Trials@uspto.gov
`571-272-7822
`
` Paper 7
`
` Entered: May 4, 2018
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`SAWAI USA, INC. and SAWAI PHARMACEUTICAL CO., LTD.,
`Petitioner,
`
`v.
`
`ASTELLAS PHARMA INC.,
`Patent Owner.
`____________
`
`Case IPR2018-00079
`Patent 6,346,532 B1
`Reexamination 6,346,532 C1
`____________
`
`
`
`Before JAMES T. MOORE, SUSAN L. C. MITCHELL, and
`KRISTI L. R. SAWERT, Administrative Patent Judges.
`
`SAWERT, Administrative Patent Judge.
`
`
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`35 U.S.C. § 314(a)
`
`
`
`
`
`571-272-7822
`
` Paper 7
`
` Entered: May 4, 2018
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`SAWAI USA, INC. and SAWAI PHARMACEUTICAL CO., LTD.,
`Petitioner,
`
`v.
`
`ASTELLAS PHARMA INC.,
`Patent Owner.
`____________
`
`Case IPR2018-00079
`Patent 6,346,532 B1
`Reexamination 6,346,532 C1
`____________
`
`
`
`Before JAMES T. MOORE, SUSAN L. C. MITCHELL, and
`KRISTI L. R. SAWERT, Administrative Patent Judges.
`
`SAWERT, Administrative Patent Judge.
`
`
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`35 U.S.C. § 314(a)
`
`
`
`
`
`
`
`
`IPR2018-00079
`Patent 6,346,532
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`INTRODUCTION
`I.
`Sawai USA, Inc. and Sawai Pharmaceutical Co., Ltd. (“Petitioner”)
`filed a Petition for an inter partes review of claims 1, 3–6, 9, 11, 12, 15, and
`16 of U.S. Patent No. 6,346,532 C1 (“the ’532 patent,” Ex. 10011). Paper 1
`(“Pet.”). Astellas Pharma Inc. (“Patent Owner”) filed a Preliminary
`Response. Paper 6 (“Prelim. Resp.”).
`We have authority to determine whether to institute an inter partes
`review. 35 U.S.C. § 314(b); 37 C.F.R. § 42.4(a). We may not institute an
`inter partes review “unless . . . there is a reasonable likelihood that the
`petitioner would prevail with respect to at least 1 of the claims challenged in
`the petition.” 35 U.S.C. § 314(a). Applying that standard, and upon
`consideration of the information presented in the Petition and the
`Preliminary Response, we deny the Petition and do not institute an inter
`partes review.
`
`A. Related Proceedings
`The parties identify Astellas Pharma Inc. v. Sawai USA, Inc., No. 16-
`cv-954 (D. Del. 2016) and Astellas Pharma Inc. v. Actavis Elizabeth LLC,
`No. 16-cv-905 (D. Del. 2016) as related matters under 37 C.F.R.
`§ 42.8(b)(2). These cases have been consolidated in the district court. Pet.
`55; Paper 4, 2.
`
`
`
`
`
`1 The ’532 patent underwent a reexamination proceeding before the
`Office, and a reexamination certificate issued on February 24, 2015. Exhibit
`1001 contains both the original patent and the reexamination certificate. For
`clarity, we use the term “Ex. 1001 B1” when citing to the original patent,
`and “Ex. 1001 C1” when citing to the reexamination certificate.
`2
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`B. The ’532 Patent
`The ’532 patent discloses amide derivatives or salts thereof. The
`amide derivatives have the following formula:
`
`
`
`
`
`where ring B is a nitrogen-containing heteroaryl group which is
`unsubstituted or substituted and is optionally fused with a benzene ring; X is
`a lower alkylene or an alkenylene, both of which are unsubstituted or
`substituted with hydroxy or a lower alkyl group, or X is a carbonyl or a
`group represented by –NH–, and when X is a lower alkylene which is
`substituted with a lower alkyl group, a carbon atom of the ring B optionally
`bonds with the lower alkyl group so that a ring is formed; A is methylene,
`ethylene, or a group represented by –CH2O–; R1a, R1b are the same or
`different and each is a hydrogen atom or a lower alkyl group; R2 is a
`hydrogen atom or a halogen atom; and Z is a group represented by =CH–; or
`a salt thereof. Ex. 1001 C1, 1:25–62. According to the ’532 patent, these
`compounds selectively stimulate β3 receptor,2 and are useful for treating
`diabetes. Id. (Abstract). The ’532 patent specifically discloses the chemical
`compound (R)-2-(2-aminothiazol-4-yl)-4′-[2-(2-hydroxy-2-phenylethyl)
`amino]ethyl]acetanilide, now known as “mirabegron.” Mirabegron is
`recited in claim 5 of the ’532 patent. Id. at 2:24–47.
