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
`U.S. Patent No. 5,886,035
`
`____________
`
`
`PATENT OWNER PRELIMINARY RESPONSE
`
`
`
`
`

`

`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`II.
`
`BACKGROUND ............................................................................................. 6
`
`A.
`
`B.
`
`C.
`
`State of the Art as of the Priority Date
`of the '035 Patent, December 26, 1996 ................................................. 6
`
`The '035 Patent .................................................................................... 15
`
`Prosecution History of the '035 Patent ................................................ 23
`
`III. LEVEL OF ORDINARY SKILL IN THE ART ........................................... 25
`
`IV. CLAIM CONSTRUCTION .......................................................................... 26
`
`V.
`
`CLAIMS 1-14 OF THE '035 PATENT WOULD
`NOT HAVE BEEN OBVIOUS AS OF DECEMBER 26, 1996 .................. 27
`
`A.
`
`Legal Standard Regarding Obviousness
`Based on Identification of an Alleged Lead Compound ..................... 30
`
`B. A POSITA Would Not Have Considered
`Compound C of Klimko To Be a Suitable Lead Compound .............. 32
`
`C.
`
`D.
`
`E.
`
`It Would Not Have Been Obvious to Modify
`Compound C of Klimko by C15 Fluorination .................................... 45
`
`It Would Not Have Been Obvious
`to Difluorinate Compound C of Klimko ............................................. 49
`
`Klimko Specifically Excluded C15 Difluorinated
`Compounds from the Scope of Its Work ............................................. 55
`
`VI. CONCLUSION .............................................................................................. 59
`
`CLAIM LISTING APPENDIX ............................................................................... 60
`
`CERTIFICATE OF COMPLIANCE ....................................................................... 63
`
`CERTIFICATE OF SERVICE ................................................................................ 64
`
`
`
`
`
`i
`
`

`

`TABLE OF AUTHORITIES
`
`Cases
`
`Otsuka Pharm. Co. v. Sandoz, Inc.,
` 678 F.3d 1280 (Fed. Cir. 2012) ..................................................................... 32, 33
`
`Pfizer Inc. v. Teva Pharm. USA, Inc.,
` 555 F. App'x 961 (Fed. Cir. 2014) ................................................................. 30, 31
`
`Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd.,
` 492 F.3d 1350 (Fed. Cir. 2007) ............................................................... 31, 32, 33
`
`
`
`
`
`ii
`
`

`

`LIST OF EXHIBITS
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`
`2008
`
`2009
`
`2010
`
`2011
`
`2012
`
`Document
`
`Exhibit
`No.
`2001 Declaration of Timothy L. Macdonald, Ph.D.
`2002 Declaration of Robert D. Fechtner, M.D.
`Camras et al., "Reduction of intraocular pressure by prostaglandins
`applied topically to the eyes of conscious rabbits," Invest. Ophthalmol.
`Vis. Sci. 16:1125-1134 (1977)
`"Pharmacia Cleared To Market Xalatan, Drug for Glaucoma," Wall St.
`J. B7 (June 7, 1996)
`Fung and Whitson, "An evidence-based review of unoprostone
`isopropyl ophthalmic solution 0.15% for glaucoma: place in therapy,"
`Clin. Ophthalmol. 8:543-554 (2014)
`Linden and Alm, "Prostaglandin Analogues in the Treatment of
`Glaucoma," Drug Aging, 14(5):387-398 (1999)
`Coleman et al., "VIII. International Union of Pharmacology
`Classification of Prostanoid Receptors: Properties, Distribution, and
`Structure of the Receptors and Their Subtypes," Pharmacol. Rev.
`46(2):205-229 (1994)
`Konturek and Pawlik, "Physiology and pharmacology of
`prostaglandins," Dig. Dis. Sci. 31(2 Suppl):6S-19S (1986)
`Stjernschantz and Alm, "Latanoprost as a new horizon in the medical
`management of glaucoma," Curr. Opin. Ophthalmol. 7(2):11-17
`(1996)
`Collins and Djuric, "Synthesis of Therapeutically Useful Prostaglandin
`and Prostacyclin Analogs," Chem. Rev. 93:1533-1564 (1993)
`Giuffrè, "The effects of prostaglandin F2α in the human eye," Graefe's
`Arch. Clin. Exp. Ophthalmol. 222:139-141 (1985)
`Bito and Baroody, "The ocular pharmacokinetics of eicosanoids and
`their derivatives: 1. Comparison of ocular eicosanoid penetration and
`distribution following the topical application of PGF2α, PGF2α -1-
`methyl ester, and PGF2α -1-isopropyl ester," Exp. Eye Res. 44:217-26
`(1987)
`Villumsen and Alm, "Prostaglandin F2α-isopropylester eye drops:
`effects in normal human eyes," Br. J. Ophthalmol. 73:419-26 (1989)
`Villumsen and Alm, "Ocular effects of two different prostaglandin F2α
`esters: a doublemasked cross-over study on normotensive eyes," Acta
`Ophthalmol. 68:341-343 (1990)
`
`2013
`
`2014
`
`iii
`
`

