Trials@uspto.gov
`571-272-7822
`
`
`
`Paper 11
`Entered: November 29, 2017
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`MICRO LABS LIMITED and
`MICRO LABS USA INC.,
`Petitioner,
`
`v.
`
`SANTEN PHARMACEUTICAL CO., LTD. and
`ASAHI GLASS CO., LTD.,
`Patent Owner.
`____________
`
`Case IPR2017-01434
`Patent 5,886,035
`____________
`
`
`
`
`Before LORA M. GREEN, JO-ANNE M. KOKOSKI, and
`CHRISTOPHER G. PAULRAJ, Administrative Patent Judges.
`
`KOKOSKI, Administrative Patent Judge.
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`571-272-7822
`
`
`
`Paper 11
`Entered: November 29, 2017
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`MICRO LABS LIMITED and
`MICRO LABS USA INC.,
`Petitioner,
`
`v.
`
`SANTEN PHARMACEUTICAL CO., LTD. and
`ASAHI GLASS CO., LTD.,
`Patent Owner.
`____________
`
`Case IPR2017-01434
`Patent 5,886,035
`____________
`
`
`
`
`Before LORA M. GREEN, JO-ANNE M. KOKOSKI, and
`CHRISTOPHER G. PAULRAJ, Administrative Patent Judges.
`
`KOKOSKI, Administrative Patent Judge.
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`IPR2017-01434
`Patent 5,886,035
`
`
`I. INTRODUCTION
`
`Micro Labs Limited and Micro Labs USA Inc. (collectively,
`
`“Petitioner”) filed a Petition (“Pet.”) to institute an inter partes review of
`
`claims 1–14 of U.S. Patent No. 5,886,035 (“the ’035 patent,” Ex. 1001).
`
`Paper 1. Santen Pharmaceutical Co., Ltd. and Asahi Glass Co., Ltd.
`
`(collectively, “Patent Owner”) filed a Preliminary Response (“Prelim.
`
`Resp.”). Paper 10.
`
`Institution of an inter partes review is authorized by statute when “the
`
`information presented in the petition . . . and any response . . . shows that
`
`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; see
`
`37 C.F.R. §§ 42.4, 42.108. Upon consideration of the Petition and
`
`Preliminary Response, and the evidence of record, we determine that
`
`Petitioner has demonstrated a reasonable likelihood of prevailing with
`
`respect to the unpatentability of claims 1–14 of the ’035 patent.
`
`Accordingly, we institute an inter partes review of those claims.
`
`A.
`
`Related Proceedings
`
`The parties indicate that the ’035 patent is being 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.
`
`B.
`
`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
`
`
`
`
`2
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`IPR2017-01434
`Patent 5,886,035
`
`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
`
`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:
`
`
`
`
`3
`
`
`
`IPR2017-01434
`Patent 5,886,035
`
`
`
`
`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-
`
`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”).
`
`C.
`
`Challenged Claims
`
`Petitioner challenges claims 1–14 of the ’035 patent. Claims 1 and 12
`
`are the only independent claims, and are reproduced below.
`
`1.
`A fluorine-containing prostaglandin derivative of
`the following formula (1) or a salt thereof:
`
`
`
`
`4
`
`
`
`
`
`IPR2017-01434
`Patent 5,886,035
`
`
`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 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
`16-phenoxy-15-deoxy-15,15-
`F2α,
`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.
`
`D.
`
`The Prior Art
`
`Petitioner relies on the following prior art references:
`
`Reference Description
`Kishi
`U.S. 5,292,754
`Klimko
`EP 0 639 563 A2
`Ueno1
`Japanese Unexamined
`Patent App. Pub. No. H7-
`70054
`
`Date
`Mar. 8, 1994
`Feb. 22, 1995
`Mar. 14, 1995
`
`Exhibit No.
`1005
`1003
`1006
`
`
`1 Ueno is a Japanese patent application, and Petitioner provided an English-
`language translation as required by 37 C.F.R. § 42.63(b). Our citations are
`
`
`
`
`5
`
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`IPR2017-01434
`Patent 5,886,035
`
`
`Reference Description
`Fluoroprostaglandins: A
`Bezuglov
`19822
`New Class of Bioactive
`Analogs of Natural
`Prostaglandins, LIPIDS OF
`BIOLOGICAL MEMBRANES
`88–91 (L. D. Bergelson,
`ed., 1982)
`Fluorodeoxy
`Prostaglandins, Synthesis
`and Perspectives,
`PROSTAGLANDINS AND
`CARDIOVASCULAR
`DISEASES 191–200
`(Takayuki Ozawa et. al.