`
`
`2 Compounds that stimulate β3 receptor go by various names known
`in the art, including: β3 agonists, β3 adrenoreceptor agonists, β3 receptor
`agonists, and β3 adrenergic agonists. See Prelim. Resp. 7 n.2.
`3
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`C. Challenged Claims
`Petitioner challenges claims 1, 3–6, 9, 11, 12, 15, and 16 of the ’532
`patent. Pet. 2. Claim 5 is illustrative of the claimed subject matter:
` 5. A compound of formula (Ia):
`
`
`
`
`or a salt thereof.
`Ex. 1001 C1, 2:24–47.
`
`
`
`D. The Prior Art
`Petitioner advances the following references as prior art on which it
`relies for the asserted grounds challenging claims 1, 3–6, 9, 11, 12, 15, and
`16 of the ’532 patent:
`1. Nathalie Blin et al., Structural and Conformational Features
`Determining Selective Signal Transduction in the β3-Adrenergic
`Receptor, 44 MOL. PHARMACO. 1097–1104 (1993) (“Blin,”
`Ex. 1006);
`
`2. Michael H. Fisher et al., U.S. Patent No. 5,541,197 (Jul. 30, 1996)
`(“Merck ’197,” Ex. 1008);
`
`
`
`
`
`
`
`3. Robert J. Mathvink et al., U.S. Patent No. 6,011,048 (Jan. 4, 2000)
`(“Merck ’048,” Ex. 1010);
`
`
`4. Richard B. Silverman, THE ORGANIC CHEMISTRY OF DRUG DESIGN
`& DRUG ACTION 19–23 (1992) (“Silverman,” Ex. 1016); and
`
`5. C.W. Thornber, Isosterism and Molecular Modification in Drug
`Design, 8 CHEM. SOC. REV. 563–580 (1979) (“Thornber,”
`Ex. 1017).
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`E. Asserted Grounds of Unpatentability
`Petitioner challenges the patentability of claims 1, 3–6, 9, 11, 12, 15,
`and 16 of the ’532 patent on the following two grounds:
`Claims
`Basis
`References
`1, 3–6, 9, 11, 12,
`35 U.S.C. § 103 Merck ’197 in view of Blin, and
`15, and 16
`Silverman or Thornber
`1, 3–6, 9, 11, 12,
`35 U.S.C. § 103 Merck ’197 in view of Blin, and
`15, and 16
`Merck ’048 and Silverman or
`Thornber
`
`
`
`Pet. 10. Petitioner also relies on the Declaration of Robert M. Williams,
`Ph.D. (Ex. 1002). Id. at 2 n.2.
`II. ANALYSIS
`We address below whether the Petition meets the threshold showing
`for institution of an inter partes review under 35 U.S.C. § 314(a). We
`consider each ground of unpatentability in view of the understanding of a
`person of ordinary skill in the art. For this Decision, we find that the prior
`art itself is sufficient to demonstrate the level of ordinary skill in the art at
`the time of the invention. Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed.
`Cir. 2001). Further, based on the information presented at this stage of the
`proceeding, we consider Petitioner’s declarant, Dr. Williams, qualified to
`opine from the perspective of an ordinary artisan at the time of the invention.
`See Ex. 1003 (curriculum vitae of Dr. Williams).
`
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`A. Broadest Reasonable Interpretation
`The Board interprets claims in an unexpired patent using the “broadest
`reasonable construction in light of the specification of the patent.” 37 C.F.R.
`§ 42.100(b); Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2144–46
`(2016). Under that standard, claim terms are given their ordinary and
`customary meaning in view of the specification, as would be understood by
`one of ordinary skill in the art at the time of the invention. In re Translogic
`Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007). Any special definitions
`for claim terms must be set forth with reasonable clarity, deliberateness, and
`precision. In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994).
