throbber
Trials@uspto.gov Paper 10
`Tel: 571-272-7822
`
`Entered: August 23, 2016
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
`MYLAN LABORATORIES LIMITED,
`Petitioner,
`
`v.
`
`AVENTIS PHARMA S.A.,
`Patent Owner.
`_____________
`
`Case IPR2016-00627
`Patent 5,847,170
`
`
`______________
`Before: BRIAN P. MURPHY, TINA E. HULSE, and CHRISTOPHER M.
`KAISER, Administrative Patent Judges.
`
`MURPHY, Administrative Patent Judge.
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
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`IPR2016-00627
`Patent 5,847,170
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`INTRODUCTION
`I.
`Mylan Laboratories Limited (“Petitioner”) filed a Petition requesting
`an inter partes review of claims 1 and 2 of U.S. Patent No. 5,847,170 (Ex.
`1001, “the ’170 patent”). Paper 3 (“Pet.”). Aventis Pharma S.A. (“Patent
`Owner”), filed a Preliminary Response to the Petition. Paper 8 (“Prelim.
`Resp.”). We have statutory authority under 35 U.S.C. § 314(a), which
`provides that an inter partes review may not be instituted “unless . . . there is
`a reasonable likelihood that the petitioner would prevail with respect to at
`least 1 of the claims challenged in the petition.”
`Petitioner challenges claims 1 and 2 of the ’170 patent as unpatentable
`under 35 U.S.C. § 103(a). Pet. 13–14. Based on the arguments and
`evidence presented in the Petition and Preliminary Response, we are not
`persuaded there is a reasonable likelihood Petitioner would prevail with
`respect to at least one of the claims challenged in the Petition. Therefore, we
`decline to institute inter partes review.
`A. Related Proceedings
`Petitioner identifies the following as related district court proceedings
`in the District of New Jersey regarding the ’170 patent: Sanofi-Aventis U.S.
`LLC, Aventis Pharma S.A. and Sanofi v. Mylan Laboratories Ltd., C. A. No.
`3:15-cv-00290 (MAS)(LHG); Sanofi-Aventis U.S. LLC et al. v. Fresenius
`Kabi USA, LLC, C. A. No. 14-07869 (MAS)(LHG); Sanofi-Aventis U.S.
`LLC et al. v. Accord Healthcare, Inc., C. A. No. 14-08079 (MAS)(LHG);
`Sanofi-Aventis U.S. LLC et al. v. BPI Labs, LLC et al., C. A. No. 14-08081
`(MAS)(LHG); Sanofi-Aventis U.S. LLC et al. v. Fresenius Kabi USA, LLC,
`C. A. No. 14-08082 (MAS)(LHG); Sanofi-Aventis U.S. LLC et al. v. Apotex
`Corp. et al., C. A. No. 15-0287 (MAS)(LHG); Sanofi-Aventis U.S. LLC et
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`al. v. Breckenridge Pharmaceutical, Inc., C. A. No. 15-0289 (MAS)(LHG);
`Sanofi-Aventis U.S. LLC et al. v. Mylan Laboratories Limited, C. A. No. 15-
`0290 (MAS)(LHG); and Sanofi-Aventis U.S. LLC et al. v. Actavis LLC et al.,
`C. A. No. 15-0776 (MAS)(LHG). Pet. 12–13.
`B. Proposed Grounds of Unpatentability
`Petitioner advances two grounds of unpatentability under 35 U.S.C.
`§ 103(a) in relation to the challenged claims in the ’170 patent:
`Reference[s]
`Statutory
`Challenged
`Basis
`Claims
`§ 103
`1 and 2
`
`1 and 2
`
`Kant (Ex. 1005)1 in view of Klein (Ex.
`1006)2
`Colin (Ex. 1007)3 in view of Klein and
`Kant
`
`§ 103
`
`Pet. 13–14. Petitioner supports its challenge with a Declaration by Eric N.
`Jacobsen, Ph.D. (“Jacobsen Decl.”). Ex. 1002.
`
`C. The ’170 Patent
`The ’170 patent, titled “Taxoids, Their Preparation and
`Pharmaceutical Compositions Containing Them,” issued December 8, 1998,
`
`
`1 Kant et al., A Chemoselective Approach to Functionalize the C-10
`Position of 10-Deacetylbaccatin III Synthesis and Biological Properties of
`Novel C-10 Taxol® Analogues, Tetrahedron Letters, 35 (31), 5543–46
`(1994) (“Kant”). Ex. 1005.
