Trials@uspto.gov
`571-272-7822
`
`
`
`Paper 53
`Entered: November 27, 2018
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`MICRO LABS LIMITED and
`MICRO LABS USA INC.,1
`Petitioner,
`
`v.
`
`SANTEN PHARMCEUTICAL CO., LTD. and
`ASAHI GLASS CO., LTD.,
`Patent Owner.
`____________
`
`Case IPR2017-01434
`Patent 5,886,035
`____________
`
`
`
`Before JO-ANNE M. KOKOSKI, CHRISTOPHER G. PAULRAJ, and
`DEBRA L. DENNETT, Administrative Patent Judges.
`
`KOKOSKI, Administrative Patent Judge.
`
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`
`
`1 The Board terminated Petitioner’s involvement without terminating the
`proceeding under 35 U.S.C. § 317(a). Paper 52.
`
`
`571-272-7822
`
`
`
`Paper 53
`Entered: November 27, 2018
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`MICRO LABS LIMITED and
`MICRO LABS USA INC.,1
`Petitioner,
`
`v.
`
`SANTEN PHARMCEUTICAL CO., LTD. and
`ASAHI GLASS CO., LTD.,
`Patent Owner.
`____________
`
`Case IPR2017-01434
`Patent 5,886,035
`____________
`
`
`
`Before JO-ANNE M. KOKOSKI, CHRISTOPHER G. PAULRAJ, and
`DEBRA L. DENNETT, Administrative Patent Judges.
`
`KOKOSKI, Administrative Patent Judge.
`
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`
`
`1 The Board terminated Petitioner’s involvement without terminating the
`proceeding under 35 U.S.C. § 317(a). Paper 52.
`
`
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`IPR2017-01434
`Patent 5,886,035
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`
`I. INTRODUCTION
`
`We have jurisdiction to conduct this inter partes review under
`
`35 U.S.C. § 6, and this Final Written Decision is issued pursuant to
`
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73. For the reasons that follow, we
`
`determine that Petitioner has not shown by a preponderance of the evidence
`
`that claims 1–14 of U.S. Patent No. 5,886,035 (“the ’035 patent,” Ex. 1001)
`
`are unpatentable.
`
`A.
`
`Procedural History
`
`Micro Labs Limited and Micro Labs USA Inc. (collectively,
`
`“Petitioner”) filed a Petition (“Pet.,” Paper 1) to institute an inter partes
`
`review of claims 1–14 (“the challenged claims”) of the ’035 patent. Santen
`
`Pharmaceutical Co., Ltd. and Asahi Glass Co., Ltd. (collectively, “Patent
`
`Owner”) filed a Preliminary Response (“Prelim. Resp.,” Paper 10). Pursuant
`
`to 35 U.S.C. § 314(a), we instituted an inter partes review based on the
`
`following grounds: (1) whether claims 1–14 are unpatentable under 35
`
`U.S.C. § 103 as obvious over the combined teachings of Klimko,2 Kishi,3
`
`and Ueno;4 and (2) whether claims 1–14 are unpatentable under 35 U.S.C.
`
`§ 103 as obvious over the combined teachings of Klimko, Kishi, Bezuglov
`
`
`2 EP 0 639 563 A2, published Feb. 22, 1995 (Ex. 1003).
`3 U.S. 5,292,754, issued March 8, 1994 (Ex. 1005).
`4 Japanese Unexamined Patent App. Pub. No. H7-70054, published Mar. 14,
`1995 (Ex. 1006). We refer to “Ueno” as the English translation of the
`original reference.
`
`
`
`
`2
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`IPR2017-01434
`Patent 5,886,035
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`19825 and/or Bezuglov 1986,6 and Ueno. Paper 11 (“Dec. on Inst.” or
`
`“Institution Decision”), 20.
`
`After institution of trial, Patent Owner filed a Patent Owner Response
`
`(“PO Resp.,” Paper 22) and Petitioner filed a Reply (“Reply,” Paper 24).
`
`Petitioner relies on the Declaration and Supplemental Declaration of
`
`Mitchell A. deLong, Ph.D. (“deLong Declaration,” Ex. 1027; “Supplemental
`
`deLong Declaration,” Ex. 1031), and the Declaration and Supplemental
`
`Declaration of Aron D. Rose, M.D. (“Rose Declaration,” Ex. 1028;
`
`“Supplemental Rose Declaration,” Ex. 1032). Patent Owner relies on the
`
`Declaration and Supplemental Declaration of Timothy L. Macdonald, Ph.D.
