`Filed: September 22, 2016
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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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`_____________________________
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`MYLAN LABORATORIES LIMITED,
`Petitioner,
`v.
`AVENTIS PHARMA S.A.,
`Patent Owner.
`
`_____________________________
`
`Case IPR2016-00627
`Patent 5,847,170
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`_____________________________
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`PETITIONER MYLAN LABORATORIES LIMITED’S
`REQUEST FOR REHEARING PURSUANT TO 37 C.F.R. § 42.71
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`Case IPR2016-00627
`Patent 5,847,170
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`TABLE OF CONTENTS
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`I.
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`PRECISE RELIEF REQUESTED ................................................................ 1
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`II.
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`BASIS FOR REHEARING........................................................................... 1
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`A.
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`Legal Standard for Rehearing ............................................................. 1
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`B.
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`Summary of the Petition ..................................................................... 1
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`III. KANT COMPOUND 20 AS A LEAD COMPOUND .................................. 3
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`A.
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`Erroneous Legal Standards ................................................................. 3
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`1.
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`2.
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`3.
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`Requiring Motivation to Modify to Justify Lead Selection ........ 3
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`Confusing a Synthetic Precursor with a Lead Compound.......... 5
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`Requiring More Potency than Docetaxel & Compound 22 ........ 7
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`4. Misattributing Graham Factor 3 Analysis as Improper
`Hindsight .................................................................................. 8
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`B.
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`The Decision Overlooks Evidence About Taxane Formulation ........... 9
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`IV. PROPOSED MODIFICATION OF THE LEADS ...................................... 11
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`A.
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`“Synthetic Simplicity” for Simultaneous Methylation ....................... 11
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`B.
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`C.
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`Neither Ground Requires Deacetylation at the C-10 Hydroxyl .......... 12
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`Synthetic Simplicity and Ring Rearrangement Rationales For
`Retaining the C-9 Carbonyl .............................................................. 13
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`D.
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`Lipophilicity and Potency Analyses .................................................. 14
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`V.
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`CONCLUSION .......................................................................................... 15
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`-i-
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`Case IPR2016-00627
`Patent 5,847,170
`I.
`PRECISE RELIEF REQUESTED
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`Mylan Laboratories Limited (“Petitioner”) respectfully requests that the
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`Board reconsider its decision (Paper 10) denying inter partes review.
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`II. BASIS FOR REHEARING
`A. Legal Standard for Rehearing
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`Pursuant to 37 C.F.R. § 42.71(d), a party may request rehearing of an
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`institution decision by “specifically identify[ing] all matters the party believes the
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`Board misapprehended or overlooked, and the place where each matter was
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`previously addressed in a motion, an opposition, or a reply.” Id. The Board reviews
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`the prior decision for abuse of discretion, 37 C.F.R. § 42.71(c), such as an
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`erroneous interpretation of law, a factual finding that is not supported by
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`substantial evidence, or an unreasonable judgment in weighing relevant factors.
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`IPR 2013-00369, Paper 39 at 2-3.
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`B.
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`Summary of the Petition
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`The Petition shows in Ground 1 that a combination of Kant (Ex. 1005) and
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`Klein (Ex. 1006) renders obvious the compound of claim 1, based on (i) the
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`selection of 10-methoxy docetaxel (Compound 20) as a lead compound from Kant,
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`(ii) Klein’s teaching that methylation of both docetaxel and paclitaxel analogues at
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`the C-7 hydroxyl results in potent anti-cancer compounds, and (iii) the simpler
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`synthetic pathway that was known to result from simultaneously methylating both
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`Patent 5,847,170
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`the C-7 and C-10 hydroxyls when making taxanes from the readily available
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`synthetic precursor 10-DAB. Pet. at 31-35.
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`In Ground 2, (i) Colin (Ex. 1007) provides docetaxel as a lead compound,
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`(ii) Klein teaches that functionalization of both the C-7 and C-10 hydroxyls (e.g.,
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`methylation of the C-7 hydroxyl and acetylation of the C-10 hydroxyl) provides
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`potent anti-cancer compounds, (iii) Klein demonstrates that reduction of the C-9
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`carbonyl to form 9-dihydro analogues is not responsible for the increased potency
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`observed with functionalization of the C-7 and C-10 hydroxyls as the C-9
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`reduction diminished potency somewhat; and (iv) Kant teaches methylation is
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`more potent than acetylation at the C-10 hydroxyl. Pet. at 38-39, 41, 43-44.