`eds., 1986)
`
`Bezuglov
`1986
`
`Date
`1982
`
`Exhibit No.
`1007
`
`1986
`
`1008
`
`
`to that translation, which we assume for purposes of this Decision is
`accurate. Although the translation of Ueno is accompanied by a translator’s
`certificate attesting to the accuracy of the translation (Ex. 1006, 67), the
`certificate is not an “affidavit” as required by 37 C.F.R. § 42.63(b) and as
`defined by 37 C.F.R. §§ 1.68 and 42.63(b). Specifically, the translator’s
`certificate does not warn the translator “that willful false statements and the
`like are punishable by fine or imprisonment, or both.” 37 C.F.R. § 1.68.
`Petitioner must file, as a new exhibit, a satisfactory affidavit attesting to the
`accuracy of the translation within ten business days of this Decision.
`2 Bezuglov 1982 is a Russian book chapter, and Petitioner provided an
`English-language translation as required by 37 C.F.R. § 42.63(b). Our
`citations are to that translation, which we assume for purposes of this
`Decision is accurate. As is the case with Ueno’s translator’s certificate, the
`translator’s certificate accompanying Bezuglov 1982 (Ex. 1007, 11) is not an
`“affidavit” as required by 37 C.F.R. § 42.63(b) and as defined by 37 C.F.R.
`§§ 1.68 and 42.63(b). Petitioner must file, as a new exhibit, a satisfactory
`affidavit attesting to the accuracy of the translation within ten business days
`of this Decision.
`
`
`
`
`6
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`IPR2017-01434
`Patent 5,886,035
`
`E.
`
`The Asserted Grounds of Unpatentability
`
`Petitioner challenges the patentability of claims 1–14 on the following
`
`grounds:
`
`References
`
`Basis
`
`Klimko, Kishi, and Ueno
`Klimko, Kishi, Bezuglov 1982
`and/or Bezuglov 1986, and Ueno
`
`§ 103(a)
`§ 103(a)
`
`
`
`A.
`
`Claim Interpretation
`
`II. ANALYSIS
`
`Challenged
`Claims
`1–14
`1–14
`
`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); see Cuozzo Speed Techs.,
`
`LLC v. Lee, 136 S. Ct. 2131, 2144–46 (2016). Only those terms in
`
`controversy need to be construed, and only to the extent necessary to resolve
`
`the controversy. See Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d
`
`795, 803 (Fed. Cir. 1999). For purposes of this Decision, based on the
`
`record before us, we determine that none of the claim terms requires an
`
`explicit construction.
`
`B.
`
`Obviousness over Klimko, Kishi, and Ueno
`
`Petitioner contends that the subject matter of claims 1–14 would have
`
`been obvious over the combined teachings of Klimko, Kishi, and Ueno.
`
`Pet. 41–62. Petitioner relies on the Declaration of Mitchell A. deLong,
`
`Ph.D. (“deLong Declaration,” Ex. 1027) and the Declaration of Aron D.
`
`Rose, M.D. (“Rose Declaration,” Ex. 1028) in support of its contentions. Id.
`
`
`
`
`7
`
`
`
`IPR2017-01434
`Patent 5,886,035
`
`
`1.
`
`Overview of 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
`
`topical ocular instillation, but generally cause inflammation, as well as
`
`surface irritation characterized by conjunctival hyperemia and edema,” and
`
`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
`
`
`
`
`
`
`8
`
`
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`IPR2017-01434
`Patent 5,886,035
`
`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
`
`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,
`
`
`
`
`9
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`IPR2017-01434
`Patent 5,886,035
`
`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 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
`
`“is both more potent and produces a greater maximum response for IOP
`
`reduction than compound E.” Id. at 19:33–35.
`
`2.
`
`Overview of 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.