`
`(“Macdonald Declaration,” Ex. 2001; “Supplemental Macdonald
`
`Declaration,” Ex. 2028), and the Declaration and Supplemental Declaration
`
`of Robert D. Fechtner, M.D. (“Fechtner Declaration,” Ex. 2002;
`
`“Supplemental Fechtner Declaration,” Ex. 2029). Patent Owner filed
`
`observations regarding the cross-examination of Dr. deLong (Paper 34) and
`
`Dr. Rose (Paper 35), and Petitioner filed responses (Papers 39, 40).
`
`Petitioner filed a Motion to Exclude Exhibits 2023, 2027, 2034, 2038–
`
`2041, 2044, and 2047, and paragraphs 8–26 of the Supplemental Macdonald
`
`Declaration (Ex. 2028). Paper 30. Patent Owner filed an Opposition
`
`(Paper 37), and Petitioner filed a Reply (Paper 44). Patent Owner filed a
`
`Motion to Exclude Exhibits 1033–1035, 1037, 1038, 1040–1043, and 1045–
`
`
`5 Fluoroprostaglandins: A New Class of Bioactive Analogs of Natural
`Prostaglandins, LIPIDS OF BIOLOGICAL MEMBRANES 88–91 (L. D.
`Bergelson, ed., 1982) (Ex. 1007). We refer to “Bezuglov 1982” as the
`English translation of the original reference.
`6 Fluorodeoxy Prostaglandins, Synthesis and Perspectives,
`PROSTAGLANDINS AND CARDIOVASCULAR DISEASES 191–200 (Takayuki
`Ozawa et. al. eds., 1986)
`
`
`
`
`3
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`IPR2017-01434
`Patent 5,886,035
`
`1060, certain paragraphs of the Supplemental deLong and Rose
`
`Declarations, and the testimony at lines 117:23–118:23 of the deposition of
`
`Dr. Rose (Ex. 2026). Paper 32. Petitioner filed an Opposition (Paper 41),
`
`and Patent Owner filed a Reply (Paper 45).
`
`An oral hearing was held on September 6, 2018, and a transcript is
`
`included in the record. Paper 49 (“Tr.”).
`
`On November 27, 2018, with Board authorization, the parties filed a
`
`joint motion to terminate the instant proceeding. Papers 50, 51; Ex. 2066.
`
`In light of the advanced stage of the instant proceeding, the Board granted-
`
`in-part the motion to terminate. Paper 52. Consequently, the proceeding
`
`has been terminated with respect to Petitioner, but is not terminated with
`
`respect to Patent Owner. Id.
`
`B.
`
`Related Proceedings
`
`The parties indicate that the ’035 patent is asserted in Santen
`
`Pharmaceutical Co., Ltd. v. Micro Labs Limited, Case No. 16-cv-00353
`
`(D. Del. 2016) and Santen Pharmaceutical Co., Ltd. v. Sandoz Inc., Case
`
`No. 16-cv-00354 (D. Del. 2016). Pet. 4; Paper 3, 1.
`
`C.
`
`The ’035 Patent
`
`The ’035 patent, titled “Difluoroprostaglandin Derivatives and Their
`
`Use,” is directed to “fluorine-containing prostaglandin derivatives having
`
`two fluorine atoms at the 15-position (or their salts) and medicines
`
`containing the compounds as an active ingredient, particularly, preventative
`
`or therapeutic medicines for eye diseases.” Ex. 1001, 1:4–8. These
`
`compounds are derivatives of a class of prostaglandins referred to as
`
`“prostaglandin Fs” or “PGFs.” Id. at 1:11–21, 61–63. The ’035 patent states
`
`that, although naturally-occurring prostaglandin Fs “are known to lower
`
`
`
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`4
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`IPR2017-01434
`Patent 5,886,035
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`intraocular pressure when topically applied to the eye,” they are also “irritant
`
`to the eye and have a problem of their inflammatory side effects such as
`
`congestion and damage to the cornea” (id. at 1:12–19), and “extensive
`
`research has been conducted both at home and abroad for development of
`
`long-lasting PGF derivatives having much the same biological activities as
`
`the naturally occurring one and few side effects” (id. at 1:44–47).