`2 Klein et al., Ch. 20 Chemistry and Antitumor Activity of 9(R)-
`Dihydrotaxanes in Taxane Cancer Agents, ACS Symposium
`Series Vol. 58, 276–287 (Georg et al., eds., 1994). Ex. 1006.
`3 U.S. Patent No. 4,814,470 issued March 21, 1989 to Colin et al. (“Colin”).
`Ex. 1007.
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`from an application filed March 26, 1996. Ex. 1001.4 The ’170 patent is
`directed to new taxoids of general formula (I):
`
`
`Ex. 1001, 1:7–28. The ’170 patent discloses and claims, in particular, a
`compound known as cabazitaxel, pharmaceutical compositions containing
`cabazitaxel, and processes to prepare cabazitaxel. Id. at 12:52–13:33. The
`compounds of the ’170 patent, including cabazitaxel, inhibit abnormal cell
`proliferation and have “antitumour properties, and more especially activity
`against tumours which are resistant to Taxol® or to Taxotere®.”5 Id. at
`11:59–61, 26:32–37. Cabazitaxel is indicated for treatment of certain types
`of prostate cancer. Ex. 2002.
`
`
`4 The ’170 patent claims priority to a provisional application dated January
`17, 1996 and to French applications 95 03545 and 95 15381, dated March
`27, 1995 and December 22, 1995, respectively. Ex. 1001, [60], [30].
`5 Taxol® is the brand name for paclitaxel. Taxotere® is the brand name for
`docetaxel. We also refer to “Taxol” and “Taxotere” in this Decision.
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`The chemical name for cabazitaxel is 4α-acetoxy-2α-benzoyloxy-
`5β,20-epoxy-lβ-hydroxy-7β,10β-dimethoxy-9-oxo-ll-taxen-13α-yl(2R,3S)-
`3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate. Id. at 13:9–12,
`28:57–60. The chemical structure of cabazitaxel is:
`
`
`Pet. 3. Of particular interest in cabazitaxel are the presence of a methoxy
`group (OCH3) at both the C-7 position (R5 in formula I) and C-10 position
`(R4 in formula I), and a carbonyl (C=O) at the C-9 position. Ex. 1001, 2:40–
`42, 3:1–3.
`The prior art paclitaxel and docetaxel compound structures are shown
`below.
`
`Pet. 9; Ex. 1002 ¶¶ 36–38. Paclitaxel and docetaxel are synthesized from a
`key “advanced precursor” known as 10-deacetyl baccatin III (“10-DAB”).
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`Ex. 1002 ¶¶ 37–38. Paclitaxel has a different synthetic side chain (left side
`of molecule) than docetaxel, attached to the C-13 position of the core taxoid
`structure, and an acetyl (CH3CO or “Ac”) group rather than a hydroxyl (OH)
`group at C-10. In contrast to cabazitaxel, neither paclitaxel nor docetaxel
`has a methoxy group at C-7 or C-10, although both have a carbonyl at C-9.
`Id. Cabazitaxel has a docetaxel side chain (i.e., 3’-NHBOC or (3-tert-
`butoxycaronylamino)). Id. ¶¶ 11, 38.
`D. Challenged Claims
`Petitioner challenges claims 1 and 2 of the ’170 patent, which are
`reproduced below:
`1. 4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-lβ-hydroxy-7β,10β-
`dimethoxy-9-oxo-ll-taxen-13α-yl(2R,3S)-3-tert-
`butoxycarbonylamino-2-hydroxy-3-phenylpropionate.
`
`2. A pharmaceutical composition comprising at least the product
`according to claim 1 in combination with one or more
`pharmaceutically acceptable diluents or adjuvants and optionally one
`or more compatible and pharmacologically active compounds.
`
`
`II. ANALYSIS
`A. Claim Construction
`We determine that no claim terms require express construction for
`purposes of this Decision. See, e.g., Wellman, Inc. v. Eastman Chem. Co.,
`642 F.3d 1355, 1361 (Fed. Cir. 2011) (“[C]laim terms need only be
`construed ‘to the extent necessary to resolve the controversy.’”) (quotation
`omitted).