`

`Exhibit
`No.
`
`Document
`
`2015
`
`2016
`2017
`
`2018
`
`2019
`
`2020
`
`Camras and Alm, "Initial Clinical Studies with Prostaglandins and
`Their Analogues," Surv. Ophthalmol. 41(Suppl. 2):S61-S68 (1997)
`Camras, "Prostaglandins," in The Glaucomas 69:1449-1461 (1996)
`European Patent Application No. 0364417 A1
`Qiu, "Revisit Rescula and Cystoid Macular Edema and Refractory
`Glaucoma," J. Clin. Exp. Ophthalmol. 6:5 (2015)
`"R-Tech Ueno Starts Early Phase II Clinical Trial For RK-023" (2009)
`Schoenwald and Ward, "Relationship between Steroid Permeability
`across Excised Rabbit Cornea and Octanol-Water Partition
`Coefficients, " J. Pharm. Sci. 67(6):786-788 (1978)
`Klimko et al., "15-Fluoro prostaglandin FP agonists: a new class of
`topical ocular hypotensives," Bioorg. Med. Chem. 12:3451-3469
`(2004)
`2022 WO 1995/026729
`
`2021
`
`
`
`
`
`iv
`
`

`

`
`
`I.
`
`INTRODUCTION
`
`Patent Owners Santen Pharmaceutical Co., Ltd. and Asahi Glass Co., Ltd.
`
`(together, "Patent Owner") submit this Preliminary Response to the Petition for
`
`inter partes review of claims 1-14 of U.S. Patent No. 5,886,035 ("the '035 Patent"),
`
`filed by Micro Labs Limited and Micro Labs USA Inc. (together, "Petitioner" or
`
`"Micro Labs"). As detailed herein, and in the accompanying Declarations of
`
`Timothy L. Macdonald, Ph.D. (a leading expert with respect to the medicinal
`
`chemistry and molecular pharmacology of lipid signaling systems) and Robert D.
`
`Fechtner, M.D. (a renowned ophthalmologist and glaucoma expert), Petitioner has
`
`not established a reasonable likelihood of unpatentability as to any claim of the
`
`'035 Patent. Patent Owner respectfully requests that the Board deny the Petition in
`
`its entirety, such that inter partes review is not instituted as to any claim of the '035
`
`Patent.
`
`The claims of the '035 Patent are generally directed to a genus of compounds
`
`(and particular species) which includes tafluprost - the active ingredient of
`
`Zioptan® eye drops for the treatment of glaucoma and ocular hypertension.
`
`Tafluprost is a "prostaglandin analog," i.e., a derivative of a diverse class of
`
`naturally-occurring compounds known as prostaglandins. In particular, tafluprost
`
`is 16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranor prostaglandin F2α
`
`1
`
`