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`Following either route, the wide availability of the synthetic taxane
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`precursor 10-DAB provided further motivation for methylating at both the C-10
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`and C-7 hydroxyls simultaneously, rather than a more laborious selective
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`modification process of one, or sequential modification of one and then the other.
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`Pet. at 39-41, 44, 47. Both Grounds also rely on synthetic simplicity to support
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`retention of the C-9 carbonyl present in docetaxel and paclitaxel as an obvious
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`choice for making a potent anti-cancer compound. Pet. at 34-35, 43-45. Both
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`Grounds show dependent claim 2 (pharmaceutical composition) as obvious. Pet. at
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`35-38, 46-47.
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`Patent 5,847,170
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`III. Kant Compound 20 as a Lead Compound
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`The Petition, with supporting evidence, shows in Ground 1 that a skilled
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`artisan would reasonably select Compound 20 of Kant “as an anti-tumor
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`compound” because of its “superior combination of tubulin binding ability and
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`potency.” Pet. at 31. The Decision misapprehends the legal standards, and
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`misunderstands or overlooks key arguments and evidence.
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`A. Erroneous Legal Standards
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`The evaluation of Kant Compound 20 as a lead compound misapprehends
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`the proper legal test by: (1) requiring Kant itself teach or suggest modifications to
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`Compound 20; (2) conflating “lead compound” with the ideal synthetic precursor;
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`(3) requiring proof Compound 20 was more potent than docetaxel and Compound
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`22; and (4) labeling a Graham factor 3 analysis as improper hindsight.
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`1. Requiring Motivation to Modify to Justify Lead Selection
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`The Decision rejects Compound 20 as a lead compound, reasoning that Kant
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`does not teach or suggest modifications of Compound 20. Dec. at 12 (“Kant does
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`not teach or suggest additional structural modifications to Compound 20 or
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`docetaxel, which cuts against the notion of selecting Kant Compound 20 as a lead
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`compound for further modification of this docetaxel analogue.”); id. at 13 (“Kant
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`also does not teach or suggest the possibility of simultaneous substitution of both
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`the C-7 and C-10 positions…”). This holding contradicts Federal Circuit precedent
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`that lead compound selection and motivation to modify analysis are separate and
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`sequential:
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`First, the court determines whether a chemist of ordinary skill would
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`have selected the asserted prior art compounds as lead compounds, or
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`starting points, for further development efforts.… The second inquiry
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`in the analysis is whether the prior art would have supplied one of
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`ordinary skill in the art with a reason or motivation to modify a lead
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`compound to make the claimed compound with a reasonable
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`expectation of success.
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`Otsuka Pharm. Co. Ltd. v. Sandoz Inc., 678 F.3d 1280, 1291-92 (Fed. Cir. 2012)
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`(emphasis added). Requiring a motivation in Kant itself to modify Compound 20 to
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`select it as a lead compound misapprehends the case law.
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`Consistent with the case law, describing a lead compound as a compound for
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`further development or modification does not require proof of motivation to
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`modify to justify lead selection. Such language merely reflects that the lead
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`identification is merely the first step. Id. at 1292 (lead compound analysis focuses
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`on whether “the skilled artisan would have had a reason to select” proposed leads
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`from the prior art). The second step then considers modifications to improve
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`properties or show other obvious variations to the known structure. Requiring that
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`Kant alone provide motivation to modify Compound 20 in order to select it as a
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`lead was legal error. See Daiichi Sankyo Co., Ltd. v. Matrix Labs., 619 F.3d 1346,
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`1352 (2010) (“the flexible nature of the inquiry after KSR” means “the motivation
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`to select and modify a lead compound need not be explicit in the art”).
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`2. Confusing a Synthetic Precursor with a Lead Compound
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`The Decision conflates the legal concept of a “lead compound” with “the
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`ideal starting material to synthesize” various taxane analogues. Dec. at 12 (“We
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`begin by observing that Kant uses 10-DAB as ‘the ideal starting material’ to
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`synthesize paclitaxel analogues by selective substitution at only the C-10
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`position”). However, the fact (discussed in the Petition at 18-19, 24-25, and 35)
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`that 10-deacetylbaccatin III (10-DAB) served as the synthetic precursor for
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`paclitaxel and docetaxel analogues, including Compound 20, does not preclude or
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`even weigh against Compound 20 as a lead compound. But, as discussed below in
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`Section IV.A-B, it supports Petitioner’s rationale for simultaneous methylation.
