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` Paper No. 13
`Filed: March 7, 2019
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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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`NEPTUNE GENERICS, LLC
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`PETITIONER
`
`V.
`
`AVENTIS PHARMA S.A.
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`PATENT OWNER
`
`___________________
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`CASE NO.: IPR2019-00136
`PATENT NO. 5,847,170
`FILED: MARCH 26, 1996
`ISSUED: DECEMBER 8, 1998
`INVENTORS: HERVÉ BOUCHARD,
`JEAN-DOMINIQUE BOURZAT, ALAIN COMMERÇON
`
`
`TITLE: TAXOIDS, THEIR PREPARATION, AND PHARMACEUTICAL
`COMPOSITIONS CONTAINING THEM
`___________________
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`PETITIONER’S REPLY TO
`PATENT OWNER’S PRELIMINARY RESPONSE
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`TABLE OF CONTENTS
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`I.
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`Petitioner’s Arguments were not presented By Mylan ...................................... 1
`A. Neptune’s Reliance on Commerçon is Not Cumulative. ............................... 1
`B. Neptune’s and Mylan’s Lead Compound Analyses are Not Equivalent. ...... 2
`C. Neptune’s and Mylan’s Petitions Rely on Different Arguments to Motivate
`Simultaneous Methylation at C-7 and C-10. ......................................................... 3
`D. The Teachings of Klein and Wong are Not Equivalent. ................................ 3
`II. The Court Did Not Consider Petitioner’s Arguments ....................................... 4
`III. Patent Owner Uses Incorrect Obviousness Standard ........................................ 5
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`i
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`I.
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`PETITIONER’S ARGUMENTS WERE NOT PRESENTED BY
`MYLAN
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`A. Neptune’s Reliance on Commerçon is Not Cumulative.
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`Sanofi asserts, incorrectly, that Neptune’s reliance on Commerçon (Ex.
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`1009) duplicates arguments made in a previous IPR petition filed by Mylan.
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`(POPR, 23-25). Yet Mylan’s petition did not identify or rely upon the Commerçon
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`reference at all - a fact that Sanofi does not dispute. Sanofi conveniently limits and
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`recasts Commerçon’s disclosures while ignoring that Neptune provided a deep
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`background on the state of the art and best practices in analog research,
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`demonstrating that a POSA would have been motivated to maintain and/or improve
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`biological activity of a given analog. Accordingly, Neptune relied upon
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`Commerçon to show that a POSA would have known which portions of paclitaxel
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`were “crucial” to activity and would have been motivated not to modify those
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`“crucial” portions, thus motivating a POSA to make changes only to known
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`“flexible” portions of the molecule - also identified by Commerçon as being C-7
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`through C-10. (Petition, 39-42, fig, 42). Mylan’s petition did not rely on
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`Commerçon at all, let alone its disclosures demonstrating which portions of the
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`analog to maintain and which to modify based on the known structure-activity
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`relationships and best laboratory practices known at the time.
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`1
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`B. Neptune’s and Mylan’s Lead Compound Analyses are Not
`Equivalent.
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`Sanofi improperly conflates Neptune’s and Mylan’s “lead compound
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`analyses” as centering “on a paclitaxel analog having a C-10 methoxy group and
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`BOC sidechain, i.e., Kant Compound 20.” (POPR, 20-22). Yet Neptune and
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`Mylan arrive at Kant Compound 20 through completely different pathways and
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`motivations. Mylan simply unilaterally declared Kant Compound 20 as its lead
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`compound and did not engage in a “lead compound analysis” for this compound
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`(Ex. 2011, 31), a fact that did not escape the Board.1 Neptune, on the other hand,
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`engaged in a detailed lead compound analysis, supported by an expert declaration
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`and numerous exhibits, to justify selecting paclitaxel as a lead compound.
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`(Petition, 37-38). Furthermore, Sanofi already admits paclitaxel is a proper lead
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`compound. (Id., 38). Sanofi cannot have it both ways, arguing that paclitaxel is the
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`lead compound in one instance and then arguing against it later on. As indicated,
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`Neptune provided a deep background on the state of the art, exploring the
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`motivations of a POSA to modify paclitaxel. Indeed the Commerçon reference (Ex.
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`1009) clearly motivated a POSA to maintain and change various portions of the
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`paclitaxel lead compound, and provided additional motivations to focus on the C-7
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`and C-10 positions. It is therefore nonsensical for Sanofi to allege that Neptune’s
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`1 Indeed, the Board denied Mylan’s petition, in significant part due to Mylan’s
`failure to establish Kant 20 as a lead compound. (Ex. 2020, 10-11).
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`2
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`and Mylan’s lead compound analyses are equivalent, when Mylan did not even
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`engage in a lead compound analysis for Kant Compound 20, and Neptune analyzed
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`the pertinent Kant compound outside of and separately from its lead compound
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`analysis.2
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`C. Neptune’s and Mylan’s Petitions Rely on Different Arguments to
`Motivate Simultaneous Methylation at C-7 and C-10.
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`Sanofi argues both petitions relied on Kant and a preference for synthetic
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`convenience to simultaneously methylate C-7 and C-10. (POPR, 26-28). However,
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`Neptune additionally supported simultaneous methylation with the best analog
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`development practices of (i) homologation, which involves lengthening readily
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`accessible hydroxyl groups outside the pharmacophore through the addition of a
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`carbon atom (Petition, 45-46); and (ii) increasing an analog’s stability through
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`methylation to avoid a potential deleterious retro-aldol reaction. (Petition, 50).