`
`Kishi states that “[t]he inventors of the invention have found new useful
`
`compounds by screening a large amount of prostaglandin derivatives which
`
`are stable and capable of being chemically synthesized,” and also “found
`
`that derivatives of conventional prostaglandins which are derived from said
`
`conventional prostaglandins by deleting the hydroxy group at 15-position are
`
`more stable, particularly in the liquid phase, than the conventional
`
`prostaglandins, and that they show the intraocular pressure-reducing
`
`activity.” Id. at 1:62–2:3. According to Kishi, the described 15-
`
`deoxyprostaglandins “have a significant intraocular pressure-reducing
`
`activity, while they do not produce any side effects such as hyperemia of
`
`conjunctiva, and initial increase in intraocular pressure which are often
`
`observed in known prostaglandins.” Id. at 2:5–9.
`
`
`
`
`10
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`IPR2017-01434
`Patent 5,886,035
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`
`3.
`
`Overview of Ueno
`
`Ueno “relates to a new application for a 15-dehydroxy-prostaglandin
`
`compound, and to a specific new compound.” Ex. 1006 ¶ 1. Ueno
`
`recognizes that “[i]t is known that a group of 15-dehydroxy-PG compounds
`
`that do not have a hydroxyl group at position 15 of a so-called natural PG
`
`has intraocular pressure reducing action,” and that “15-dehydroxy-16-oxo
`
`PG compounds that do not have a hydroxyl group at position 15 and that
`
`have an oxo group at position 16 are effective for allergies, inflammation,
`
`and the like.” Id. ¶ 7. Ueno then states that “the present inventors
`
`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
`
`superior antagonistic effect toward histamines, and therefore are useful for
`
`treating patients with allergies and inflammatory diseases.” Id. ¶ 8.
`
`Based on testing in guinea pigs, Ueno reports that 13,14-dihyrdro-15-
`
`dehydroxy-17,17-difluoro-PGE 1 methyl ester “has an antagonistic action
`
`against histamine, which is an inducer of allergic diseases and inflammatory
`
`diseases,” and “is useful as an agent for treating allergic diseases,
`
`inflammatory diseases, and as a tracheal dilator.” Id. ¶¶ 87–88. Ueno
`
`includes conjunctivitis, iritis, uveitis, and central retinitis as examples of
`
`inflammatory diseases. Id. ¶ 12.
`
`4.
`
`Analysis
`
`We generally follow a two-part inquiry to determine whether a new
`
`chemical compound would have been obvious over particular prior art
`
`compounds. Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1291–93
`
`(Fed. Cir. 2012). First, we determine “whether a chemist of ordinary skill
`
`would have selected the asserted prior art compounds as lead compounds, or
`
`
`
`
`11
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`IPR2017-01434
`Patent 5,886,035
`
`starting points, for further development efforts.” Id. at 1291. Second, we
`
`analyze whether there was a reason to modify a lead compound to make the
`
`claimed compound with a reasonable expectation of success. Id. at 1292.
`
`A lead compound is defined 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.” Otsuka, 678 F.3d at 1291
`
`(alteration in original) (citing Takeda Chem. Indus., Ltd. v. Alphapharm Pty.,
`
`Ltd., 492 F.3d 1350, 1357 (Fed. Cir. 2007)). Stated another way, “a lead
`
`compound is ‘a natural choice for further development efforts.’” Id. (citing
`
`Altana Pharma AG v. Teva Pharms. USA, Inc., 566 F.3d 999, 1008 (Fed.
`
`Cir. 2009)). Importantly, the analysis of whether a person of ordinary skill
`
`in the art 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.
`
`“Absent 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.” Otsuka, 678 F.3d
`
`at 1292; see also Daiichi Sankyo Co., Ltd. v. Matrix Labs., Ltd., 619 F.3d
`
`1346, 1354 (Fed. Cir. 2010) (“[P]roviding 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.”). Establishing that a chemical compound would have been
`
`obvious over a structurally similar compound requires “a showing that the
`
`prior art would have suggested making the specific molecular modifications
`
`necessary to achieve the claimed invention.” Takeda, 492 F.3d at 1356.
`
`
`
`
`12
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`
`Petitioner contends that it would have been obvious to start with
`
`Klimko’s compound C as the “lead compound” and replace the hydroxyl
`
`group at the C-15 position with two fluorine (F) atoms to arrive at 16-
`
`phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglandin F2α
`
`(“tafluprost”), a compound that is specifically identified in dependent claim
`
`3 and independent claim 12, and which falls within the scope of the generic
`
`formula of independent claim 1, of the ’035 patent. The chemical structures
`
`of Klimko’s compound C and tafluprost are shown side-by-side below:
`
`
`
`Pet. 11. As indicated above, the only structural difference between the two
`
`compounds is the presence of a hydroxyl group versus two fluorine atoms at
`
`the C-15 position.