`

`
`
`("PGF2α") isopropyl ester ("IE"), where each carbon of the skeleton is numbered
`
`sequentially, beginning with C1:
`
`
`
`Because prostaglandins and their analogs typically interact with multiple cellular
`
`receptors - which mediate a wide array of distinct biological activities - side effects
`
`are often a problem. For example, in the context of glaucoma and ocular
`
`hypertension, the primary therapeutic goal is lowering pressure in the eye (i.e.,
`
`intraocular pressure or "IOP"). Since as early as 1977, it was known that certain
`
`prostaglandins possessed such activity. But intolerable side effects, including
`
`conjunctival hyperemia (eye redness), eye irritation and pain, and headaches
`
`featured in early trials of naturally-occurring PGF2α for IOP-lowering. As of
`
`December 26, 1996 (after two decades of research efforts), only two prostaglandin
`
`analogs had been marketed for the treatment of glaucoma and ocular hypertension:
`
`latanoprost (approved in the U.S. in June 1996) and isopropyl unoprostone
`
`(approved in Japan in October 1994). Although latanoprost and isopropyl
`
`unoprostone reduced certain side effects, they had their own deficiencies.
`
`Latanoprost exhibited other significant side effects, e.g., iridial pigmentation
`
`2
`
`

`

`
`
`(discoloration of the iris of the eye) due to increased production of melanin
`
`pigment. Isopropyl unoprostone, in turn, exhibited less effectiveness than
`
`latanoprost and at least 20 times less potency. In contrast, in the '035 Patent,
`
`tafluprost demonstrated similar or better IOP-lowering activity than latanoprost,
`
`but without the excessive melanin production induced by latanoprost.
`
`A number of significant structural differences account for those functional
`
`differences. Tafluprost departed in 3 key respects from the commercially-available
`
`prostaglandin analogs as of December 26, 1996 (shown with the parental PGF2α-IE
`
`compound below):
`
`Of the above compounds, only tafluprost incorporates two fluorines at the 15
`
`position (indicated in blue above) instead of the single hydroxyl (-OH) group of
`
`
`
`3
`
`

`

`
`
`the naturally-occurring PGF2α prostaglandin (which was believed to be critical for
`
`IOP-lowering activity); tafluprost also uniquely incorporates a phenoxy group at
`
`the 16 position (indicated in red above).
`
`The Petition should be denied in its entirety. It is undisputed that the prior
`
`art does not expressly disclose tafluprost or the broader claimed genus. Petitioner
`
`instead argues in two grounds of unpatentability that the tafluprost compound
`
`would have been obvious as of December 26, 1996 over the piecemeal
`
`combination of 3-5 alleged prior art references. Impermissible hindsight is the
`
`driving force behind both obviousness grounds.
`
`As an initial matter, both of Petitioner's obviousness grounds feature a fatal
`
`flaw in the selection of the alleged lead compound - "Compound C" of Klimko
`
`(Ex. 1003). Petitioner cherry-picks Compound C as a lead compound based on
`
`certain structural similarities to tafluprost. But, instead of directing a POSITA to
`
`Compound C as a lead compound, Klimko does the opposite. Klimko explicitly
`
`teaches away from further development of Compound C due to an
`
`"unacceptable therapeutic profile," i.e., "an initial increase in IOP" and severe
`
`side effects such as "unacceptable hyperemia." Ex. 1003 at 3:39-44 (underlining in
`
`original).
`
`The medicinal chemistry of prostaglandins was highly unpredictable as of
`
`December 26, 1996 (and remains so today); there is a wide range of distinct
`
`4
`
`

`

`
`
`biological activities and side effects without known, direct correlation to structure.
`
`Indeed, decades of intensive research yielded only two commercially-available
`
`prostaglandin analogs for the treatment of glaucoma and ocular hypertension - that
`
`nonetheless featured undesirable side effects or low potency. And yet, Petitioner
`
`advances two obviousness grounds that assume a POSITA would somehow
`
`discount the severe side effects of Compound C based on a reasonable expectation
`
`of eliminating such side effects with chemical modification.
`
`It is readily apparent that impermissible hindsight dictates Petitioner's
`
`convoluted, proposed trajectory from Compound C to tafluprost:
`
` replacing the C15 hydroxyl with a hydrogen to diminish side effects
`
`(based on Kishi (Ex. 1004)), despite the undisputed expectation of a
`
`reduction in IOP-lowering activity;
`
` replacing the C15 hydrogen of Kishi with fluorine (based on Bezuglov
`
`1982 (Ex. 1007), Bezuglov 1986 (Ex. 1008) and/or Ueno Japan (Ex.
`
`1006)), in order to mimic the hydroxyl group that had just been
`
`removed, in the hopes of restoring the IOP-lowering activity while
`
`somehow not also reinstating Compound C's severe side effects;
`
` inserting two fluorines at C15 (based on Ueno Japan), even though
`
`that difluoride bears little (if any) resemblance to the one hydroxyl
`
`that the modification is meant to mimic.
`
`5
`
`