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`Moreover, the Decision’s further characterization (at 12) of compounds
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`(including those with docetaxel side chains) as “paclitaxel analogues” made via
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`selective substitution also does not preclude selection of Compound 20 as a lead
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`and misapprehends that Kant studied compounds with the paclitaxel and the
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`docetaxel side chains. Kant itself highlights Compound 20 compared to other
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`analogues with the characteristic paclitaxel or docetaxel side chains:
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`Kant teaches the greater potency of docetaxel analogues with a C-10
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`methoxy group as opposed to a C-10 acetyl group, or to an
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`unfunctionalized, free hydroxyl group. Ex. 1005 at 5545; Ex. 1002,
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`¶¶61-63. Kant states that: ‘Analogues with C-10 methyl ether
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`([compound] 20) or methyl carbonate (22) with [the] TaxotereTM side
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`chain (i.e., 3’-NHBOC) were found to be more cytotoxic than
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`paclitaxel (1) or 10-acetyl taxotere (15).’ Ex. 1005 at 5546, Table II.
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`Pet. at 6. Table II confirms that the tubulin ratio of Compound 20 vs. paclitaxel
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`(Taxol®) was 0.3, representing an improvement of more than three times the
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`tubulin binding affinity of paclitaxel. Ex. 1002, ¶¶62, 79 (cited in Pet. at 6, 28, 31).
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`Table II also confirms that the IC50 of Compound 20 was 1.3 nM, as compared to
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`2.0 nM for paclitaxel, representing almost a doubling of cytotoxicity. Id.
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`The Petition explains why comparison of Compound 20 to paclitaxel was
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`notable and appropriate, stating that paclitaxel was “approved by the [FDA] for the
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`treatment of cancer and is known to exhibit impressive biological activities against
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`a range of human cancers” at least in part because of its “ability to promote tubulin
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`polymerization and stabilization of microtubules, thereby leading to cell death.”
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`Pet. at 17-18. Thus, the Petition argues that the “superior combination of tubulin
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`binding ability and potency” of Compound 20 would have provided ample
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`motivation for the skilled artisan to select Compound 20 as a lead. Id. at 31. This
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`evidence was sufficient to establish that “the skilled artisan would have had a
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`reason to select [Compound 20] from the panoply of known compounds in the
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`prior art.” See Otsuka, 678 F.3d at 1292.
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`3. Requiring More Potency than Docetaxel & Compound 22
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`The Decision states that “without a docetaxel control, Kant does not provide
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`any information as to whether a particular compound performs better or worse than
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`docetaxel.” Dec. at 12. Petitioner, however, need not prove that Compound 20
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`would have better efficacy than docetaxel. Rather, the law requires only that “a
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`medicinal chemist of ordinary skill would have been motivated to [i] select and
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`then [ii] to modify a prior art compound (e.g., a lead compound) to arrive at a
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`claimed compound with a reasonable expectation that the new compound would
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`have similar or improved properties compared with the old.” Daiichi, 619 F.3d at
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`1352 (emphasis added); see also Otsuka, 678 F.3d at 1293 (“As we have
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`explained, ‘it is sufficient to show that the claimed and prior art compounds
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`possess a sufficiently close relationship… to create an expectation, in light of the
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`totality of the prior art, that the new compound will have similar properties’ to the
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`old.’” (quoting Aventis Pharma Deutschland GmbH v. Lupin, Ltd., 499 F.3d 1293,
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`1301 (Fed. Cir. 2007) (emphasis added)). Kant appropriately used paclitaxel, the
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`first FDA-approved taxane, as a potency comparator for new taxanes.
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`After erroneously requiring superiority over docetaxel (Dec. at 12), the
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`Decision also overlooks the Petition’s reliance on Table II of Kant and Table I of
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`Klein, which permit a direct comparison of the tubulin binding activity of Kant
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`Compound 20 to both paclitaxel and docetaxel, as well as provide cytotoxicity data
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`in various cell lines. Klein provides a comparison between docetaxel and
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`paclitaxel. Ex. 1006 at 280 & Table I. At pages 7, 28 and 43, the Petition refers to
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`the data in Table I of Klein. At pages 6, 28, and 31, the Petition references the data
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`in Kant for Compounds 20 and 22, paclitaxel (Compound 1), and 10-acetyl
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`docetaxel (Compound 15). Even if superior properties to docetaxel were required,
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`Kant and Klein disclose the superior tubulin binding activity of Compound 20 (0.3)
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`as compared to docetaxel (0.7) and paclitaxel (1.00).