`
`In that regard, the ’035 patent discloses that “15,15-difluoro-15-
`
`deoxy-PGF2α and its derivatives are superior to the known natural PGF2α in
`
`the effect of lowering intraocular pressure[,] are scarcely irritant to the eye,
`
`scarcely affect the ocular tissues such as the cornea, the iris, and the
`
`conjunctive, and have long-lasting efficacy.” Id. at 2:7–12. The disclosed
`
`fluorine-containing prostaglandin derivatives also “are unlikely to
`
`decompose through metabolic processes such as hydrolysis and oxidation
`
`and [are] stable in the body,” and “hardly stimulate melanogenesis.” Id. at
`
`19:21–28. As a result, “the medicine of the present invention is effective as
`
`a therapeutic agent, particularly for glaucoma or ocular hypertension.” Id.
`
`at 29–31.
`
`The fluorine-containing prostaglandin derivatives disclosed in
`
`the ’035 patent have the following generic formula:
`
`Ex. 1001, 2:20–29. These fluorine-containing derivatives “may be the same
`
`as the naturally occurring type except for the two fluorine atoms at the 15-
`
`
`
`
`
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`5
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`IPR2017-01434
`Patent 5,886,035
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`position”, i.e., “compounds wherein A is a vinylene group, R1 is a n-pentyl
`
`group, both R2 and R3 are hydrogen atoms, X is –CH2–, Z is –OH, and the
`
`dual line is a cis-double bond.” Id. at 2:53–58. The ’035 patent further
`
`teaches that fluorine-containing prostaglandin derivatives “having an ω-
`
`chain which is not of the naturally[-]occurring type (namely, wherein A is a
`
`vinylene group, and R1 is a n-pentyl group) are preferred.” Id. at 2:59–62;
`
`see also id. at 4:11–7:53 (setting forth compounds for A, X, R1–R7, and Z
`
`that “are preferred from the standpoint of biological activities and physical
`
`properties”).
`
`Claims 1 and 12 are the challenged independent claims, and are
`
`reproduced below.
`
`1.
`A fluorine-containing prostaglandin derivative of
`the following formula (1) or a salt thereof:
`
`
`
`wherein A is an ethylene group, a vinylene group, an ethylene
`group, –OCH2– or –SCH2–,
`
` R1 is a substituted or unsubstituted aryloxyalkyl group,
`
` each of R2 and R3 which are independent of each other, is a
`hydrogen atom or an acyl group, or forms a single bond
`together with Z,
`
` X is –CH2–, –O– or –S–,
`
` Z is –OR4, –NHCOR5, –NHSO2R6 or –SR7, or forms a single
`bond together with R2 or R3,
`
` each of R4, R5, R6 and R7 which are independent of one
`another, is a hydrogen atom, an alkyl group, an alkenyl
`
`
`
`
`6
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`IPR2017-01434
`Patent 5,886,035
`
`
`group, an alkynyl group, a cycloalkyl group, an aryl
`group or an aralkyl group,
`
` and a dual line consisting of solid and broken lines is a single
`bond, a cis-double bond or a trans-double bond.
`
`Ex. 1001, 31:2–26
`
`12. A medicine containing 16-phenoxy-15-deoxy-
`15,15-difluoro-17,18,19,20-tetranorprostaglandin F2α, 16-(3-
`chlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-
`tetranorprostaglandin F2α, 16-phenoxy-15-deoxy-15,15-
`difluoro-13,14-dihydro-17,18,19,20-tetranorprostaglandin F2α
`or an alkyl ester or salt thereof as an active agent.
`
`Id. at 32:22–27.
`
`The compound 16-phenoxy-15-deoxy-15,15-difluoro-
`
`17,18,19,20-tetranorprostaglandin F2α (also referred to as tafluprost),
`
`which is specifically recited in dependent claim 3 and independent
`
`claim 12 and encompassed by the other challenged claims, is the focus
`
`of the parties’ obviousness arguments and our analysis in this
`
`proceeding.
`
`A.
`
`Level of Ordinary Skill in the Art
`
`II. ANALYSIS
`
`Petitioner contends that a person having ordinary skill in the art
`
`(“POSA”) at the time of the ’035 patent would have had “a Ph.D. in
`
`medicinal and/or organic chemistry” with “at least several years of
`
`experience researching and developing preventative or therapeutic medicines
`
`for treatment of eye diseases,” and “familiarity designing, formulating and
`
`evaluating ophthalmic compositions for treatment of eye conditions that
`
`include glaucoma or ocular hypertension.” Pet. 23–24. According to
`
`Petitioner, the POSA “would also have sufficient familiarity interpreting or
`
`evaluating studies that use animal models to test for [intraocular pressure]
`
`
`
`
`7
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`IPR2017-01434
`Patent 5,886,035
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`reducing activity and side-effects of compounds having the potential to treat
`
`glaucoma or ocular hypertension,” and “would also draw upon the
`
`specialized experiences and skills of others on his team with these skills
`
`since it would be reasonable that the POSA would be working as part of a
`
`multi-disciplinary team with respect to the subject research.” Id. at 24
`
`(citing Ex. 1027 ¶ 28; Ex. 1028 ¶ 22).