`

`
`
`There would have been no motivation for a POSITA to pursue Petitioner's
`
`elaborate and unpredictable combination with a reasonable expectation of success.
`
`Critically, none of the asserted prior art references discloses any fluorinated
`
`compound with demonstrated IOP-lowering activity or an acceptable ocular
`
`side effect profile. As for the only asserted prior art reference that discloses
`
`difluorination of a prostaglandin - Ueno Japan - it has nothing to do with IOP-
`
`lowering or ocular side effects. Ueno Japan is directed to allergic, inflammatory,
`
`liver and biliary diseases. Ueno Japan would not have motivated a POSITA to
`
`incorporate two fluorines at the C15 position of Compound C of Klimko.
`
`Petitioner's reliance on the unpublished Klimko '671 patent application (Ex.
`
`1012) - which is neither prior art, nor state of the art - is likewise misplaced.
`
`Klimko '671 expressly excludes difluorination at the C15 position of a
`
`prostaglandin analog. Klimko '671 stands for the counterintuitiveness of
`
`tafluprost, with its difluorination at the C15 position for purposes of IOP-lowering.
`
`The Board should reject both Grounds. Petitioner has not established a
`
`reasonable likelihood of unpatentability as to any claim of the '035 Patent.
`
`II. BACKGROUND
`
`A.
`
`State of the Art as of the Priority Date
`of the '035 Patent, December 26, 1996
`
`Glaucoma is a leading cause of irreversible vision loss worldwide. Ex.
`
`2002, ¶16. It is a group of diseases of the optic nerve that is commonly associated
`
`6
`
`

`

`
`
`with elevated pressure in the eye (above ~21 mm Hg), i.e., elevated IOP. Id.
`
`Patients with high IOP, but without optic nerve damage or vision loss, are
`
`classified as having ocular hypertension. Id. In both glaucoma and ocular
`
`hypertension, the primary therapeutic goal is reduction of IOP. Id.
`
`Since at least as early as 1977, researchers investigated the potential use of
`
`prostaglandins to reduce IOP. Ex. 2001, ¶ 18 (citing Ex. 2003). However, as of
`
`December 26, 1996 (nearly two decades later), only two prostaglandin analogs had
`
`made it to market. Id. Xalatan® (latanoprost), developed by Pharmacia &
`
`Upjohn, was approved earlier in 1996 in the US, but only as second-line treatment.
`
`Id. (citing Ex. 2004). A second drug, Rescula® (isopropyl unoprostone),1
`
`developed by R-Tech Ueno, had been marketed in Japan since 1994, but there was
`
`limited experience with the drug outside of Japan, and it had not been approved yet
`
`in US or Europe. Id. (citing Ex. 2006 at 22).
`
`
`1 In recent years, it has been determined that isopropyl unoprostone is not a
`
`prostaglandin analog; it is now considered to be a "docosanoid" (a derivative of
`
`docosahexaenoic acid) that exhibits virtually no binding to prostaglandin receptors.
`
`Ex. 2001, ¶ 18 (citing Ex. 2005 at 2).
`
`2 Except for citations to patents and patent publications (which refer to the
`
`originally-published column and line numbers) and citations to the declarations
`
`7
`
`

`

`
`
`Prostaglandins are lipid compounds with the 20-carbon skeleton of
`
`prostanoic acid, which includes an alpha chain (α-chain), a cyclopentane ring, and
`
`an omega chain (ω-chain):
`
`
`
`Id., ¶ 19 (citing Ex. 1026 at 1). As illustrated above, it was known that each
`
`carbon of the skeleton was numbered sequentially, C1 through C20. Id.
`
`As of December 26, 1996, prostaglandins were broken down into subclasses,
`
`A through J, based on the functional groups of the cyclopentane ring, e.g.:
`
`
`
`Id., ¶ 20 (citing Ex. 1026 at 1-2). (In the case of PGF, the stereochemistry of the
`
`hydroxyl (-OH) group at the C9 position was indicated by an α or β designation.
`
`Id.) It was known that such small structural differences lead to preferential binding
`
`to different classes of receptors; for example, PGD, PGE, PGF and PGI
`
`
`(which refer to the paragraph number), this Preliminary Response cites to the page
`
`numbers added at the bottom of each Exhibit.
`
`8
`
`