`Neither Petitioner nor Patent Owner propose any claim term for
`interpretation. See Pet. 11; see generally Prelim. Resp. Only those claim
`terms or phrases that are in controversy need be construed, and only to the
`extent necessary to resolve the controversy. Vivid Techs., Inc. v. Am. Sci. &
`Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999). For purposes of this
`decision, therefore, we determine that no claim term requires express
`construction.
`
`B. The Prior Art
`Petitioner’s obviousness challenges are based on the following
`references.
`
`1. Merck ’197
`Merck ’197 discloses compounds having the following formula I:
`
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`Ex. 1008, 2:15–25. Formula I represents substituted sulfonamide
`compounds that are selective β3 adrenergic receptor agonists. Id. at
`Abstract. The compounds are prepared by coupling an aminoalkylphenyl-
`sulfonamide with a substituted epoxide. Id. Merck ’197 specifically names
`209 representative compounds falling within the scope of formula I, id. at
`7:2–15:3, and provides 118 examples of complete or partial compounds, see
`id. at 30:65–53:18.
`
`
`
`2. Blin
`Blin presents a structure-activity relationship analysis between β3-
`adrenoreceptor (“β3-AR”) and β3-AR ligands (both agonists and
`antagonists). Ex. 1006 (Abstract). Blin found that the potent β3-AR agonists
`share a similar structure portion: aromatic carbon-CH(OH)-CH2(NH) or
`aromatic carbon-O-CH2-CH(OH)-CH2(NH). Id. at 1101. Blin thus
`identified two “minimal pharmacophores” based on those studies:
`
`
`
`Figure 7 is a schematic representation of the β3-AR minimal
`pharmacophore.
`Id. at 1102 (Figure 7). Blin explains that the aromatic group “could stabilize
`aryl-aryl interactions,” the beta-hydroxyl or ether function “could establish a
`hydrogen bond,” and the protonated amine “should create an ionic bridge
`with a negatively charged carboxyl function inside the pocket site [of β3-
`AR].” Id. at 1101–2. Blin also found that β3-AR ligands contain “a long
`and bulky amine substituent moiety which is able to adopt and exchange
`
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`extended and stacked conformations.” Id. (Abstract). In particular, Blin
`suggests that the moiety “may interact with helices positioned on the
`opposite side, relative to those implicated more specifically in ligand
`binding.” Id. at 1099.
`
`
`
`3. Silverman
`Silverman describes using bioisosterism as an approach to lead
`compound modification. Ex. 1016, 19. “Bioisosteres,” Silverman explains,
`“are substituents or groups that have chemical or physical similarities, and
`which produce broadly similar biological properties.” Id. The bioisosterism
`approach “allows the medicinal chemist to tinker with only some of the
`parameters” (i.e., size, shape, electronic distribution, lipid solubility, water
`solubility, pKa, chemical reactivity, and hydrogen bonding), “in order to
`augment the potency, selectivity, and duration of action and to reduce
`toxicity.” Id. at 21. But “[m]ulitple alterations may be necessary to
`counterbalance [negative] affects.” Id. Silverman lists several classical and
`non-classical bioisosteres. Id. at 19–20 (Table 2.2–2.3). For the carbonyl
`group, Silverman lists six bioisoteres, as follows:
`
`Id. at 20 (Table 2.3).
`
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`4. Thornber
`Like Silverman, Thornber also provides an overview of the role of
`bioisosterism and drug design. Ex. 1017, 563–80. Thornber lists the same
`bioisosteres for the carbonyl group:
`
`
`
`
`
`Id. at 569 (Table 3).
`
`5. Merck ’048
`Merck ’048 discloses compounds having the following formula I:
`
`
`
`
`Ex. 1008, 2:15–25. Formula I represents thiazole-substituted
`benzenesulfonamides that are selective β3 adrenergic receptor agonists. Id.
`at Abstract. The compounds are prepared by coupling an aminoalkylphenyl-
`sulfonamide with a substituted epoxide. Id. Merck ’048 specifically names
`41 representative compounds falling within the scope of formula I, id. at
`6:42–8:41, and provides 41 examples of complete or partial compounds, see
`id. at 25:20–35:53.