`B. Asserted Obviousness of Claims 1 and 2 over Kant and Klein
`Petitioner asserts that the subject matter of claims 1 and 2 of the ’170
`patent would have been obvious to a person of ordinary skill in the art
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`(“POSA”) based on the combined teachings of Kant and Klein. Pet. 29–38.
`Patent Owner opposes. Prelim. Resp. 18–38. We address the parties’
`arguments below.
`1. Kant
`Kant discloses a “chemoselective approach to functionalize the C-10
`position of 10-deacetyl baccatin III [10-DAB], a key intermediate for the
`semi-synthesis of paclitaxel.” Ex. 1005, 5543 (Abstract). Kant selects 10-
`DAB as “the ideal starting material” for synthesizing analogues of paclitaxel
`with the “aim of obtaining drugs having more desirable properties.” Id.
`¶¶ 2–3. Kant’s reasoning is that “with the more reactive C-7 hydroxyl
`protected, an opportunity was available to selectively deprotonate the C-10
`hydroxyl.” Id. at 5544. Thus, Kant selectively introduced a variety of
`substituents at the C-10 position of 10-DAB to synthesize “a variety of C-10
`paclitaxel analogues” shown in our annotated Table II, below.
`
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`Id. at 5545. Kant Compound 20 contains a methoxy group at C-10 (R1 is
`“Me” (methyl)), a hydroxyl group at C-7, a carbonyl at C-9, and a docetaxel
`side chain (R2 is “OBut” (tert-butoxy)). Id. Kant concludes “it is reasonable
`to suggest that the functional group present at the C-10 position does
`modulate the antitumor activity, which is quite contrary to some of the
`earlier predictions.” Id. at 5546.
`2. Klein
`Klein discloses 9(R)-dihydrotaxanes, a new family of compounds
`having “increased water solubility and stability as compared to taxol
`[paclitaxel] and also exhibit[ing] excellent activity in tumor models.” Ex.
`1006, 276 (Abstract). Klein highlights several advantages of replacing the
`C-9 carbonyl with a hydroxyl in both Taxol (paclitaxel) and Taxotere
`
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`(docetaxel): 1) the C-9 hydroxyl “serves as an additional site for
`modifications,” 2) the C-9 hydroxyl “increase[s] the water solubility of these
`analogs,” and 3) the absence of a C-9 carbonyl “stabilize[s] the system.” Id.
`at 277. Klein discloses the synthesis of 9(R)-dihydrotaxol and 9(R)-
`dihydrotaxotere, which exhibit enhanced stability and aqueous solubility
`compared to paclitaxel and docetaxel due to the C-9 hydroxyl replacing the
`C-9 carbonyl, while maintaining “good efficacy.” Id. at 279–280 (Table I).
`Klein also experiments with substituting the C-7 and/or the C-9
`hydroxyl groups with various alkylating substituents. Id. at 281. The
`experimental compounds include a methoxy group at C-9 (entry 7) or at C-7
`(entries 8 and 10, with a hydroxyl at C-9), and all have an acetyl at C-10, as
`shown in our annotated Table III, below.
`
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`Id. at 281. Klein observes that the methylated C-7 analog in entry 10
`exhibits “extremely potent cytotoxicity.” Id. at 282.
`3. Analysis
` Petitioner acknowledges that “Kant does not describe the C-7
`methoxy substitution needed to form” cabazitaxel.6 Pet. 28. Petitioner
`further acknowledges that “Klein does not disclose the C-10 methoxy
`substitution” in cabazitaxel. Id. Petitioner argues, however, that a POSA
`would have selected Kant’s Compound 20 “for further modification” (a so-
`
`
`6 Petitioner refers to cabazitaxel as 7,10-dimethoxy docetaxel. Pet. 28.
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`called “lead compound”) because of its superior binding ability and
`cytotoxicity among the chemical analogues having the docetaxel side chain.
`Pet. 31 (citing Ex. 1002 ¶¶ 79–81). Petitioner reasons that a POSA would
`have modified Kant Compound 20 in view of Klein’s Table III (compounds
`8 and 10), teaching increased anti-tumor potency by substituting a methoxy
`group for a hydroxyl group at C-7, which would have led to the synthesis of
`cabazitaxel. Id. at 32–33.
