not have resulted in the compound
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`everolimus. Id. at 22, 27.
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` 1
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` For the Board’s convenience, Novartis reproduces below the segment of the
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`chemical structures of rapamycin and everolimus relevant to the arguments
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`referenced in the body of the instant motion. Dec. 3; Pet. 12.
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`HO
`
`H3CO
`
`40
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`
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`Rapamycin
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`
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`4
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`CH2
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`CH2
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`O
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`HO
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`40
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`H3CO
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`Everolimus
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`IPR2016-00084
` U.S. Patent No. 5,665,772
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`Novartis also argued that relying on Lemke would not have provided a
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`
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`reasonable basis to expect that everolimus would exhibit improved water
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`solubility over rapamycin. Id. at 23, 26. As Novartis explained, everolimus
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`differs chemically from rapamycin in that it has an ether oxygen (-O-) and
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`two carbon groups (-CH2-) interposed between the C40 carbon and its
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`hydroxyl group. Supra n.1. According to Lemke’s Table 16-1,2 the addition
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`of an ether group provides a water solubilizing potential of two carbons in a
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`polyfunctional molecule. Prelim. Resp. 23. Thus, Lemke indicates that any
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`increase in water solubility resulting from the addition of an ether oxygen
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` 2
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` For the Board’s convenience, Lemke’s Table 16-1 is reproduced below. Ex.
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`1008 at 116.
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`IPR2016-00084
` U.S. Patent No. 5,665,772
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`would be offset by the addition of two carbons. Id. The addition of an ether
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`oxygen and two carbons would, therefore, be expected to have a net zero
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`impact on water solubility. Id. As a result, one of ordinary skill would not
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`reasonably have expected everolimus to be more water-soluble than
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`rapamycin. Id. at 23, 26.
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`Novartis also showed that a second method set forth by Lemke for
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`assessing water solubility similarly indicates that everolimus would not have
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`improved water solubility over rapamycin in view of the chemical differences
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`between the two molecules. Id. In particular, Novartis explained that in “the
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`ᴨ fragment method depicted in Lemke’s Table 16-2 (but disregarded by Par),
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`the addition of an ether oxygen is given a value of -1.0 and the addition of
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`two carbon atoms is given a value of +1.0 (+0.5 x 2).” Id.at 23 (citing Ex.
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`1008 at 119). As -1.0 and +1.0 cancel each other out, one of ordinary skill
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`would not have expected the addition of an ether oxygen and two carbons to
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`increase water solubility. Id.
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`Lemke, therefore, teaches that rapamycin and everolimus would be
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`expected to have the same water solubility. Id. Lemke thus fails to provide a
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`motivation to modify rapamycin to make everolimus or a reasonable
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`expectation that everolimus would have improved water solubility. Prelim.
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`Resp. 22–23, 26. As Lemke is the sole reference upon which Par relies to
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`IPR2016-00084
` U.S. Patent No. 5,665,772
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`support the selection of the 2-hydroxyethyl ether functional group present in
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`everolimus, Par cannot show that it is reasonably likely to establish the
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`unpatentability of the challenged claims of the ’772 patent under Grounds 1
`
`or 2. See 35 U.S.C. § 314(a).
`
`C. The Board’s Decision Overlooked
`Novartis’s Arguments On Yalkowsky
`
`In instituting trial on Grounds 1 and 2, the Board also overlooked the
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`argument presented at pages 23–26 of Novartis’s Preliminary Response
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`regarding Yalkowsky. As shown below, that argument explained why no
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`reasonable interpretation of Yalkowsky justifies Par’s reliance on this
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`reference to support a motivation to add flexible side chains to rapamycin
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`with an expectation of improving water solubility. Prelim. Resp. 23–26.
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`Par relies on Yalkowsky’s formula for calculating the internal entropy
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`of flexible chains to argue that everolimus would be expected to have
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`improved water solubility over rapamycin because it has a flexible side chain
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`at the C40 position. Prelim. Resp. 23; Pet. 32–33, 45; Dec. 9. In particular,
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`Par contends that Yalkowsky shows that each added rotatable bond of a
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`flexible chain contributes to the free energy of fusion, favoring dissolution.