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`C. 35 U.S.C. § 325(d)
`Patent Owner argues that we should invoke our discretion under
`35 U.S.C. § 325(d) and deny Petitioner’s obviousness challenges, because
`Petitioner presents “the same arguments on substantially the same prior art”
`raised during prosecution. Prelim. Resp. 12–15. Institution of an inter
`partes review is discretionary. See 35 U.S.C. § 314(a) (authorizing
`institution of an inter partes review under particular circumstances, but not
`requiring institution under any circumstances); 37 C.F.R. § 42.108(a) (“the
`Board may authorize the review to proceed” (emphasis added)); Harmonic
`Inc. v. Avid Tech., Inc., 815 F.3d 1356, 1367 (Fed. Cir. 2016) (explaining
`that under § 314(a), “the PTO is permitted, but never compelled, to institute
`an [inter partes review] proceeding”). We decline the invitation to exercise
`our discretion under § 325(d). Instead, we find that, on the merits, Petitioner
`fails to show a reasonable likelihood that it would prevail in its obviousness
`challenges to claims 1, 3–6, 9, 11, 12, 15, and 16 of the ’532 patent.
`D. Ground I: Alleged Obviousness over Merck ’197 in view of Blin, and
`Silverman and/or Thornber
`Petitioner contends that claims 1, 3–6, 9, 11, 12, 15, and 16 (“the
`challenged claims”) are unpatentable as obvious over Merck ’197 in view of
`Blin, and Silverman and/or Thornber. See Pet. 14–36. The crux of
`Petitioner’s argument is that the Federal Circuit’s “lead compound analysis”
`framework for determining the obviousness vel non of a new chemical
`compound is wrong. In particular, Petitioner argues that, “[b]y imposing a
`strict threshold ‘lead compound’ requirement in some cases, the Federal
`Circuit has improperly constructed the concept of obviousness.” Id. at 16.
`Petitioner contends that, under In re Dillion, 919 F.2d 688, 692 (Fed. Cir.
`
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`1990), the proper obviousness analysis begins with any structurally similar
`prior-art compound. Id. at 14. That prior-art compound “can be any
`compound that has utility, and the motivation to modify it could be to make
`another compound with similar utility.” Id. at 15. Petitioner concludes that
`strict application of the lead compound analysis “effectively restricts the
`knowledge of the POSA in contravention of the Patent Act, as well as
`Supreme Court precedent and Dillion.” Id.
`1. Applicable Law
`A claim is unpatentable under 35 U.S.C. § 103(a) if the differences
`between the claimed subject matter and the prior art are such that the subject
`matter, as a whole, would have been obvious at the time of the invention to a
`person having ordinary skill in the art. KSR Int’l Co. v. Teleflex, Inc., 550
`U.S. 398, 406 (2007). The question of obviousness is resolved on the basis
`of underlying factual determinations including: (1) the scope and content of
`the prior art; (2) any differences between the claimed subject matter and the
`prior art; (3) the level of ordinary skill in the art; and (4) objective evidence
`of nonobviousness. Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966).
`For new chemical compounds, the Federal Circuit has articulated a
`two-part inquiry to determine whether that compound would have been
`obvious over other prior art compounds. Otsuka Pharm. Co. v. Sandoz, Inc.,
`678 F.3d 1280, 1291–93 (Fed. Cir. 2012). First, the fact finder must
`determine “whether a chemist of ordinary skill would have selected the
`asserted prior art compounds as lead compounds, or starting points, for
`further development efforts.” Id. at 1291. Second, the fact finder must
`analyze whether the ordinarily skilled artisan would have had a reason to
`
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`modify a lead compound to make the claimed compound with a reasonable
`expectation of success. Id. at 1292.
`The Federal Circuit defines a lead compound as “a compound in the
`prior art that would be most promising to modify in order to improve upon
`its . . . activity and obtain a compound with better activity.” Takeda Chem.
`Indus., Ltd. v. Alphapharm Pty., Ltd., 492 F.3d 1350, 1357 (Fed. Cir. 2007).
`Put differently, “a lead compound is ‘a natural choice for further
`development efforts.”’ Id. (citing Altana Pharma AG v. Teva Pharm. USA,
`Inc., 566 F.3d 999, 1008 (Fed. Cir. 2009)). The analysis of whether an
`ordinarily skilled artisan would have chosen the prior art compound as a lead
`compound “is guided by evidence of the compound’s pertinent properties”
`including “positive attributes such as activity and potency,” “adverse effects
`such as toxicity,” “and other relevant characteristics in evidence.” Id. at
`1292.