`We agree with Patent Owner that Petitioner’s evidence is insufficient
`to establish a sufficient motivation for a POSA to have selected Kant’s
`Compound 20 as a lead compound for further modification in view of
`Klein’s Table III (compounds 8 and 10), to synthesize cabazitaxel with a
`reasonable expectation of success. Prelim. Resp. 20–37. For compositions
`containing new chemical compounds, there must have been a reason for a
`POSA to: (1) select the prior art “most promising to modify” (referred to as
`the “lead compound”), and (2) make all of the necessary modifications to
`arrive at the claimed invention. Otsuka Pharm. Co., Ltd. v. Sandoz, Inc.,
`678 F.3d 1280, 1291–92 (Fed. Cir. 2012); see also Daiichi Sankyo Co. v.
`Matrix Labs., Ltd., 619 F.3d 1346, 1354 (Fed. Cir. 2010) (“[T]he attribution
`of a compound as a lead compound after the fact must avoid hindsight bias;
`it must look at the state of the art at the time the invention was made to find
`a motivation to select and then modify a lead compound to arrive at the
`claimed invention.”). There also must have been a “reasonable expectation”
`both of making the new compound, and of its advantageous properties.
`Otsuka Pharm., 678 F.3d at 1292 (citing Takeda Chem. Indus., Ltd. v.
`Alphapharm Pty., Ltd., 492 F.3d 1350, 1357 (Fed. Cir. 2007)).
`
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`a. Kant Compound 20 as a lead compound
`We begin by observing that Kant uses 10-DAB as “the ideal starting
`material” to synthesize paclitaxel analogues by selective substitution at only
`the C-10 position. Ex. 1005, 5543 ¶ 3. Kant does not teach or suggest
`additional structural modifications to Compound 20 or docetaxel, which cuts
`against the notion of selecting Kant Compound 20 as a lead compound for
`further modification of this docetaxel analogue. Kant itself indicates the
`authors chose to use 10-DAB as the starting material for making selective C-
`10 substitutions in order to synthesize “novel paclitaxel analogues.” Id.
`We agree with Patent Owner that Petitioner also errs by starting with a
`hindsight-biased structural comparison of docetaxel, Kant Compound 20,
`and cabazitaxel in side-by-side fashion. Prelim. Resp. 31–34 (citing Pet.
`31). As noted by Patent Owner, without a docetaxel control, Kant does not
`provide any information as to whether a particular compound performs
`better or worse than docetaxel. Id. at 33. Kant makes clear that the authors
`were synthesizing paclitaxel analogues and using paclitaxel, not docetaxel,
`as a control. Ex. 1005, 5545 Table II n.a (IC50 cytotoxicity measured as a
`“[r]atio of analogue relative to paclitaxel”). In addition to Compound 20,
`Kant also identifies Compound 22, which has a methyl carbonate group
`rather than a methoxy group at C-10, as more cytotoxic than paclitaxel or C-
`10 acetyl taxotere (docetaxel). Ex. 1005, 5546. Kant does not otherwise
`analyze the significance of the structural differences between Compounds 20
`and 22 or the other synthesized compounds, apart from generally
`recognizing that the functional group at C-10 modulates antitumor activity.
`Id.
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`Kant also does not teach or suggest the possibility of simultaneous
`substitution of both the C-7 and C-10 positions, whether to increase potency
`and lipophilicity (cell membrane permeability) as argued by Petitioner (Pet.
`21–22, 33), or for some other reason. Prelim. Resp. 20–26. Rather, Kant
`focuses on the possibility of improving anti-tumor cytotoxicity of paclitaxel
`analogues by selective substitution and functionalization of only the C-10
`position, a point aptly made in the title, abstract, and text of Kant’s article.
`Ex. 1005, 5543 (“a chemoselective approach to functionalize the C-10
`position of 10-deacetyl baccatin III”), 5544 (“with the more reactive C-7
`hydroxyl protected, an opportunity was available to selectively deprotonate
`the C-10 hydroxyl”), 5545 (“a variety of C-10 paclitaxel analogues were
`synthesized”).