`

`
`
`preferentially bind DP, EP, FP and IP receptors, respectively. Id. (citing Ex. 2007
`
`at 3).
`
`As of December 26, 1996, it was known that naturally-occurring
`
`prostaglandins contained a hydroxyl group at the C15 position, as well as a trans
`
`double bond between C13 and C14. Id., ¶ 21 (citing Ex. 1026 at 1-2). (PGG was
`
`the lone exception, as it contains a C15 hydroperoxyl (-O-OH) group, rather than a
`
`C15 hydroxyl; but it was believed to be quickly converted in vivo to PGH. Id.)
`
`Prostaglandins were further classified by the numbers 1 through 3, representing the
`
`number of double bonds, e.g., PGE1 (1 double bond) or PGF2α (2 double bonds).
`
`Id. For example, PGF2α contained the requisite C15 hydroxyl and C13-C14 trans
`
`double bond, as well as a second cis double bond at the C5-C6 position:
`
`
`
`Id. It was known as of December 26, 1996 that such structural differences among
`
`prostaglandins - and the resulting preferential binding to different receptors -
`
`manifest in a wide-range of biological activities (e.g., constriction or dilation of
`
`smooth muscle of circulatory, respiratory and gastrointestinal systems, aggregation
`
`or disaggregation of platelets, uterine contraction, regulation of hormones,
`
`9
`
`

`

`
`
`regulation of inflammation, regulation of gastric acid, bicarbonate and mucus
`
`secretion, and regulation of mucosal integrity). Id., ¶ 22 (citing Ex. 2008 at 5-11;
`
`Ex. 2007 at 2).
`
`And yet, certain structural similarities among the prostaglandins (i.e., the
`
`prostanoic acid skeleton, C15 hydroxyl, C13-C14 trans double bond, and some
`
`shared functional groups on the cyclopentane ring) are associated with
`
`promiscuous, overlapping binding of multiple receptors to varying degrees - and
`
`trigger undesirable side effects. Id., ¶ 23 (citing Ex. 2009 at 2; Ex. 2010 at 1).
`
`As of December 26, 1996, medicinal chemistry was a highly unpredictable
`
`art, and it remains so to this day. Id., ¶ 24. This is especially true with respect to
`
`prostaglandins - a large class of compounds with distinct, yet overlapping, receptor
`
`profiles, associated with a wide range of biological activities. Id. (citing Ex. 2010
`
`at 1-2). Because of the complex relationship for prostaglandins between chemical
`
`structure and biological activity ("SAR"), there was slow progress toward a
`
`feasible prostaglandin-based compound for the reduction of IOP in patients with
`
`glaucoma and ocular hypertension. Id., ¶ 25. As of 1977, researchers knew, based
`
`on animal studies, of the potential IOP-reducing activity of prostaglandins. Id.
`
`(citing Ex. 2003). And, by 1985, it had been demonstrated that PGF2α could lower
`
`IOP in humans. Id. (citing Ex. 2011). However, administration of PGF2α also
`
`caused severe side effects, including conjuctival hyperemia (eye redness), eye
`
`10
`
`

`

`
`
`irritation and pain, and headaches. Id. (citing Ex. 2011 at 1, 3). Such side effects
`
`made prostaglandins an unattractive therapeutic option. Id. There had also been
`
`concern regarding the initial increase in IOP after administration of
`
`prostaglandins, an unacceptable outcome for a drug intended to reduce IOP. Id.
`
`(citing Ex. 2003 at 1). Intensive research and development efforts pursued a
`
`prostaglandin analog that could significantly reduce IOP while minimizing side
`
`effects. Id.
`
`Subsequent efforts unsuccessfully focused on esterification of PGF2α, a
`
`modification previously shown to increase potency. Id., ¶ 26. For example,
`
`researchers investigated the following isopropyl ester (indicated in red) of PGF2α
`
`("PGF2α-IE"):
`
`
`
`Id. (citing Ex. 2012). It was found that the enhanced potency of PGF2α-IE was due
`
`to enhanced penetration of the compound into the eye. Id. (citing Ex. 2012 at 7).
`
`PGF2α-IE acted as a pro-drug, and converted inside the eye to the active, free-acid
`
`form of PGF2α. Id. However, while PGF2α-IE analog provided enhanced
`
`bioavailability and IOP-lowering activity, it did not eliminate the side effects
`
`11
`
`