`Importantly, “[a]bsent a reason or motivation based on such prior art
`evidence, mere structural similarity between a prior art compound and the
`claimed compound does not inform the lead compound selection.” Id.; see
`also Daiichi Sankyo Co. v. Matrix Labs., Ltd., 619 F.3d 1346, 1354
`(“[P]roving a reason to select a compound as a lead compound depends on
`more than just structural similarity, but also knowledge in the art of the
`functional properties and limitations of the prior art compounds”).
`Moreover, there must be “identification of some motivation that would have
`led one of ordinary skill in the art to select and then modify a known
`compound (i.e. a lead compound) in a particular way to achieve the claimed
`compound.” Eisai Co. v. Dr. Reddy’s Labs., Ltd., 533 F.3d 1353, 1357 (Fed.
`Cir. 2008); see also Genetics Inst., LLC v. Novartis Vaccines & Diagnostics,
`
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`Inc., 655 F.3d 1291, 1304 (Fed. Cir. 2011) (stating that the obviousness
`inquiry requires “the identification of some reason that would have
`prompted a researcher to modify the prior art compounds in a particular
`manner to arrive at the claimed compounds”).
`2. Analysis
`We reject Petitioner’s argument that the Federal Circuit’s lead
`compound analysis precedents are contrary to Dillion and Supreme Court
`precedents. See Pet. 15–36. As an initial matter, the Federal Circuit is our
`reviewing court, and as such, we are bound by its decisions. See 35 U.S.C.
`§ 319; see also Eisai, 533 F.3d at 1359 (“[P]ost-KSR, a prima facie case of
`obviousness for a chemical compound still, in general, begins with the
`reasoned identification of a lead compound.”).
`Moreover, as Patent Owner points out, the lead compound analysis for
`new chemical compounds is a well-established practice in inter partes
`review. Prelim. Resp. 17–18 (citing Incyte Corp. v. Concert Pharms., Inc.,
`Case IPR2017-01256 (PTAB April 9, 2017) (Paper 9); Sawai USA, Inc. v.
`Nissan Chem. Indus., Ltd., Case IPR2015-01647 (PTAB Feb. 4, 2016)
`(Paper 9); Mylan Pharms. Inc. v. Nissan Chem. Indus., Ltd., Case IPR2015-
`01069 (PTAB Oct. 20, 2015) (Paper 24); Apotex Inc. v. Merck Sharp &
`Dohme Corp., Case IPR2015-00419 (PTAB June 25, 2015) (Paper 14);
`Torrent Pharms. Ltd. v. Merck Frosst Canada & Co., Case IPR2014-00559
`(PTAB Oct. 1, 2014) (Paper 8)). Petitioner fails to point us to any relevant
`inter partes review decision abandoning lead compound analysis for new
`chemical compounds.
`Indeed, as Patent Owner also points out, previous Board decisions
`have rejected the notion that applying the lead compound analysis
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`framework in an inter partes review violates the holding of Dillion. See
`Apotex Inc. v. Merck Sharp & Dohme Corp., Case IPR2015-00419, slip op.
`at 2–3 (PTAB Oct. 27, 2015) (Paper 18) (denying Petitioner’s request for
`rehearing and rejecting argument that structural similarity alone is sufficient
`to provide a reason for modifying a prior-art compound under Dillion);
`Torrent Pharms. Ltd. v. Merck Frosst Canada & Co., Case IPR2014-00559,
`slip op. 7 (PTAB Jan. 7, 2015) (Paper 10) (denying Petitioner’s request for
`rehearing based on the panel’s application of the lead compound analysis
`framework); Prelim. Resp. 18–19.
`Finally, we disagree with Petitioner that the lead compound analysis
`framework violates the holding of Dillion. Critically, Dillion relates to the
`rejection-and-response regime of patent examination, rather than the
`adjudicatory process of an inter partes review. Dillion explains that
`if an examiner considers that he has found prior art close enough
`to the claimed invention to give one skilled in the relevant
`chemical art the motivation to make close relatives (homologs,
`analogs, isomers, etc.) of the prior art compound(s), then there
`arises what has been called a presumption of obviousness or a
`prima facie case of obviousness. The burden then shifts to the
`applicant, who then can present arguments and/or data to show
`that what appears to be obvious, is not in fact that, when the
`invention is looked at as a whole.