`
`Patent Owner contends that a POSA “would have been an individual
`
`or team” having “a Ph.D. degree in medicinal or organic chemistry, 3 years
`
`of work experience in medicinal chemistry, and sufficient familiarity with
`
`interpreting or evaluating studies that use animal models to test for
`
`[intraocular pressure] reducing activity and side effects of compounds
`
`having the potential to treat glaucoma or ocular hypertension.” PO Resp.
`
`23–24 (citing Ex. 2001 ¶ 51). Patent Owner disputes Petitioner’s contention
`
`that a POSA would be a chemist with experience researching therapies for
`
`eye diseases and familiarity interpreting and evaluating studies using animal
`
`models because “[c]hemists working on such projects often do not have
`
`specific prior experience with eye diseases or animal studies,” and, instead,
`
`would work as part of a multi-disciplinary team with respect to the subject
`
`research. Id. at 24 (citing Ex. 2001 ¶ 52; Ex. 2025, 247:17–23, 249:6–
`
`251:16). Patent Owner also disputes Petitioner’s contention that a POSA
`
`would have been familiar with designing, formulating, and evaluating
`
`ophthalmic compositions. Id. at 24–25. According to Patent Owner, the
`
`claims of the ’035 patent that “are generally directed to medicines containing
`
`at least one of the novel compounds as an active ingredient . . . do not recite
`
`any particular formulation details.” Id. at 26(citing Ex. 2001 ¶ 53).
`
`
`
`
`8
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`
`Patent Owner’s assessment appears consistent with the level of
`
`ordinary skill in the art at the time of the invention as reflected in the prior
`
`art in this proceeding. See Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed.
`
`Cir. 2001) (explaining that specific findings regarding ordinary skill level
`
`are not required “where the prior art itself reflects an appropriate level and a
`
`need for testimony is not shown” (quoting Litton Indus. Prods., Inc. v. Solid
`
`State Sys. Corp., 755 F.2d 158, 163–64 (Fed. Cir. 1985))). Accordingly,
`
`when evaluating the parties’ contentions regarding the scope and content of
`
`the art, and the differences between the prior art and the challenged claims,
`
`we take into consideration Patent Owner’s assertions regarding the level of
`
`ordinary skill. Nonetheless, we also note that our analysis and conclusions
`
`herein would not change even under Petitioner’s proposed skill level for a
`
`POSA.
`
`B.
`
`Claim Interpretation
`
`We interpret claims of an unexpired patent using the “broadest
`
`reasonable construction in light of the specification of the patent in which
`
`[the claims] appear[].” 37 C.F.R. § 42.100(b) (May 2, 2016); see Cuozzo
`
`Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2144–46 (2016).7 Consistent
`
`with the broadest reasonable construction, claim terms are presumed to have
`
`their ordinary and customary meaning as understood by a person of ordinary
`
`
`7 The revised claim construction standard for interpreting claims in inter
`partes review proceedings as set forth in the final rule published October 11,
`2018 does not apply to this proceeding, because the new “rule is effective on
`November 13, 2018 and applies to all IPR, PGR and CBM petitions filed on
`or after the effective date.” Changes to the Claim Construction Standard for
`Interpreting Claims in Trial Proceedings Before the Patent Trial and Appeal
`Board, 83 Fed. Reg. 51340 (Nov. 13, 2018) (to be codified at 37 C.F.R.
`pt. 42).
`
`
`
`
`9
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`IPR2017-01434
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`skill in the art in the context of the entire patent disclosure. In re Translogic
`
`Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007). Only those terms in
`
`controversy need to be construed, and only to the extent necessary to resolve
`
`the controversy. See Nidec Motor Corp. v. Zhongshan Broad Ocean Motor
`
`Co., 868 F.3d 1013, 1017 (Fed. Cir. 2017) (“we need only construe terms
`
`‘that are in controversy, and only to the extent necessary to resolve the
`
`controversy’”) (quoting Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200
`
`F.3d 795, 803 (Fed. Cir. 1999)).
`
`For purposes of the Institution Decision, we determined that, based on
`
`the record at that time, no claim term required express construction (Dec. on
`
`Inst. 7), and we see no reason to modify that determination in light of the
`
`record developed at trial.
`
`C.