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`Moreover, contrary to any suggestion in the Decision at page 12 (“Kant does
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`not otherwise analyze the significance of the structural differences between
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`Compounds 20 and 22”), Petitioner was not required to prove Compound 22,
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`which had about half as much tubulin affinity as Compound 20 (0.8 vs. 0.3) and
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`was somewhat less potent in the cell line tested, was not also an obvious lead
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`compound. Altana Pharma AG v. Teva Pharms. USA Inc., 566 F.3d 999, 1008
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`(Fed. Cir. 2009) (“[T]o the extent Altana suggests that the prior art must point to
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`only a single lead compound for further development efforts, that restrictive view
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`of the lead compound test would present a rigid test similar to the teaching-
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`suggestion-motivation test that the Supreme Court explicitly rejected in KSR.”).
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`4. Misattributing Graham Factor 3 Analysis as Improper Hindsight
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`As part of its lead compound analysis, the Decision states: “We agree with
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`Patent Owner that Petitioner also errs by starting with a hindsight-biased structural
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`comparison of docetaxel, Kant Compound 20, and cabazitaxel in side-by-side
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`fashion. Prelim. Resp. 31-34.” Dec. at 12. However, nowhere does the Petition
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`argue that Compound 20 should be selected as a lead because of its structural
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`similarity to cabazitaxel. As discussed above in Sections III.A.2-3, the Petition
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`relies on the potency of Compound 20 compared to paclitaxel and other Kant
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`analogues, including tubulin ratios and IC50 values, and argues that the skilled
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`artisan would have selected Compound 20 as a lead “because of its superior
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`combination of tubulin binding ability and potency.” Pet. at 31.
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`In contrast, the structures of docetaxel, 10-methoxy docetaxel (Compound
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`20), and 7,10-dimethoxy docetaxel depicted on page 31 simply and appropriately
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`display the differences between the claimed invention and the prior art, the third
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`factor required by the Graham analysis. Graham v. John Deere Co., 383 U.S. 1,
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`17-18 (1966) (obviousness requires evaluating “(3) the differences between the
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`claimed invention and the prior art”). Petitioner’s illustrations comply with
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`Graham and were not improper hindsight.
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`B.
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`The Decision Overlooks Evidence About Taxane Formulation
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`In its lead compound analysis for Ground 1, the Decision at pp. 13-14 states,
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`“Petitioner … does not address the well-known problems with lipophilicity and
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`limited aqueous solubility of intravenously administered paclitaxel and docetaxel.”
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`Regarding Ground 2, the Decision again mistakenly states that Petitioner did not
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`address “the well-known difficulties of formulating highly lipophilic, water-
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`insoluble paclitaxel and docetaxel into a useful intravenous dosage form.” Id. at 19.
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`These statements overlook the extensive evidence set out in the Petition
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`(including in the Grounds) and in the supporting Jacobsen declaration that taxane
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`solubility issues had been thoroughly addressed through formulation optimization
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`well prior to the priority date of the alleged invention. See, e.g., Pet. at 25-26, 35-
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`36, 47; Ex. 1002, ¶¶54-55, 93-94. Dr. Jacobsen is a Professor of Chemistry and
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`former Chair of the Department of Chemistry at Harvard University. Pet. at 12; Ex.
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`1002, ¶1; Ex. 1003. Despite briefly acknowledging the existence of Dr. Jacobsen’s
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`testimony, the Decision fails to address the substance of this testimony, as relied on
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`in the Petition. Instead, the Decision credits the unsupported attorney argument
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`from the Patent Owner’s Preliminary Response. The decision provides no basis for
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`crediting mere attorney argument over testimony from an unchallenged expert.
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`See 37 C.F.R. § 42.108(c) (genuine issue of material fact created by testimonial
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`evidence must be viewed in light most favorable to petitioner in institution
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`decision).
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`IV. Proposed Modification of the Leads
`A.
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`“Synthetic Simplicity” for Simultaneous Methylation
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`The Decision misapprehends Petitioner’s argument as being “that a POSA
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`would have selectively methylated both the C-7 and C-10 positions of docetaxel to
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`create a more potent analogue (cabazitaxel) based on the teachings of Klein and
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`Kant,” and deems it “not persuasive.” Dec. at 20 (emphasis added). This shows the
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`Decision fundamentally misapprehended Petitioner’s evidence.