`919 F.2d at 696 (citations omitted). In contrast to examination, inter partes
`review is an adjudicatory process, and as the Federal Circuit has explained,
`the burden shifting analysis applied in prosecution “does not apply in the
`adjudicatory context of an IPR.” In re Magnum Oil Tools Int’l, Ltd., 829
`F.3d 1364, 1375 (Fed. Cir. 2016).
`In sum, Petitioner’s first asserted obviousness ground is based on the
`contention that the lead compound analysis framework is not the proper
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`obviousness analysis for a new chemical compound. Because we reject that
`argument, we determine that Petitioner has not shown a reasonable
`likelihood of prevailing with respect that at least one claim challenged in the
`Petition based on this ground.
`E. Ground II: Alleged Obviousness over Merck ’197 in view of Blin, and
`Merck ’048 and Silverman and/or Thornber
`Petitioner contends that claims 1, 3–6, 9, 11, 12, 15, and 16 are
`unpatentable as obvious over Merck ’197 in view of Blin, in combination
`with Merck ’048 and Silverman and/or Thornber. See Pet. 36–52. Petitioner
`contends that an ordinarily skilled artisan would have selected the
`compounds disclosed in Table 3 of Merck ’197 as lead compounds and
`would have been motivated to modify these compounds to make mirabegron
`with a reasonable expectation of success. Id. at 36–37.
`1. Selection of Lead Compounds
`As explained above, Merck ’197 discloses substituted sulfonamide
`compounds of the following formula I that are selective β3-AR agonists:
`
`
`Ex. 1008, Abstract, 2:15–25. Petitioner argues that the ordinarily skilled
`artisan would have selected Examples 90, 91, and 92 disclosed in Table 3 of
`Merck ’197 as lead compounds. Pet. 37–41. These Examples have the
`following chemical formula:
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`Ex. 1008, 46:1–10. In Example 90, R is 4-iodophenyl, trifluoroacetate salt;
`in Example 91, R is 2-naphthyl, trifluoroacetate salt; and in Example 92, R
`is 3-quinolinyl, trifluoroacetate salt. Id. at 46:11–20.
`
`Petitioner walks us through the selection of these Examples for lead
`compounds as follows. First, Petitioner alleges that the ordinarily skilled
`artisan, looking to prepare compounds having selective β3-AR activity,
`would have been motivated to use the “minimal pharmacophore” disclosed
`in Blin, which possesses an aromatic group, a beta-hydroxyl functionality,
`and a protonated amine. Pet. 37–38 (citing Ex. 1006, 1101–02; Ex. 1002 ¶
`168; Ex. 1007, PTO_00001116, PTO_00001474). Petitioner also contends
`that the ordinarily skilled artisan would have been motivated by Blin’s
`teaching to use a long and bulky amine substituent, as well as the R optical
`isomer at the chiral carbon in the minimal pharmacophore. Id. at 38 (citing
`Ex. 1005, 2821; Ex. 1006, 1099, 1103; Ex. 1008, 15:13–31, 55:35–45 (claim
`3)). Thus, Petitioner asserts, “a POSA looking for a new β3-AR agonist
`would have been looking for lead compounds with the following structure:
`
`
`where R is a long and bulky chain that is flexible enough to allow for
`extended conformations, which Blin taught ‘could be adopted in the less
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`encumbered β3 site [and] may induce agonistic effects.’” Id. at 38–39
`(quoting Ex. 1006, 1103).