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`Prelim. Resp. 25 (citing Pet. 33; Ex. 1003 at ¶ 79).
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`IPR2016-00084
` U.S. Patent No. 5,665,772
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`However, as Novartis explained, and as the Board’s decision notes,
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`
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`Yalkowsky itself clearly states that the very formula upon which Par relies
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`applies only to “longer chains,” i.e., chains with more than five atoms.
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`Prelim. Resp. 25 (citing Ex. 1007 at 111 (“For longer chains we can estimate
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`the contribution to internal entropy by adding 2.5 (n – 5) eu, where n is the
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`total number of chain atoms (exclusive of protons).” (emphasis added))); 3
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`Dec. 9 (citing Ex. 1007 at 111 (“Longer chains are said to contribute to
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`internal entropy by 2.5 (n – 5) eu, where n is the number of atoms in the
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`chain.” (emphasis added)). Indeed, as Novartis also explained, Yalkowsky
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` 3
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` For the Board’s convenience, Novartis has reproduced below the cited
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`paragraph of Yalkowsky. Ex. 1007 at 111.
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`IPR2016-00084
` U.S. Patent No. 5,665,772
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`states that chains of five or fewer atoms (excluding protons) “do not
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`contribute appreciably” to the change in entropy resulting from
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`conformational changes and therefore do not qualify as “longer chains” for
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`which the formula 2.5 (n – 5) eu applies. Prelim. Resp. 25 (citing Ex. 1007 at
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`110–11). Par ignores these express teachings of Yalkowsky, which
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`demonstrate that the C40 substituent of everolimus (which has four atoms,
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`excluding protons, and thus an n value of 4), is not one of the “longer chains”
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`to which Yalkowsky’s formula is applicable. Prelim. Resp. 25–26.
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`Therefore, Yalkowsky would not have taught one of ordinary skill to
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`pursue a derivative with the 4-atom substituent that is present in everolimus.
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`Id. Nor would Yalkowsky have provided one of ordinary skill with a
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`reasonable expectation that everolimus would have greater water solubility
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`than rapamycin. Id. As Par relies only on Yalkowsky to assert that one of
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`ordinary skill would have selected a flexible C40 substituent with a
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`reasonable expectation of successfully increasing water solubility, for this
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`additional reason, Par cannot show that it is reasonably likely to establish the
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`unpatentability of the challenged claims of the ’772 patent under Grounds 1
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`or 2. See 35 U.S.C. § 314(a).
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`III. CONCLUSION
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`IPR2016-00084
` U.S. Patent No. 5,665,772
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`For the reasons set forth above, Novartis respectfully submits that the
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`Board’s institution decision constituted an abuse of discretion and requests
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`that the Board reconsider its decision with respect to Grounds 1 and 2 of the
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`Petition and decline to institute inter partes review on claims 1–3 and 8–10 of
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`the ’772 patent. 37 C.F.R. § 42.71(c) and (d).
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`
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`Dated: May 13, 2016
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`Respectfully submitted,
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`
`
`/Nicholas N. Kallas/
`Nicholas N. Kallas
`Registration No. 32,530
`Counsel for Patent Owner
`FITZPATRICK, CELLA,
`HARPER & SCINTO
`1290 Avenue of the Americas
`New York, NY 10104-3800
`Tel. 212-218-2100
`
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`IPR2016-00084
` U.S. Patent No. 5,665,772
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`CERTIFICATE OF SERVICE
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`I certify that a copy of the foregoing Patent Owner Novartis’s Request For
`
`Rehearing Under 37 C.F.R. § 42.71(c) and (d) was served on May 13, 2016 by
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`causing it to be sent by email to counsel for Petitioner at the following email
`
`addresses:
`
`
`
`Daniel G. Brown (daniel.brown@lw.com)
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`Robert Steinberg (bob.steinberg@lw.com)
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`
`
`
`/Nicholas N. Kallas/
`Nicholas N. Kallas
`Registration No. 32,530
`Lead Counsel for Patent Owner
`FITZPATRICK, CELLA, HARPER
`& SCINTO
`1290 Avenue of the Americas
`New York, NY 10104-3800
`Tel. 212-218-2100
`
`
`
`
`
`
`
`
`
`Dated: May 13, 2016
`
`1
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