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`Ground 1 sets forth at least three rationales for methylating the C-7
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`hydroxyl, to create “a compound with [1] improved potency, [2] a simpler
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`synthetic pathway, and [3] improved lipophilicity.” Pet. at 29. The Decision
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`overlooks or misunderstands the simpler synthetic pathway rationale.
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`The Petition first explains that a skilled artisan would reasonably select 10-
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`methoxy docetaxel (Kant Compound 20) “as an anti-tumor compound” because of
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`its “superior combination of tubulin binding ability and potency.” Pet. at 31. Klein
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`teaches that methylating the C-7 hydroxyl of a docetaxel analogue results in a more
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`potent compound than leaving the C-7 hydroxyl un-methylated. Id. at 32. The
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`skilled artisan “would have appreciated that a simultaneous functionalization of C-
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`7 and C-10 hydroxyls” present on 10-DAB “would have been more straightforward
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`than a chemo-selective approach.” Pet. at 34-35 (italics added; citing Ex. 1016, Ex.
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`1008, and Ex. 1002 ¶¶50, 53, 90). Thus, the skilled worker would have been
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`motivated to methylate simultaneously to create a potent anti-cancer compound
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`using a simpler synthetic pathway. Id. (citing Jacobsen Ex. 1002 ¶¶87-89; see also
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`Pet. at 44-45 (synthetic simplicity in Ground 2 (citing Ex. 1002 at ¶¶107-08)).
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`The Jacobsen declaration supports this rationale, explaining that 7,10-
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`dimethoxy docetaxel was favored “from a synthetic standpoint,” because the
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`“selective substitution at the C-10 hydroxyl [described in Kant] required two
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`additional synthetic steps i.e., a chemoselective protection, followed by a
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`deprotection reaction, that would not be necessary for the preparation of a 7,10-
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`disubstituted docetaxel analogue.” Ex. 1002, ¶90 (emphasis in original); Pet. at 34.
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`Dr. Jacobsen explains that preparing 7,10-dimethoxy docetaxel “would have been
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`synthetically easier to access than a docetaxel analogue chemoselectively modified
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`at the C-10 hydroxyl.” Id. However, because the Decision misapprehends it as a
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`selective methylation, it never addresses simultaneous methylation of the C-10 and
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`C-7 hydroxyls as a rationale for creating a potent anti-cancer compound through a
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`simpler synthetic pathway.
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`B. Neither Ground Requires Deacetylation at the C-10 Hydroxyl
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`In its analysis of Ground 1, the Decision states:
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`Petitioner argues that a POSA would have retained Kant Compound
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`20’s C-10 methoxy group over Klein’s C-10 acetyl.... Klein, however,
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`states that “facile deacetylation of the C-10 acetate is not trivial in the
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`C-9 carbonyl series and reflects the greater stability of the 9(R)-
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`dihydro series.” Ex. 1006, 279. Klein, therefore, does not necessarily
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`teach or suggest replacing the C-10 acetyl unless the C-9 carbonyl is
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`reduced to a hydroxyl group[.]
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`Dec. at 16-17. However, the Decision misapprehends that neither Ground requires
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`a synthesis pathway that involves deacetylation at C-10. 7,10-Dimethoxy
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`docetaxel could be most simply synthesized from the well-established synthetic
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`taxane precursor, 10-DAB, in two steps – simultaneous methylation at the C-7 and
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`C-10 position, and addition of the docetaxel side chain at the C-13 hydroxyl. Ex.
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`1002, ¶52; Pet. at 24-25, 33-34, 44-45. Deacetylation is simply not involved in this
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`process. Whether 10-DAB, docetaxel, or 10-methoxy docetaxel was the synthetic
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`precursor, the reaction would still not require deacetylization because there is no
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`C-10 acetyl to remove. Pet. at 19, 31, 33-35, 44-45; Ex. 1002, ¶¶87-90, 107-08.
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`C.
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`Synthetic Simplicity and Ring Rearrangement Rationales For
`Retaining the C-9 Carbonyl
`The Decision overlooks the Petitioner’s argument that “a preference for a
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`more simple synthesis pathway would countenance in favor of retaining the C-9
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`carbonyl of Kant over the C-9 hydroxyl of Klein because the C-9 carbonyl
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`reduction requires an additional synthetic step.” Pet. at 34-35; see also id. at 42-45.