`
`As support for its contention that a person having ordinary skill in the
`
`art would have selected Klimko’s compound C as a lead compound,
`
`Petitioner cites to data presented in Klimko’s Table 4 and Figure 2, which
`
`shows that compounds A–D “were found to exhibit significantly more IOP-
`
`reducing activity than the reference standard compound latanoprost that
`
`garnered FDA approval in June 1996.” Pet. 46 (citing Ex. 1003, Example 6,
`
`Tbl. 4, Fig. 2; Ex. 1027 ¶ 61; Ex. 1028 ¶ 55). Although compound C shows
`
`more hyperemia than compounds A, B, D, and E (latanoprost), Petitioner
`
`cites Klimko’s finding that “compound C showed longer-lasting efficacy
`
`
`
`
`13
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`IPR2017-01434
`Patent 5,886,035
`
`than the other compounds up through 6 hours after administration of the fifth
`
`dose” and also showed “the greatest percent IOP-reduction of all of the
`
`compounds at the first tabulated time point of 16 hours following
`
`administration of the fourth dose.” Id. at 46–47 (citing Ex. 1003, 18:1–
`
`19:35; Ex. 1028 ¶¶ 56–59, 63); see also Ex. 1027 ¶ 108 (Dr. deLong
`
`testifying that a person having ordinary skill in the art would not have been
`
`dissuaded from selecting compound C based on the tests showing hyperemia
`
`in guinea pigs because compound C also demonstrated a long-lasting
`
`efficacy and the largest initial percent IOP reduction from baseline at 16
`
`hours after administration of the fourth dose.).
`
`Having selected Klimko’s compound C as a lead compound that
`
`might benefit from modification, Petitioner contends that a person having
`
`ordinary skill in the art would have turned to Kishi’s teaching that the
`
`hydroxyl at the C-15 position “is an underlying cause of the undesired
`
`hyperemia, and that removing the hydroxyl group at the C-15 position
`
`results in compounds that ‘do not produce any side effects such as
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`hyperemia.’” Pet. 50 (citing Ex. 1005, 1:65–2:11). Petitioner argues that a
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`person having ordinary skill in the art “would also be aware from Kishi that
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`removal of the hydroxyl group at the C-15 position of a PGF2α isopropyl
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`ester analogue like compound C could result in some loss of IOP-reducing
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`activity,” and, therefore, “would be further motivated to replace the C-15
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`hydroxyl group in compound C with a substituent other than hydrogen that
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`could ameliorate any loss of IOP-reducing activity, with the reasonable
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`expectation that the substitution would ameliorate or restore loss of IOP-
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`reducing activity.” Id. at 51.
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`According to Petitioner, a person having ordinary skill in the art
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`would then consider Ueno’s teachings “because it would have been known
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`to one operating in the field at the time, but also because Ueno . . .
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`specifically references Kishi.” Pet. 51. Petitioner reasons that the
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`combination of Kishi and Ueno teaches a person having ordinary skill in the
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`art “to replace the hydroxyl group at the C-15 position of compound C
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`disclosed in Klimko with two fluorine atoms in order to (1) eliminate the
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`hyperemia associated with compound C, and (2) restore the IOP-reducing
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`efficacy of compound C lost when the hydroxyl group is removed.” Id. at
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`52 (citing Ex. 1027 ¶ 115).
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`Relying on the Declarations of Timothy L. Macdonald, Ph.D.
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`(“Macdonald Declaration,” Ex. 2001) and Robert D. Fechtner, M.D.