`Patent Owner persuasively argues that Petitioner does not address
`why a POSA would have simultaneously modified the C-7 and C-10
`positions in Kant Compound 20 to optimize lipophilicity, thereby
`minimizing aqueous solubility, when a POSA would have known docetaxel
`and paclitaxel were highly lipophilic and insoluble in water, which made
`their commercial formulation challenging. Prelim. Resp. 21–24 (citing Ex.
`1006; Ex. 1011, 495 (“[Paclitaxel] is highly lipophilic and insoluble in
`water, but soluble in Cremophor EL, polyethylene glycols 300 and 400,
`chloroform, acetone, ethanol and methanol. For clinical use paclitaxel is
`formulated in 50% Cremophor EL and 50% dehydrated alcohol . . . .
`[Docetaxel] is insoluble in water . . . . The formulation used in the most
`recent clinical studies consists of 100% polysorbate 80.”); Ex. 1015; Ex.
`1019, 1:64–67; Ex. 1020, 206 (“Taxol is a promising antitumor agent with
`poor water solubility. Intravenous administration of a current taxol
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`formulation in a non-aqueous vehicle containing Cremophor EL may cause
`allergic reaction and precipitation upon aqueous dilution. . . . The purpose
`of this study was to develop an aqueous based i.v. formulation of taxol that
`did not cause precipitation of the drug upon dilution and did not contain
`Cremophor EL.”); Ex. 2004, 2:42–44; Ex. 2015, 648 (“Because of its limited
`aqueous solubility, it was necessary to formulate taxol in a vehicle
`consisting of 50% ethanol and 50% Cremophor EL (polyoxyethlated castor
`oil), a vehicle with known toxicity in dogs.”); Ex. 2024, 45 (“Docetaxel . . .
`is practically insoluble in water but freely soluble in alcohol, and is currently
`formulated in polysorbate 80”); Ex. 2025, 91 (“[Paclitaxel’s] poor water
`solubility poses delivery problems that have not been adequately resolved.”);
`Ex. 2026, 996. Petitioner recognizes that alkylating the C-7 and C-10
`functional groups would optimize lipophilicity (Pet. 22) but does not address
`the well-known problems with lipophilicity and limited aqueous solubility of
`intravenously administered paclitaxel and docetaxel. Therefore, we are not
`persuaded by Petitioner’s argument that a POSA would have been motivated
`to optimize lipophilicity in a paclitaxel or docetaxel analogue via
`simultaneous substitution of the C-7 and C-10 positions.
`For the reasons given above, there is insufficient evidence for us to
`conclude that a POSA would have selected Kant Compound 20 as a lead
`compound for further modification of both the C-7 and C-10 positions.
`b. Rationale for further modifying Kant Compound 20 based
`on the teachings of Klein
`We also are not persuaded by Petitioner’s rationale and supporting
`evidence that a POSA would have modified Kant Compound 20 in view of
`Klein to make the required substitutions at C-7 and C-10 to synthesize
`
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`cabazitaxel. According to Petitioner, after selecting Kant Compound 20 for
`further modification, a POSA would have needed to make at least three more
`significant decisions to achieve the cabazitaxel structure from the teachings
`of Klein: 1) substitute Kant Compound 20’s protected C-7 hydroxyl group
`with Klein’s methoxy group, 2) retain Kant Compound 20’s methoxy group
`at C-10 instead of Klein’s C-10 acetyl group, and 3) retain Kant’s carbonyl
`at C-9 instead of using Klein’s C-9 hydroxyl to improve chemical stability
`and aqueous solubility of the compound. Pet. 32–34. Petitioner represents
`the proffered structural teachings below.
`
`
`
`
`Id. at 32–33. The Petition, however, does not explain persuasively why a
`POSA would have disregarded two key teachings of Klein – i) increase
`aqueous solubility and chemical stability by reducing the C-9 carbonyl to a
`hydroxyl, and ii) maintain the C-10 acetyl (9-dihydrotaxol) to modulate
`activity while retaining good efficacy – in order to synthesize cabazitaxel
`from Kant Compound 20. Prelim. Resp. 27–30, 34–38 (citing Ex. 1006,
`276–77); Ex. 1006, 279–280.
`Klein expressly teaches the reduction of the C-9 carbonyl to a C-9
`hydroxyl to increase aqueous solubility and chemical stability of the
`compounds, while maintaining “excellent in vivo activity in several solid
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`tumor models.” Ex. 1006, 276; Prelim. Resp. 28 (citing Ex. 1006, 276–77).