`
`Principles of Law
`
`To prevail on its challenges to the patentability of the claims, a
`
`petitioner must establish facts supporting its challenge by a preponderance
`
`of the evidence. 35 U.S.C. § 316(e); 37 C.F.R. § 42.1(d). “In an [inter
`
`partes review], the petitioner has the burden from the onset to show with
`
`particularity why the patent it challenges is unpatentable.” Harmonic Inc. v.
`
`Avid Tech., Inc., 815 F.3d 1356, 1363 (Fed Cir. 2016) (citing 35 U.S.C.
`
`§ 312(a)(3) (requiring inter partes review petitions to identify “with
`
`particularity . . . the evidence that supports the grounds for the challenge to
`
`each claim”)). This burden of persuasion never shifts to the patent owner.
`
`See Dynamic Drinkware, LLC v. Nat’l Graphics, Inc., 800 F.3d 1375, 1378–
`
`79 (Fed. Cir. 2015) (discussing the burdens of persuasion and production in
`
`inter partes review).
`
`
`
`
`10
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`A claim is unpatentable under 35 U.S.C. § 103 if the differences
`
`between the subject matter sought to be patented and the prior art are such
`
`that the subject matter as a whole would have been obvious to a person
`
`having ordinary skill in the art to which the subject matter pertains. KSR
`
`Int’l Co. v. Teleflex, Inc., 550 U.S. 398, 406 (2007). The question of
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`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. See Graham
`
`v. John Deere Co., 383 U.S. 1, 17–18 (1966).
`
`A determination of whether a new chemical compound would have
`
`been obvious over the prior art typically follows a two-part inquiry that first
`
`considers “whether a chemist of ordinary skill would have selected the
`
`asserted prior art compounds as lead compounds, or starting points, for
`
`further development efforts,” and second, analyzes whether there was a
`
`reason to modify a lead compound to make the claimed compound with a
`
`reasonable expectation of success. Otsuka Pharm. Co. v. Sandoz, Inc., 678
`
`F.3d 1280, 1291–93 (Fed. Cir. 2012).
`
`D. Overview of the Prior Art
`
`1.
`
`Klimko
`
`Klimko “relates to the use of cloprostenol, fluprostenol, their
`
`analogues and their pharmaceutically acceptable salts and esters to treat
`
`glaucoma and ocular hypertension.” Ex. 1003, 2:3–5. Cloprostenol and
`
`fluprostenol “are synthetic analogues of PGF2α, a naturally-occurring F-
`
`series prostaglandin (PG).” Id. at 2:6–7. Klimko states that “[n]aturally-
`
`occurring prostaglandins are known to lower intraocular pressure (IOP) after
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`
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`topical ocular instillation, but generally cause inflammation, as well as
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`surface irritation characterized by conjunctival hyperemia and edema,” and
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`that “[m]any synthetic prostaglandins have been observed to lower
`
`intraocular pressure, but such compounds also produce the aforementioned
`
`side effects.” Id. at 2:50–54. Klimko teaches that “the addition of a chlorine
`
`atom or a trifluoromethyl group to the meta position on the phenoxy ring at
`
`the end of the omega chain provides a compound having excellent IOP
`
`reduction without the significant side effects found with other, closely
`
`related compounds.” Id. at 3:50–53.
`
`The compounds described in Klimko have the following general
`
`formula:
`
`
`
`wherein R1 is H, C1–C12 straight-chain or branched alkyl, C1–C12 straight-
`
`chain or branched acyl, C3–C8 cycloaklyl, a cationic salt moiety, or a
`
`pharmaceutically acceptable amine moiety; R2 and R3 is H or C1–C5 straight-
`
`chain or branched alkyl, or R2 and R3 taken together may be O; X is O, S, or
`
`CH2; R9 is H, C1–C10 straight-chain or branched alkyl, or C1–C10 straight-
`
`chain or branched acyl; R11 is H, C1–C10 straight-chain or branched alkyl, or
`
`C1–C10 straight-chain or branched acyl; Y is O, or H and OR15, wherein R15
`
`is H, C1–C10 straight-chain or branched alkyl, or C1–C10 straight-chain or
`
`branched acyl; and Z is Cl or CF3. Id. at 4:14–37. Klimko teaches that the
`
`
`
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`12
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`preferred compounds include cloprostenol isopropyl ester, fluprostenol
`
`isopropyl ester, the 3-oxa form of cloprostenol isopropyl ester, 13,14-
`
`dihydrofloprostenol isopropyl ester, cloprostenol-1-ol, and 13,14-
`
`dihydrocloprostenol-1-ol pivaloate. Ex. 1003, 4:55–58.