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`None of the above arguments are even included in Mylan’s petition, nor are they
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`cumulative.
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`D. The Teachings of Klein and Wong are Not Equivalent.
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`Sanofi argues that because Klein (Ex. 1016) and Wong (Ex. 1011) are both
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`used to motivate methylation of C-7, they are equivalent—such that Neptune’s
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`reliance on Wong is not distinguishable from Mylan’s reliance on Klein, which was
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`2 Sanofi acknowledges further differences with any Mylan lead compound analysis
`regarding docetaxel in Sanofi’s footnote on page 21 of its POPR.
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`3
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`
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`rejected by the Board. (POPR, 23). But the Board rejected Mylan’s reliance on
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`Klein, at least in large part, because Klein discussed removing the carbonyl group
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`at C-9 and maintaining a carboxyl group at C-10, for reasons of increased stability
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`and solubility, which were inconsistent with Mylan’s motivation to increase an
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`analog’s lipophilicity (Ex. 2020, 15-17). The Wong reference does not contain any
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`such limitations or motivations and is therefore a fundamentally different
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`reference—nor does Neptune’s petition focus on a motivation to increase an
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`analog’s lipophilicity. Moreover, Neptune’s petition separately addressed and
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`accounted for motivations regarding increased stability (though the methylation of
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`C-7 to remove vulnerability to Aldol reactions, discussed above) and any solubility
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`concerns (Petition, 22-24, 44-45, 49-50) that would offset conflicting motivations
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`by Klein.
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`II. THE COURT DID NOT CONSIDER PETITIONER’S ARGUMENTS
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`Citing Mylan Pharm. v. Bayer, No. IPR2018-01143 Paper 13 (PTAB Dec. 3,
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`2018), Sanofi argues the Board should rely on §314 because Sanofi’s earlier
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`district court litigation that upheld the ’170 patent referenced some of the same
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`prior art as this petition. (POPR, 27-28). However, Mylan involved identical
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`parties, experts, and prior art. Id. at 1, 13. Neptune was never a party to any
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`litigation involving the ’170 patent, it relies upon a declarant not involved in any
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`related litigation, and this petition relies on the Commerçon-Kant-Wong
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`4
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`obviousness combination while Sanofi’s district court evaluated entirely different
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`combinations. Sanofi acknowledges “the district court defendants asserted two
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`separate obviousness challenges – the first combined Kant with Klein [] and the
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`second combined Wong with two BMS patents.” (POPR at 12-13). This
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`underscores how Sanofi’s district court action differs from this IPR petition and
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`that §314 discretion is not appropriate in this instance.
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`III. PATENT OWNER USES INCORRECT OBVIOUSNESS STANDARD
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`During prosecution of the ’170 patent, Sanofi argued that the activity of the
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`claimed cabazitaxel against drug-resistant cancer strains was unexpected. (Ex.
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`1042 at 4-5). Sanofi now argues Neptune failed to established prima facia
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`obviousness because it “failed to show a POSA would have had a reasonable
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`expectation that modifying paclitaxel,” would have led to a compound containing
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`allegedly unexpected activity certain cell lines. (POPR, 49). Arguments regarding
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`unexpected results have no place at the prima facia stage of obviousness. Bristol-
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`Myers Squibb Co. v. Teva Pharms. USA, Inc., 752 F.3d 967, 976-77 (Fed. Cir.
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`2014); In re Dillon, 919 F.2d 688, 693 (Fed. Cir. 1990)(en banc). Caselaw cited by
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`Sanofi suggesting the contrary is distinguishable as relating to patents containing
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`specific treatment or efficacy limitations, or alleged properties relied upon as a
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`motivation to combine that were absent from the relied-upon references, none of
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`which are applicable to this petition. (See POPR, 17).
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`5
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`
`
`/Alexander E. Gasser/
`Alexander E. Gasser (Reg. No. 48,760)
`SKIERMONT DERBY LLP
`1601 Elm Street, Suite 4400
`Dallas, TX 75201
`P: 214-978-6600/F: 214-978-6601
`Lead Counsel for Petitioner
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`Sarah Spires (Reg. No. 61,501)
`Paul J. Skiermont (pro hac vice being requested)
`SKIERMONT DERBY LLP
`1601 Elm Street, Suite 4400
`Dallas, TX 75201
`P: 214-978-6600/F: 214-978-6601
`
`Mieke Malmberg (pro hac vice being requested)
`SKIERMONT DERBY LLP
`800 Wilshire Blvd., Suite 1450
`Los Angeles, CA 90017
`P: 213-788-4500/F: 213-788-4545.
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`Back-Up Counsel for Petitioner
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`6
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`CERTIFICATE OF SERVICE
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`I hereby certify that on 3/7/2019, copies of this Petitioner’s Reply to Patent
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`Owner’s Preliminary Response, including any exhibits and papers filed therewith,
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`were served as follows:
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`VIA ELECTRONIC MAIL
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`Daniel J. Minion (Reg. No. 53,329)
`Dominick A. Conde (Reg. No. 33,856)
`William E. Solander
`Melinda R. Roberts
`Venable LLP
`1290 Avenue of the Americas
`New York, NY
`Telephone: (212) 218-2538
`Facsimile: (212) 218-2200
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`DMinion@Venable.com
`DConde@Venable.com
`WSolander@Venable.com
`MRRoberts@Venable.com
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`/Alexander E. Gasser/
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`Alexander E. Gasser
`Reg. No. 48,760
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`7
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