`Petitioner argues that Klein teaches a “reduction at C-9 results in reduced
`potency” when compared to docetaxel (Pet. 34, 42-43), but the cytotocity
`data in Klein Table I shows that 9-Dihydrotaxotere (docetaxel with a C-9
`hydroxyl) has comparable activity to docetaxel (Table I) and compound 10
`(Table III) in at least 3 out of 4 cell lines. Ex. 1006, 280 (Table I), 281
`(Table III). Klein, moreover, clearly teaches that “[t]hese products [i.e.,
`those with a C-9 hydroxyl] were shown to have excellent tubulin assembly
`activity and similar in vitro activity as compared to taxol and taxotere;
`therefore, these preliminary results establish that the C-9 carbonyl is not
`required for activity.” Id. at 279 (emphasis added). Contrary to Petitioner’s
`argument, Klein teaches that a C-9 carbonyl was not required to maintain
`anti-tumor activity and that reducing the C-9 carbonyl to a hydroxyl
`improves aqueous solubility and chemical stability of these notoriously
`insoluble compounds. Id. at 277, 279. Thus, we are not persuaded a POSA
`would have disregarded the improved aqueous solubility and stability
`provided by a C-9 hydroxyl, a key teaching in Klein, when considering
`possible modifications to Kant Compound 20.
`We reach the same conclusion with respect to Klein’s C-10 acetyl.
`Petitioner argues that a POSA would have retained Kant Compound 20’s
`C-10 methoxy group over Klein’s C-10 acetyl, because Kant teaches
`increased cytotoxicity of Compound 20 having a methoxy group at C-10
`when compared to the C-10 acetyl of docetaxel (compound 15). Pet. 32–33
`(citing Ex. 1005, 5546; Ex. 1002 ¶ 89). Klein, however, states that “facile
`deacetylation of the C-10 acetate is not trivial in the C-9 carbonyl series and
`reflects the greater stability of the 9(R)-dihydro series.” Ex. 1006, 279.
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`Klein, therefore, does not necessarily teach or suggest replacing the C-10
`acetyl unless the C-9 carbonyl is reduced to a hydroxyl group, such as in
`9(R)-dihydrotaxotere. Id. We also are persuaded by Patent Owner’s
`argument that Petitioner’s analysis reflects improper hindsight by having a
`POSA select the C-7 methyl from compound 10 in Klein’s Table III but
`reject the other teachings of Klein, as reflected in Patent Owner’s diagram,
`reproduced below.
`
`
`
`Prelim. Resp. 29.
`Therefore, for the reasons given above, we are not persuaded
`Petitioner has established a reasonable likelihood of prevailing in its
`assertion that the subject matter of claims 1 and 2 of the ’170 patent would
`have been obvious to a POSA over Kant and Klein.
`
`
`C. Asserted Obviousness of Claims 1 and 2 over Colin, Klein, and
`Kant
`
`Petitioner asserts that the subject matter of claims 1 and 2 of the ’170
`patent would have been obvious to a POSA based on the combined
`teachings of Colin, Klein, and Kant. Pet. 38–49. Patent Owner opposes.
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`Prelim. Resp. 38–43. We incorporate our findings with respect to Klein and
`Kant and address the parties’ arguments below.
`1. Colin
`Colin discloses four taxane compounds that are “useful anti-tumor
`agents.” Ex. 1007, Abstract. Colin specifically describes docetaxel as
`having “valuable biological activities” and the four taxane compounds as
`being “approximately twice as active as taxol.” Id. at 3:19-23, 3:29-30. The
`structure of docetaxel is shown below, to the right of paclitaxel.
`
`
`
`Pet. 9; Ex. 1002 ¶ 71. As can be seen, docetaxel has a different side chain
`(3-tertbutoxycarbonylamino) from paclitaxel. Docetaxel has a hydroxyl
`group at C-7 and at C-10, and paclitaxel has a hydroxyl group at C-7 and an
`acetyl at C-10. Both have a carbonyl group at C-9. Colin discloses
`formulating docetaxel (the product of Example 1) for intravenous
`administration by dissolving it in Emulphor EL 620 (an emulsifier) and
`ethanol. Id. at 10:5–11.