`
`Klimko reports studies comparing the IOP-lowering activity and side
`
`effects of five compounds: A) cloprostenol isopropyl ester; B) fluprostenol
`
`isopropyl ester; C) 16-phenoxy-17,18,19,20-tetranor PGF2α, isopropyl ester;
`
`D) 17-phenyl-18,19,20-trinor PGF2α, isopropyl ester; and E) 13,14-dihydro-
`
`17-phenyl-18,19,20-trinor PGF2α, isopropyl ester (known as latanoprost). Id.
`
`at 14:47–50; see also id. at 15, Tbl. 2 (showing the structures of compounds
`
`A–E). Tests of compounds A–E for hyperemia in guinea pigs show that
`
`compound C “produces significant hyperemia at low doses,” compound D
`
`“produces less hyperemia than compound C, but significantly more than
`
`compound E . . ., which produces only mild hyperemia,” and the hyperemia
`
`produced by compound A and compound B “appear to be intermediate
`
`between that of compound D and compound E, but this degree of hyperemia
`
`is also mild, and cannot be distinguished from that produced by compound
`
`E.” Id. at 17:56–18:6. Compounds A–E were also tested for IOP-lowering
`
`effects in cynomolgus monkey eyes. Id. at 18:10–25. Based on these tests,
`
`Klimko reports “that compounds A, B, C, and D produce similar degrees of
`
`IOP reduction with 0.3 µg doses,” but that “compound E is essentially
`
`inactive at this dose.” Id. at 19:29–30. Klimko further reports “that the IOP
`
`reduction with 1 µg of compound A is greater than that produced by 0.3 µg
`
`of compound A, and the response to either of these doses of compound A is
`
`greater than the maximum reduction produced by either dose of compound
`
`E.” Id. at 19:31–33. According to Klimko, these tests indicate compound A
`
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`“is both more potent and produces a greater maximum response for IOP
`
`reduction than compound E.” Id. at 19:33–35.
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`2.
`
`Kishi
`
`Kishi “relates to the use of 15-deoxy-prostaglandin derivatives for the
`
`treatment of hypertension or glaucoma in the eyes.” Ex. 1005, 1:15–17.
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`Kishi states that “[t]he inventors of the invention have found new useful
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`compounds by screening a large amount of prostaglandin derivatives which
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`are stable and capable of being chemically synthesized,” and also “found
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`that derivatives of conventional prostaglandins which are derived from said
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`conventional prostaglandins by deleting the hydroxy group at 15-position are
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`more stable, particularly in the liquid phase, than the conventional
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`prostaglandins, and that they show the intraocular pressure-reducing
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`activity.” Id. at 1:62–2:3. According to Kishi, the described 15-
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`deoxyprostaglandins “have a significant intraocular pressure-reducing
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`activity, while they do not produce any side effects such as hyperemia of
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`conjunctiva, and initial increase in intraocular pressure which are often
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`observed in known prostaglandins.” Id. at 2:5–9.
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`3.
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`Ueno
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`Ueno “relates to a new application for a 15-dehydroxy-prostaglandin
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`compound, and to a specific new compound.” Ex. 1006 ¶ 1. Ueno
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`recognizes that “[i]t is known that a group of 15-dehydroxy-PG compounds
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`that do not have a hydroxyl group at position 15 of a so-called natural PG
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`has intraocular pressure reducing action,” and that “15-dehydroxy-16-oxo
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`PG compounds that do not have a hydroxyl group at position 15 and that
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`have an oxo group at position 16 are effective for allergies, inflammation,
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`and the like.” Id. ¶ 7. Ueno then states that “the present inventors
`
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`
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`14
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`IPR2017-01434
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`discovered that” the 15-dehydroxy-prostaglandin compounds that do not
`
`have a hydroxyl group or an oxo group at position 15 or position 16 “have
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`superior antagonistic effect toward histamines, and therefore are useful for
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`treating patients with allergies and inflammatory diseases.” Id. ¶ 8.
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`Based on testing in guinea pigs, Ueno reports that 13,14-dihydro-15-
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`dehydroxy-17,17-difluoro-PGE 1 methyl ester “has an antagonistic action
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`against histamine, which is an inducer of allergic diseases and inflammatory
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`diseases,” and “is useful as an agent for treating allergic diseases,
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`inflammatory diseases, and as a tracheal dilator.” Id. ¶¶ 87–88. Ueno
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`includes conjunctivitis, iritis, uveitis, and central retinitis as examples of
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`inflammatory diseases. Id. ¶ 12.