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`Moreover, the Petition points out that Klein’s additional synthetic step (C-9
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`reduction) could not have caused the increased potency shown in Klein’s C-7 and
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`C-10 functionalized analogues because C-9 reduction diminished potency. Id. C-9
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`reduction also resulted in novel rearrangement analogues with even more reduced
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`efficacy. Id. at 34, 43; see also Jacobsen Decl. Ex. 1002, ¶¶84, 89 (in one case a
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`10- to 30-fold reduction in potency). The Decision overlooks or misunderstands
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`synthetic simplicity as a reason it would have been an obvious choice to retain the
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`C-9 carbonyl present in 10-DAB, docetaxel, and Compound 20.
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`The Decision further misapprehends Petitioner’s argument: “Contrary to
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`Petitioner’s argument, Klein teaches that a C-9 carbonyl was not required to
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`maintain anti-tumor activity and that reducing the C-9 carbonyl to a hydroxyl
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`improves aqueous solubility and chemical stability of these notoriously insoluble
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`compounds.” Dec. at 15. As discussed above, however, Petitioner identifies
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`reasons to make a potent anti-cancer compound by retaining the C-9 carbonyl
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`found in 10-DAB, docetaxel, and Compound 20. Petitioner did not argue, and was
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`not required to argue, that the C-9 carbonyl was required to maintain activity.
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`D. Lipophilicity and Potency Analyses
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`In its lead compound analysis, the Decision appears to require the Petition to
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`prove that methylation of the C-7 and C-10 hydroxyls would achieve significantly
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`improved anti-cancer activity or lipophilicity over that of docetaxel to establish a
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`motivation to modify the lead compound. E.g., Dec. at 12 (“…Kant does not
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`provide any information as to whether a particular compound performs better or
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`worse than docetaxel.”); id. at 13 (“…a POSA would have known docetaxel and
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`paclitaxel were highly lipophilic and insoluble in water, which made their
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`commercial formulation challenging.”). However, proper reasons to modify are not
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`restricted to increasing potency or solubility over docetaxel. See KSR International
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`Co. v. Teleflex Inc., 550 U.S. 398, 420 (2007) (“Under the correct analysis, any
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`need or problem known in the field of endeavor at the time of invention and
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`addressed by the patent can provide a reason for combining the elements in the
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`manner claimed.”). Moreover, as discussed in Section III.A.3 above, Compound
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`20 provides approximately twice as much improvement in tubulin binding over
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`paclitaxel as was obtained with docetaxel. Thus, the Decision overlooks the
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`superior properties established by the tables cited and discussed in the Petition.
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`Finally, as noted above in Section III.B, the Petition and Jacobsen
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`declaration extensively discuss how taxane solubility issues had been thoroughly
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`addressed by formulation optimization prior to the priority date of the alleged
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`invention. Pet. at 25-26, 35-36, 47; Ex. 1002, ¶¶54-55, 93-94.
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`V. CONCLUSION
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`For the reasons set forth above, Petitioner respectfully requests rehearing
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`and institution of inter partes review of claims 1 and 2 of the ’170 patent.
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`Dated: September 22, 2016
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`Respectfully submitted,
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` / Steven W. Parmelee /
`Steven W. Parmelee, Lead Counsel
`Reg. No. 31,990
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`-15-
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`Case IPR2016-00627
`Patent 5,847,170
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`CERTIFICATE OF SERVICE
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`This is to certify that I caused to be served a true and correct copy of the
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`foregoing Petitioner Mylan Laboratories Limited’s Request for Rehearing Pursuant
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`to 37 C.F.R. § 42.71, on this 22 day of September, 2016, on the Patent Owner at
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`the correspondence address of the Patent Owner as follows:
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`Dominick A. Conde
`William E. Solander
`Jason A. Leonard
`FITZPATRICK, CELLA, HARPER & SCINTO
`1290 Avenue of the Americas
`New York, NY 10104-3800
`Email: dconde@fchs.com
`Email: wsolander@fchs.com
`Email: jleonard@fchs.com
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`Dated: September 22, 2016
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`Respectfully submitted,
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` / Steven W. Parmelee /
`Steven W. Parmelee, Lead Counsel
`Reg. No. 31,990
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`
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`-16-