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`(“Fechtner Declaration,” Ex. 2002), Patent Owner challenges Petitioner’s
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`identification of Klimko’s compound C as a lead compound meriting further
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`study and modification. Prelim. Resp. 32–45. Patent Owner argues that
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`Klimko teaches away from further development of compound C “because of
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`its unfavorable IOP-lowering profile and intolerable side effects.” Id. at 32–
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`33. In particular, Patent Owner points to Klimko’s identification of EP 364
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`417 A1 (“Stjernschantz,” Ex. 2017), which Klimko says demonstrates that
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`16-phenoxy-17,18,19,20-tetranor PGF2α isopropyl ester (which is compound
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`(4) in Stjernschantz and Klimko’s compound C) displays an initial increase
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`in IOP followed by a decrease, and unacceptable hyperemia, and, therefore,
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`displays an unacceptable therapeutic profile. Id. at 33–34 (citing Ex. 1003,
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`2:54–56, 3:38–44).
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`At this stage of the proceeding, Petitioner sets forth evidence in the
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`deLong and Rose Declarations that Klimko’s compound C potentially was a
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`useful medicine for reducing intraocular pressure and treating glaucoma and
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`ocular hypertension with longer-lasting efficacy than other compounds
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`tested in Klimko, and Patent Owner provides evidence in the Macdonald and
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`Fechtner Declarations that Klimko’s compound C had known drawbacks and
`
`that other prostaglandins were also promising. See, e.g., Pet. 45–50;
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`Ex. 1027 ¶¶ 57–71, 103–109; Ex. 1028 ¶¶ 52–63; Prelim. Resp. 32–45;
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`Ex. 2001 ¶¶ 72–96; Ex. 2002 ¶¶ 24–41. This conflicting expert testimony
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`creates a genuine issue of material fact as to whether Klimko’s compound C
`
`would have been selected as a lead compound. For purposes of deciding
`
`whether to institute an inter partes review, we must view the facts in the
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`light most favorable to Petitioner. See 37 C.F.R. § 42.108(c).
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`Patent Owner raises other arguments indicating potential flaws in
`
`Petitioner’s lead compound analysis or disputing Petitioner’s interpretation
`
`of the disclosures of the cited references. For example, Patent Owner argues
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`that a person having ordinary skill in the art would not have been motivated:
`
`(1) to replace the C15 hydroxyl in compound C with a hydrogen to diminish
`
`side effects (based on Kishi) because doing so would reduce IOP-lowering
`
`activing; (2) to replace the C15 hydrogen with fluorine (based on Ueno) to
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`restore the IOP-lowering activity lost when the hydrogen was substituted for
`
`the hydroxyl; and (3) to insert two fluorines at C15 (based on Ueno), “even
`
`though that difluoride bears little (if any) resemblance to the one hydroxyl
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`that the modification is meant to mimic.” Prelim. Resp. 5. Additionally,
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`Patent Owner argues that Ueno is not directed to using fluorination to
`
`improve IOP-lowering activity, and a person having ordinary skill in the art
`
`“would not have formed a reasonable expectation of success of IOP-
`
`lowering based on prostaglandin activity in wholly different contexts.” Id. at
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`16
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`48 (citing Ex. 2001 ¶ 100). We have considered these and the other
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`arguments raised by Patent Owner, and although they cast some doubt on
`
`certain elements of Petitioner’s lead compound analysis and create a genuine
`
`issue of material fact, we are persuaded, based on the current record, that
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`Petitioner has established a reasonable likelihood of prevailing on its
`
`assertion that claims 1–14 would have been obvious over the combined
`
`teachings of Klimko, Kishi, and Ueno. The parties will have the opportunity
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`to further develop these facts and arguments during trial, and the Board will
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`evaluate the fully-developed record at the close of the evidence.
`
`C. Obviousness over Klimko, Kishi, Bezuglov 1982
`and/or Bezuglov 1986, and Ueno
`
`Petitioner contends that the subject matter of claims 1–14 would have
`
`been obvious over the combined teachings of Klimko, Kishi, Bezuglov 1982
`
`and/or Bezuglov 1986, and Ueno. Pet. 62–66. Petitioner relies on the
`
`deLong Declaration and the Rose Declaration in support of its contentions.
`
`Id.
`
`1.
`
`Overview of Bezuglov 1982 and Bezuglov 1986
`
`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
`
`activity compared to natural prostaglandins.” Id. at 90. According to
`
`Bezuglov 1982, replacing the 15-hydroxyl group with fluorine can lead “to
`
`
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`17
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`Patent 5,886,035
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`the appearance of new properties in the analogs that were essentially absent
`
`in the corresponding natural prostaglandins.” Id. at 91.