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`4.
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`Bezuglov 1982
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`Bezuglov 1982 describes the synthesis and biological testing of 15-
`
`fluorine-15-deoxyfluoroprostaglandins. Ex. 1007, 88. Bezuglov 1982
`
`teaches that “the replacement of the 15-hydroxyl group with fluorine
`
`protects the prostaglandin from the effects of 15-oxyprostaglandin
`
`dehydrogenase, which is a key enzyme in the metabolism of prostaglandins
`
`in the body.” Id. Bezuglov 1982 reports the results of biological tests that
`
`show that the synthesized 15-fluoroprostaglandins A2, E2α, F2, and I2 “did
`
`not lose the activity characteristic of prostaglandins” and “have prolonged
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`activity compared to natural prostaglandins.” Id. at 90. According to
`
`Bezuglov 1982, replacing the 15-hydroxyl group with fluorine can lead “to
`
`the appearance of new properties in the analogs that were essentially absent
`
`in the corresponding natural prostaglandins.” Id. at 91.
`
`
`
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`15
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`
`5.
`
`Bezuglov 1986
`
`Bezuglov 1986 describes investigations of the synthesis and biological
`
`activity of fluorodeoxy prostaglandins. Ex. 1008, 191. In particular,
`
`Bezuglov 1986 focuses on the “substitution of the 15-hydroxyl group”
`
`because “biological deactivation of prostaglandins was induced by the action
`
`of 15-prostaglandin dehydrogenase.” Id. at 199. Bezuglov 1986 reports that
`
`the substitution of fluorine for the hydroxyl group in prostaglandins at C15
`
`“changed also the character of their pharmacological action” and, in some
`
`cases, increase selectivity. Id. at 194. Bezuglov 1986 also reports that “[a]s
`
`expected, fluorination of prostaglandins in position 15 rendered them stable
`
`towards 15-prostaglandin dehydrogenase leading to prolonged activity of
`
`15-fluorodeoxy prostaglandins upon intravenous injection in narcotized
`
`animals.” Id.
`
`E. Obviousness over Klimko, Kishi, and Ueno
`
`Petitioner contends that claims 1–14 are unpatentable under 35 U.S.C.
`
`§ 103 as obvious over the combined teachings of Klimko, Kishi, and Ueno.
`
`Pet. 41–62; Reply 2–18. In particular, Petitioner argues that it would have
`
`been obvious for one of ordinary skill in the art to (1) identify Klimko’s
`
`compound C (16-phenoxy-17,18,19,20-tetranor PGF2α) as a lead compound
`
`for drug development; (2) recognize that the hydroxyl group at the C-15
`
`position of Klimko’s compound C causes the negative side effect of
`
`hyperemia, and that removal of that hydroxyl would eliminate hyperemia but
`
`could result in loss of IOP-reducing activity; and (3) address these concerns
`
`by replacing the hydroxyl at the C-15 position with 2 fluorine atoms.
`
`Pet. 41–62. According to Petitioner, replacing the hydroxyl group at the C-
`
`15 position of Klimko’s compound C with two fluorine (F) atoms results in
`
`
`
`
`16
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`IPR2017-01434
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`tafluprost (16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-
`
`tetranorprostaglandin F2α), a compound that is specifically identified in
`
`dependent claim 3 and independent claim12, and which falls within the
`
`scope of the generic formula of independent claim 1, of the ’035 patent. Id.
`
`at 10–11, 42–44. The chemical structures of Klimko’s compound C and
`
`tafluprost are shown side-by-side below.
`
`Id. at 11. As shown in the illustration, the only structural difference between
`
`Klimko’s compound C on the left and tafluprost on the right is at the C-15
`
`position (indicated by a red box), where Klimko’s compound C has a
`
`
`
`hydroxyl group and tafluprost has two fluorine atoms.
`
`1.
`
`Obviousness of Tafluprost
`
`Petitioner contends that one of ordinary skill in the art would have
`
`selected Klimko’s compound C (“compound C”) as a lead compound in the
`
`development of PGF2α analogues “due to its apparent long-lasting efficacy
`
`relative to the other compounds” disclosed in Klimko. Pet. 48 (citing
`
`Ex. 1028 ¶ 59). Having selected compound C as a lead, Petitioner contends
`
`that, based on the disclosures in Kishi, a POSA would have removed the
`
`hydroxyl group at the C-15 position to eliminate the side effect of
`
`hyperemia, and replaced it with a substituent other than hydrogen to
`
`ameliorate any loss of IOP-reducing activity. Id. at 50–51. Petitioner
`
`further contends that Ueno “teaches a POSA to replace the hydroxyl group
`
`
`
`
`17
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`
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`IPR2017-01434
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`at the C-15 position of compound C disclosed in Klimko with two fluorine
`
`atoms in order to (1) eliminate the hyperemia associated with compound C,
`
`and (2) restore the IOP-reducing efficacy of compound C lost when the
`
`hydroxyl group is removed,” thereby yielding tafluprost, which is within the
`
`scope of the challenged claims. Id. at 52–53 (citing Ex. 1027 ¶ 115).