`
`2. Analysis
`
`Petitioner argues that Colin discloses docetaxel and a reason for a
`POSA to select docetaxel as a lead compound for “further optimization,”
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`because docetaxel was known to have greater activity against various tumor
`cell lines and a longer elimination half-life when compared to paclitaxel.
`Pet. 8–9 (citing Ex. 1002 ¶¶ 70–71), 38–40 (citing Ex. 1011, 496 [497]; Ex.
`1002 ¶¶ 98-103). Petitioner further argues that Klein and Kant provide
`sufficient reasons for a POSA to substitute the C-7 and C-10 hydroxyl
`groups in the docetaxel structure with methoxy groups, to achieve
`cabazitaxel with a reasonable expectation of success. Pet. 40–45 (citing Ex.
`1002 ¶¶ 66, 84, 87–89, 102–117). Regardless of whether Colin’s docetaxel
`would have been selected as a lead compound for further optimization,
`Petitioner’s argument is insufficient for the same reasons articulated above.
`For example, Petitioner repeats the argument that a POSA would have
`sought to optimize docetaxel’s cell membrane permeability by replacing the
`C-7 and C-10 hydroxyl groups with more lipophilic groups, without
`addressing the well-known difficulties of formulating highly lipophilic,
`water-insoluble paclitaxel and docetaxel into a useful intravenous dosage
`form. Pet. 40.
`Petitioner further argues that Klein teaches methylation of the C-7
`hydroxyl and acetylation of the C-10 hydroxyl to improve potency over a
`hydroxylated docetaxel analogue, but acknowledges that Klein compound 10
`in Table III still contains “two minor” structural differences from
`cabazitaxel. Id. at 41–42. As explained above in section II.B.3.b. of this
`Decision, Petitioner does not address persuasively the question of why a
`POSA would have disregarded Klein’s teachings to reduce the C-9 carbonyl
`to a hydroxyl group to improve aqueous solubility and chemical stability of
`the modified docetaxel compound, and to maintain a C-10 acetyl group with
`a hydroxylated C-9 to modulate biological activity of the compound. Id. at
`19
`
`
`
`

`

`IPR2016-00627
`Patent 5,847,170
`
`
`42–43. Nor does Petitioner persuasively rationalize Kant’s teaching of
`selective substitution at only the C-10 position to increase cytotoxicity, with
`Klein’s teaching to functionalize the C-7 and/or C-9 positions, particularly
`given the absence in Kant of a docetaxel control. Id. at 44–45 (citing Ex.
`1002 ¶¶ 91, 97, 107–108, 113–115, 117).
` Weighing the evidence as a whole, Petitioner’s argument that a
`POSA would have selectively methylated both the C-7 and C-10 positions of
`docetaxel to create a more potent analogue (cabazitaxel) based on the
`teachings of Klein and Kant, is not persuasive.7
`
`
`III. CONCLUSION
`Petitioner has not demonstrated a reasonable likelihood of prevailing
`with respect to its assertions of obviousness of claims 1 and 2 of the ’170
`patent.
`
`IV. ORDER
`
`Accordingly, it is
`ORDERED that the Petition is denied.
`
`
`
`
`
`
`
`
`7 In view of our Decision, we need not consider the parties’ arguments and
`evidence regarding secondary considerations of nonobviousness. Pet. 49–
`50; Prelim. Resp. 44–53; see Transocean Offshore Deepwater Drilling, Inc.,
`v. Maersk Drilling USA, Inc., 699 F.3d 1340, 1349 (Fed. Cir. 2012)
`(“objective evidence of nonobviousness . . . may be sufficient to disprove or
`rebut a prima facie case of obviousness”).
`20
`
`
`
`

`

`IPR2016-00627
`Patent 5,847,170
`
`
`
`
`For PETITIONER:
`
`Steven W. Parmelee
`Michael T. Rosato
`Jad A. Mills
`WILSON SONSINI GOODRICH & ROSATI
`sparmelee@wsgr.com
`mrosato@wsgr.com
`jmills@wsgr.com
`
`
`For PATENT OWNER:
`
`Dominic A. Conde
`FITZPATRICK CELLA HARPER & SCINTO
`dconde@fchs.com
`
`
`
`
`
`
`
`
`21
`
`

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