`
`Second, Petitioner alleges that, “armed with the above structure-
`activity relationship, a POSA would look at what large research-based
`pharmaceutical companies were doing in this area and see that Merck, a very
`large and well-respected research pharmaceutical company, was very active
`in selective β3-AR agonists based on the phenylethanolamine minimal
`pharmacophore in Blin.” Pet. 39 (citing Ex. ¶ 169; Exs. 1008–1010, 1012–
`1013). The ordinarily skilled artisan would have focused on Merck ’197,
`Petitioner contends, because the compounds disclosed and claimed in that
`patent have “the same minimal pharmacophore in Blin as well as the long
`and bulky substituents on the amine.” Id. (citing Ex. 1002 ¶ 170). The
`ordinarily skilled artisan then would have focused on Examples 90–92
`“because they are the first three of only eleven compounds specifically
`named and claimed in Claim 12” of Merck ’197, and the skilled artisan
`“would reasonably expect a company like Merck to claim particularly useful
`compounds.” Id. (citing Ex. 1002 ¶ 171; Ex. 1008, 56:22–29).
`
`Third, Petitioner alleges that the ordinarily skilled artisan also would
`have focused on Examples 90–92 of Merck ’197 because they have a core
`structure with hydrogens for R2, R3, R4, R5, and R6, and an ethylene group
`between the amine and the phenyl ring that is representative of the “vast
`majority of the disclosed specific examples” in Merck ’197. Pet. 40 (citing
`Ex. 1002 ¶ 172; Ex. 1008, 33:4–35, 41:34–45:57, 46:1–21, 47:4–20; 49:4–
`29, 52:36–53:17). Petitioner contends that the skilled artisan would have
`envisioned the phenyl ring as the substituent for “A” in general Formula I,
`because Merck ’197 lists it as a “more preferred” substituent, the phenyl ring
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`is “in the first three of the specifically claimed compounds of Claim 12,” and
`is “consistent with the minimal pharmacophore disclosed in Blin.” Id. at
`40–41 (citing Ex. 1002 ¶ 172; Ex. 1006, 1099–1103; Ex. 1008, 15:61–15:63,
`46:1–46:21 (Table 3), 56:22–56:29).
`Fourth, Petitioner alleges that the ordinarily skilled artisan would
`have been motivated to use Examples 90–92 because the amine portions of
`those compounds “are long and bulky chains that are flexible enough to
`allow for extended conformations, which Blin also taught induced agonistic
`effects.” Pet. 41 (citing Ex. 1002 ¶ 173; Ex. 1006, 1099, 1103). Fifth, and
`finally, Petitioner alleges that because Examples 90–92 “met all the
`structural criteria for selective β3-AR activity” in Blin and Merck ’197, the
`ordinarily skilled artisan “would have had a reasonable expectation of
`success” that these compounds would be a selective β3-AR agonist. Id. at 41
`(citing Ex. 1002 ¶ 174).3
`
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`3 In a footnote, Petitioner argues that Patent Owner “appears to agree”
`that Examples 90–92 are appropriate lead compounds because Patent Owner
`selected Examples 90 and 92 as comparison compounds for presenting
`unexpected results data during reexamination of the ’532 patent, and “never
`argued that these compounds were not appropriate lead compounds during
`prosecution or reexamination.” Pet. 41 n.12 (citing Ex. 1015, PTO-
`00000666; Ex. 1015; Ex. 1007). We decline to consider an argument made
`entirely in footnotes. See SmithKline Beecham Corp. v. Apotex Corp., 439
`F.3d 1312, 1320 (Fed. Cir. 2006) (arguments made in footnotes are waived).
`But even if we considered this argument, it is unpersuasive because “the
`path that leads an inventor to the invention is expressly made irrelevant to
`patentability by statute.” Life Techs., Inc. v. Clontech Labs., Inc., 224 F.3d
`1320, 1325 (Fed. Cir. 2000).
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`Upon review of Petitioner’s arguments and evidence, we determine
`that on this record Petitioner fails to show adequately, for the purpose of
`institution, that an ordinarily skilled artisan would have had a reason to
`select Examples 90–92 as lead compounds.
`As an initial matter, we generally agree with Petitioner that an
`ordinarily skilled artisan searching for potent β3-AR agonists would have
`been motivated by the teachings of Blin to select compounds possessing a
`minimal pharmacophore and “a long and bulky amine substituent moiety
`which is able to adopt and exchange extended and stacked conformations.”
`Ex. 1006 (Abstract). But we disagree with Petitioner that the skilled artisan
`would have necessarily chosen a lead compound possessing a beta-hydroxyl
`functionality rather than an ether functionality. See Pet. 37–38.