`
`As explained by the Federal Circuit, “[t]o establish obviousness in
`
`cases involving new chemical compounds, [the proponent of the
`
`compounds’ obviousness] must identify some reason that would have led a
`
`chemist to modify a known compound.” Bristol-Myers Squibb Co. v. Teva
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`Pharms. USA, Inc., 752 F.3d 967, 973 (Fed. Cir. 2014). “Generally, an
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`obviousness inquiry concerning such ‘known compounds’ focuses on the
`
`identity of a ‘lead compound.’” Id. (quoting Eisai Co. Ltd. v. Dr. Reddy’s
`
`Labs., Ltd., 533 F.3d 1353, 1359 (Fed. Cir. 2009). “A lead compound is a
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`compound in the prior art that would be ‘a natural choice for further
`
`development efforts.’” Id. (quoting Altana Pharma AG v. Teva Pharms.
`
`USA, Inc., 566 F.3d 999, 1008 (Fed. Cir. 2009). “The motivation to modify
`
`that lead compound can come from any number of sources and need not
`
`necessarily be explicit in the art.” Id. Consistent with the flexible principles
`
`enunciated in KSR, to demonstrate that a claimed compound would have
`
`been obvious, “a showing that the prior art would have suggested making the
`
`specific molecular modifications necessary to achieve the claimed invention
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`[i]s also required.” Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd., 492
`
`F.3d 1350, 1356 (Fed. Cir. 2007) (internal quotations omitted, emphasis
`
`added).
`
`Patent Owner argues that a POSA would not have considered
`
`compound C of Klimko to be a suitable lead compound. PO Resp. 28–51.
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`
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`18
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`Patent Owner also argues that a POSA would not have found it obvious to
`
`modify compound C to arrive at the claimed compound. Id. at 51–65.
`
`Based on our review of the full record in the present case, even assuming
`
`arguendo that an ordinary artisan would have selected Klimko’s compound
`
`C as a lead compound for further development, Petitioner does not persuade
`
`us that the prior art of record would have suggested making the specific
`
`modifications to compound C to yield tafluprost.
`
`Petitioner argues that a POSA would have been motivated to remove
`
`the hydroxyl group at the C-15 position of compound C because (1) Kishi
`
`teaches prostaglandin analogues used to treat glaucoma or ocular
`
`hypertension wherein “the presence of a hydroxyl at the C-15 position is an
`
`underlying cause of the undesired hyperemia,” and removing it “results in
`
`compounds that ‘do not produce any side effects such as hyperemia’”
`
`(Pet. 50 (quoting Ex. 1005, 1:65–2:11)); and (2) Kishi teaches that removing
`
`the C-15 position hydroxyl group “also imparts stability to the compound,
`
`because naturally occurring PGF2α that contain a hydroxyl group at C-15 are
`
`chemically and biological[ly] labile and easily subject to metabolic
`
`degradation” (id. (citing Ex. 1027 ¶ 74)). According to Petitioner, a POSA
`
`would have been motivated
`
`to combine the teachings of Klimko and Kishi and would have
`had a reasonable expectation of success that removing the
`hydroxyl group at the C-15 position would improve the stability
`of compound C, would eliminate side-effects such as hyperemia
`caused by the hydroxyl group, and could potentially extend or
`prolong the IOP-reducing effect of a PGF2α analogue.
`
`Id. (citing Ex. 1027 ¶¶ 111–113; Ex. 1028 ¶¶ 68–70).
`
`Petitioner further argues that “a POSA would also be aware from
`
`Kishi that removal of the hydroxyl at the C-15 position of a PGF2α isopropyl
`
`
`
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`19
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`IPR2017-01434
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`ester analogue like Compound C could result in some loss of IOP-reducing
`
`activity.” Pet. 51 (citing Ex. 1005, 41:59–43:36). Therefore, Petitioner
`
`argues, “a POSA would be further motivated to replace the C-15 hydroxyl
`
`group in compound C with a subs
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