`
`Bezuglov 1986 describes investigations of the synthesis and biological
`
`activity of fluorodeoxy prostaglandins. Ex. 1008, 191. In particular,
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`Bezuglov 1986 focuses on the “substitution of the 15-hydroxyl group”
`
`because “biological deactivation of prostaglandins was induced by the action
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`of 15-prostaglandin dehydrogenase.” Id. at 199. Bezuglov 1986 reports that
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`the substitution of fluorine for the hydroxyl group in prostaglandins at C15
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`“changed 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
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`15-fluorodeoxy prostaglandins upon intravenous injection in narcotized
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`animals.” Id.
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`2.
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`Analysis
`
`Petitioner relies on the same disclosures in Klimko, Kishi, and Ueno
`
`(and the arguments it made with respect to Petitioner’s contention that the
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`combination of Klimko, Kishi, and Ueno renders claims 1–14 obvious) to
`
`support its contention that the combination of Klimko, Kishi, Bezuglov 1982
`
`and/or Bezuglov 1986, and Ueno teach or suggest all of the limitations of
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`claims 1–14. Pet. 62. Petitioner additionally contends that a person having
`
`ordinary skill in the art “would be motivated in view of Bezuglov 1982
`
`and/or Bezuglov 1986 to replace the hydroxyl group at the C-15 position” of
`
`Klimko’s compound C “with a fluorine atom, with the reasonable
`
`expectation that this substitution would enhance and prolong the IOP-
`
`reducing activity” of compound C or, “at a minimum, restore any reduction
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`Patent 5,886,035
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`in IOP-reducing activity resulting from the removal of the hydroxyl group,”
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`and “because the exchange of fluorine for hydroxyl represents the most
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`incremental change in structure that can be made.” Id. at 64.
`
`Patent Owner’s arguments in response are generally the same as those
`
`made with respect to Petitioner’s challenge based on Klimko, Kishi, and
`
`Ueno. For example, Patent Owner argues that “none of the Bezuglov 1982,
`
`Bezuglov 1986 and Ueno . . . references are directed to fluorination in the
`
`context of IOP-lowering,” and a person having ordinary skill in the art
`
`“would not have formed a reasonable expectation of success of IOP-
`
`lowering based on prostaglandin activity in wholly different contexts.”
`
`Prelim. Resp. 48. We already determined that Petitioner demonstrates a
`
`reasonable likelihood of showing that claims 1–14 would have been obvious
`
`over the combined teachings of Klimko, Kishi, and Ueno. See supra Section
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`II.B. For the same reasons, we determine that Petitioner also demonstrates a
`
`reasonable likelihood of prevailing in showing that claims 1–14 would have
`
`been obvious over the combined teachings of Klimko, Kishi, Bezuglov 1982
`
`and/or Bezuglov 1986, and Ueno.
`
`
`
`III. CONCLUSION
`
`Based on the arguments in the Petition and the Preliminary Response,
`
`and the evidence of record, we determine that Petitioner has demonstrated a
`
`reasonable likelihood that it would prevail on its challenge to claims 1–14 of
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`the ’035 patent.
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`IV. ORDER
`
`In consideration of the foregoing, it is hereby
`
`ORDERED that inter partes review is granted as to claims 1–14 of
`
`the ’035 patent with respect to the following grounds:
`
`Whether claims 1–14 are unpatentable under 35 U.S.C. § 103 as
`
`obvious over the combined teachings of Klimko, Kishi, and Ueno; and
`
`Whether claims 1–14 are unpatentable under 35 U.S.C. § 103 as
`
`obvious over the combined teachings of Klimko, Kishi, Bezuglov 1982
`
`and/or Bezuglov 1986, and Ueno;
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`FURTHER ORDERED that, pursuant to 35 U.S.C. § 315(c) and
`
`37 C.F.R. § 42.4, notice is hereby given of the institution of a trial
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`commencing on the entry date of this Decision;
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`FURTHER ORDERED that Petitioner must file, as new exhibits,
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`affidavits attesting to the accuracy of the translations of Ueno (Ex. 1006) and
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`Bezuglov 1982 (Ex. 1007) that comply with 37 C.F.R. § 42.63(b) within ten
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`business days of this Decision; and
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`FURTHER ORDERED that no ground other than those specifically
`
`granted above is authorized for inter partes review as to the claims of
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`the ’035 patent.
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