`

`
`
`plaguing the naturally-occurring PGF2α compound: "The use of very low doses of
`
`PGF2α, made possible with the increased lipid solubility of the ester, did not cause
`
`a sufficiently efficient separation of effect and subjective side effects." Ex. 2013 at
`
`7.
`
`Similarly, because the C15 hydroxyl was believed to be essential for
`
`biological activity in prostaglandins, researchers attempted - again unsuccessfully -
`
`to esterify PGF2α at the C15 hydroxyl. Ex. 2001, ¶ 27 (citing Ex. 2014). The hope:
`
`the prostaglandin analog would exhibit decreased activity until penetrating the eye,
`
`resulting in decreased side effects. Id. (citing Ex. 2014 at 1). However, again, the
`
`researchers observed that the new compound did not "provide[] a better separation
`
`between effect [on IOP] and side effects than PGF2α-IE." Ex. 2014 at 3. The
`
`researchers expressly noted that "[o]ur results indicate that more radical changes of
`
`the parent molecule may be necessary to achieve this goal." Id.
`
`As explained above, as of December 26, 1996, there were only two
`
`prostaglandin analogs approved for reduction of IOP: Xalatan® (latanoprost) and
`
`isopropyl unoprostone. Ex. 2001, ¶ 28. Latanoprost is 13,14-dihydro-17-phenyl-
`
`18,19,20-trinor-PGF2α-IE:3
`
`
`3 The prefix "-nor" indicates the removal of carbon atoms from a parent compound;
`
`"trinor" indicates the removal of three carbon atoms, C18, C19 and C20. Ex. 2001,
`
`¶ 28.
`
`12
`
`

`

`
`
`
`
`Id. (citing Ex. 2009 at 2). Unlike PGF2α-IE, latanoprost replaced C18, C19 and
`
`C20 on the ω-chain with a phenyl group, and included a C13-C14 single bond
`
`(rather than a double bond). Id. Heralded as an improvement over PGF2α and
`
`PGF2α-IE, latanoprost exhibited less eye irritation and hyperemia, while
`
`maintaining significant IOP-lowering activity. Id. Nevertheless, latanoprost
`
`exhibited other significant side effects, e.g., iridial pigmentation (discoloration of
`
`the iris of the eye). Id. (citing Ex. 2004).
`
`As of December 26, 1996, isopropyl unoprostone was the only other
`
`commercially-available drug for IOP-reduction, but was not available in most (if
`
`not all) countries outside of Japan, including the US or Europe. Id. ¶ 29. Isopropyl
`
`unoprostone is 13,14-dihydro-15-keto-20-ethyl-PGF2α-IE:
`
`
`
`13
`
`

`

`
`
`Id. (citing Ex. 2006 at 4). Isopropyl unoprostone takes a very different approach,
`
`structurally, than latanoprost. Id. There is no 17-phenyl group on a shortened ω-
`
`chain; instead the ω-chain is lengthened by 2 carbons. Id. Moreover, the C15
`
`hydroxyl is converted to a ketone. Id. Indeed, it had been reported that isopropyl
`
`unoprostone targeted a different receptor than latanoprost; latanoprost targeted the
`
`FP receptor, whereas isopropyl unoprostone had very little affinity for that
`
`receptor. Id. (citing Ex. 2006 at 5, 8). Also, compared to latanoprost, isopropyl
`
`unoprostone was less effective and at least 20 times less potent. Id. (citing Ex.
`
`2015 at 6; Ex. 2016).
`
`Notably, both commercially available prostaglandin analogs as of December
`
`26, 1996 contained significant structural differences compared to Patent Owner's
`
`tafluprost compound (16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-
`
`tetranorprostaglandin F2α, isopropyl ester), the subject of this proceeding:
`
`
`
`Id., ¶ 30. Neither of the commercially available prostaglandin analogs as of
`
`December 26, 1996 was fluorinated (let alone difluorinated, and at the C15
`
`position specifically, as shown in blue above), neither contained a 16-phenoxy
`
`14
`
`