`Specifically, Blin identifies two minimal pharmacophores (A and B)
`and further explains that the beta-hydroxyl or the ether function “could
`establish a hydrogen bond.” Ex. 1006, 1101–02. Petitioner focuses on
`minimal pharmacophore A because the “beta-hydroxyl functionality . . .
`could establish a hydrogen bond.” Pet. 37–38. But Blin also states the ether
`functionality of pharmacophore B “could establish a hydrogen bond.”
`Ex. 1006, 1101–02. Petitioner provides no persuasive explanation why a
`skilled artisan would have focused on pharmacophore A to the exclusion of
`pharmacophore B.
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`Even if an ordinarily skilled artisan would have started with
`compounds having the pharmacophore A structure, as follows:
`
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`see Pet. 38, Petitioner has not presented sufficient evidence that Examples
`90–92 in Merck ’197 would have been the “natural choice[s] for further
`development.” Altana, 566 F.3d at 1008.
`“In determining whether a chemist would have selected a prior art
`compound as a lead, the analysis is guided by evidence of the compound’s
`pertinent properties.” Otsuka Pharm., 678 F.3d at 1292 (emphasis added).
`Instead of focusing on the properties of Examples 90–92, Petitioner looks to
`Merck itself: Specifically, that Merck (1) is “a very large and well-respected
`research pharmaceutical company,” (2) was “very active in selective β3-AR
`agonists based on the phenylethanolamine minimal pharmacophore in Blin,”
`and (3) specifically claimed Examples 90–92 as the first three of 11
`compounds recited in claim 12 of the Merck ’197 patent. Pet. 39 (citing
`Ex. 1002 ¶¶ 169, 171; Ex. 1008, 56:22–29 (claim 12); Exs. 1009–1010,
`1012–1014). We find none of these rationales persuasive.
`First, Petitioner’s expert—Dr. Williams—states that “a number of
`major pharmaceutical research organizations, including Merck &
`Co., Bristol-Myers Squibb Co., and Beecham Group Ltd.[,] were looking at
`substituted phenethanolamines as selective β3 agonists for numerous
`diseases, including obesity and diabetes, and had patented compounds that
`were structurally similar to Mirabegron.” Ex. 1002 ¶ 96. Thus, that Merck
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`was a large and well-respected pharmaceutical company and engaged in the
`study of substituted phenethanolamines as selective β3-AR agonists, would
`not have provided, in our view, sufficient reason for the skilled artisan to
`look particularly to Merck’s patents. Second, as Patent Owner points out,
`Merck published many patent applications on selective β3-AR agonists
`during the relevant time period, and, over time, these applications “show an
`increased preference for pyridine substituents” as reflected in the claims of
`those applications. Prelim. Resp. 47–48 (citing Ex. 1009; Ex. 1010, 6:39–
`41, 35:55–40:43; Ex. 1012; Ex. 1013; Ex. 1014, 62:1–68:27; Ex. 2005,
`3:13–17; Ex. 1002 ¶ 96).
`Finally, even if an ordinarily skilled artisan would have had a reason
`to focus on the compounds disclosed in Merck ’197, we find that Petitioner
`fails to provide a sufficient explanation why that artisan would have selected
`Examples 90–92 disclosed in Table 3 as lead compounds. See Pet. 42–47.
`Table 3 provides no data and, thus, gives no hint to pertinent properties of
`these compounds. Nor does Table 3 suggest that the compounds’ properties
`may be improved. Ex. 1008, 46:1–46:21 (Table 3). In addition, we observe
`that Merck ’179 specifically names 209 representative compounds falling
`within the scope of formula I, Ex. 1008, 7:2–15:3, and provides 118
`examples of complete or partial compounds, id. at 30:65–53:18. Petitioner
`does not persuade us that an ordinarily skilled artisan would have selected
`Examples 90–92 as lead compounds over the other compounds. See Daiichi,
`619 F.3d at 1354 (“While the lead compound analysis must, in keeping with
`KSR, not rigidly focus on the selection of a single, best lead compound, the
`analysis still requires the challenger to demonstrate . . . that one of ordinary
`skill in the art would have had a reason to select a proposed lead compound
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`or compounds over other compounds in the prior art.” (citation omitted)
`(emphasis added)).
`We agree with Patent Owner that, if anything, Merck ’197 would have
`led the skilled artisan to selec
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