`

`
`
`group (as shown in red above), and neither contained a C13-C14 double bond (as
`
`shown in green above). Id.
`
`B.
`
`The '035 Patent
`
`The '035 Patent is generally directed to "15,15-difluoro-15-deoxy-PGF2α and
`
`its derivatives and their use as medicines, in particular, as medicines for eye
`
`diseases," and preferably for "glaucoma or ocular hypertension." Ex. 1001 at
`
`2:16-18, 2:65-67; see also id. at 19:29-31 ("[T]he medicine of the present invention
`
`is effective as a therapeutic agent, particularly for glaucoma or ocular
`
`hypertension."). The inventive compounds include tafluprost (16-phenoxy-15-
`
`deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglandin F2α, isopropyl ester),
`
`which is within the scope of all of the claims of the '035 Patent, and is the sole
`
`subject of the Petitioner's obviousness arguments. Id. at 14:25-26, 22:36-23:15
`
`(Example 9), 31:1-32:31 (claims). Unlike the commercially-available
`
`prostaglandin analogs of the time, tafluprost was C15 difluorinated, contained a
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`16-phenoxy group, and a C13-C14 double bond.
`
`The specification explains that naturally-occurring PGF compounds are able
`
`to lower IOP, but "they are irrita[ting] to the eye and have a problem of their
`
`inflammatory side effects such as congestion and damage to the cornea." Id. at
`
`1:11-18. As a result, research into prostaglandin derivatives for the treatment of
`
`glaucoma focused on achieving a suitable side effect profile. Id. at 1:18-21.
`
`15
`
`

`

`
`
`Although licensed as of December 26, 1996 for the treatment of glaucoma and
`
`ocular hypertension, latanoprost still caused certain undesirable side effects, with
`
`room for improvement in the duration of efficacy. Id. at 1:31-43. With respect to
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`side effects, latanoprost was known to induce melanin production, causing "iridial
`
`pigmentation," i.e., discoloration of the iris of the eye. Id. at 1:40-43. "For this
`
`reason, 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.
`
`The inventors of the '035 Patent discovered that 15,15-difluoro-15-deoxy-
`
`PGF2α and its derivatives overcame the problems plaguing the prior art, and
`
`provided longer-lasting efficacy:
`
`[T]he present inventors have found 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. They are
`
`characterized in that they stimulate[] melanogenesis [i.e., melanin
`
`production, causing eye discoloration] much less as well as in that
`
`their efficacy lasts longer than Latanoprost.
`
`Id. at 2:7-15.
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`In addition to C15 difluorination, the inventors also emphasized a preference
`
`for omega chains departing from that of the naturally-occurring prostaglandin:
`
`16
`
`

`

`
`
`"[A]mong the fluorine-prostaglandin derivatives of the present invention, those
`
`having an ω-chain which is not of the naturally occurring type . . . are preferred."
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`Id. at 2:59-62. For example, the omega chain of tafluprost terminates with a 16-
`
`phenoxy group. Id. at 14:25-26 ("16-phenoxy-15-deoxy-15,15-difluoro-
`
`17,18,19,20-tetranorprostaglandin F2α, isopropyl ester") (emphasis added).
`
`In Example 23, the inventors compared latanoprost against four compounds
`
`of the '035 Patent (referred to as Compounds A-D4), with respect to IOP-lowering
`
`and melanogenesis. Id. at 28:1-30:67. The '035 Patent compounds included
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`tafluprost (referred to as "Compound D"), as well as 16-phenoxy-15-deoxy-15,15-
`
`difluoro-17,18,19,20-tetranorprostaglandin F2α methyl ester (which shares the same
`
`free acid form as tafluprost and is referred to as "Compound A"). Id. at 27:7-39.
`
`Table 1 reports on the IOP-lowering efficacy of the tested compounds, after
`
`a single administration to macaques:
`
`
`4 The '035 Patent and Petitioner's primary prior art reference (Klimko) both
`
`disclose compounds designated Compounds A-D. Other than this section of this
`
`Preliminary Response (summarizing the '035 Patent), references to Compounds A-
`
`D are to the compounds disclosed in Klimko, not the '035 Patent.
`
`17
`
`

`

`
`
`
`
`Id. at 28:16-49. The inventors observed that "the intraocular pressure had already
`
`started to decrease 4 hours after the application of compounds of the present
`
`invention and was still decreasing even 8 hours after the application." Id. at 28:50-
`
`53. In comparison to latanoprost, "Compound A lowered the intraocular pressure
`
`twice as much as Latanoprost did 6 hours after application, and about 4 times as
`
`much 8 hours after application." Id. at 28:53-56. Compound D (tafluprost)
`
`performed similarly to latanoprost at 4 and 6 hours after application, but at 8 hours,
`
`it lowered IOP about 2-3 times more than latanoprost. Id. at 28:35-49 (Table 1).
`
`This data "proves that the compound of the present invention has a long-lasting
`
`effect of lowering intraocular pressure." Id. at 28:57-58.
`
`Table 2 reports on IOP-lowering efficacy after a two week repeated
`
`application test in macaques:
`
`18
`
`

`

`
`
`
`
`Id. at 28:59-29:33. For the '035 Patent compounds in general, "the intraocular
`
`pressure had remarkably decreased since the 3rd day from the start of the
`
`application . . . and kept low till the 14th day." Id. at 29:34-37. Tafluprost
`
`(Compound D), in particular, "lowered intraocular pressure about 2 to 8 times as
`
`much as Latanoprost did." Id. at 29:37-38. And, no side effects were noted. Id. at
`
`29:39-41 ("When the intraocular pressures were measured, no turbid cornea,
`
`abnormal conjunctiva vessels, conjunctivoma or secretions were observed."). As
`
`with the data in Table 1 after a single application, the results after the two week
`
`repeated application test "proves that the compound of the present invention has an
`
`excellent effect of lowering intraocular pressure." Id. at 29:42-43.
`
`The inventors of the '035 Patent also investigated the effect of their novel
`
`compounds on melanogenesis in B16 pigment cells, as compared to latanoprost.
`
`Id. at 29:44-30:52. The free acid forms (i.e., the active forms in the body) of
`
`Compounds A-D were evaluated; because tafluprost (Compound D) and
`
`19
`
`

`

`
`
`Compound A have the same free acid form, Compound A's results are reported.
`
`Id. at 30:35-37, 30:40-41. Table 3 presented the results:
`
`Id. at 30:42-52. Each of the tested '035 Patent compounds performed better than
`
`latanoprost with respect to avoiding melanogenesis:
`
`
`
`As is evident from Table 3, compounds of the present invention did
`
`not have much effect and, the melanin contents in the presence of 100
`
`μM of them were only about 1.1 to 1.3 times higher than that in the
`
`absence of them. On the other hand, when Latanoprost was added at
`
`concentrations of 10 μM and 100 μM, the melanin contents were
`
`about 1.4 times and about 2.2 times, respectively, higher than that in
`
`its absence.
`
`Id. at 30:53-60. "This proves that compounds of the present invention have little
`
`effect on melanogenesis and do not cause irid[i]al pigmentation when applied
`
`repeatedly." Id. at 30:61-63.
`
`Overall, "[t]he results of the pharmacological tests clearly indicate that the
`
`compounds of the present invention are useful as long-lasting therapeutic
`
`20
`
`

`

`
`
`medicines for glaucoma, are hardly irritant to the eye and have little effect on
`
`melanogenesis." Id. at 30:64-67.
`
`Consistent with the data of the '035 Patent - demonstrating the advantages of
`
`the disclosed compounds over the prior art - independent claim 1 of the '035 Patent
`
`recites a genus of 15,15-difluoro-15-deoxy-PGF2α analogs, in which the omega
`
`chain is terminated by an aryloxyalkyl group:
`
`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 ethynylene
`
`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
`
`hydr