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 RESPONSE
`
`
`
`
`
`

`

`TABLE OF CONTENTS
`
`TABLE OF AUTHORITIES ................................................................................... iii
`
`LIST OF EXHIBITS ................................................................................................. iv
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`II.
`
`BACKGROUND ............................................................................................. 7
`
`A.
`
`B.
`
`C.
`
`State of the Art as of the Priority Date
`of the '035 Patent, December 26, 1996 ................................................. 7
`
`The '035 Patent .................................................................................... 15
`
`Prosecution History of the '035 Patent ................................................ 23
`
`III. LEVEL OF ORDINARY SKILL IN THE ART ........................................... 23
`
`IV. CLAIM CONSTRUCTION .......................................................................... 25
`
`V.
`
`CLAIMS 1-14 OF THE '035 PATENT WOULD
`NOT HAVE BEEN OBVIOUS AS OF DECEMBER 26, 1996 .................. 25
`
`A.
`
`Legal Standard Regarding Obviousness
`Based on Identification of an Alleged Lead Compound ..................... 26
`
`B. A POSITA Would Not Have Considered
`Compound C of Klimko To Be a Suitable Lead Compound .............. 28
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Klimko Expressly Teaches Away
`from Compound C as a Lead Compound ................................. 28
`
`Klimko Does Not Disclose Longer-Lasting
`IOP-Lowering Efficacy by Compound C ................................. 41
`
`Klimko Does Not Disclose Superior IOP-Lowering Efficacy
`by Compound C at Sixteen Hours After the Fourth Dose ........ 44
`
`A POSITA Would Not Have Selected Klimko's
`Compound C as a Lead Compound Based on Kishi ................. 45
`
`Petitioner's Identification of Compound C as a
`Lead Compound Was Improperly Based on Hindsight ............ 46
`
`
`
`i
`
`

`

`C.
`
`D.
`
`Prior Testimony by Petitioner's Main Expert, Dr. deLong,
`Directly Contradicts His Opinions in this Proceeding ........................ 47
`
`It Would Not Have Been Obvious to Modify
`Compound C of Klimko by C15 Fluorination .................................... 51
`
`1.
`
`2.
`
`A POSITA Would Not Have Been Motivated
`with a Reasonable Expectation of Success to Apply
`the Kishi Modification to Compound C of Klimko .................. 51
`
`A POSITA Would Not Have Been Motivated with a
`Reasonable Expectation of Success to
`Modify Compound C of Klimko Using both
`the Kishi Modification and C15 Fluorination ........................... 53
`
`E.
`
`It Would Not Have Been Obvious
`to Difluorinate Compound C of Klimko ............................................. 57
`
`1.
`
`2.
`
`Ueno Japan Is Irrelevant to IOP Lowering and Does
`Not Teach Any Particular Benefit of C15 Difluorination ........ 57
`
`A POSITA Would Have Considered C15 Difluorination
`To Be a Radical Departure from Compound C of Klimko ....... 61
`
`F.
`
`Klimko Specifically Excluded C15 Difluorinated
`Compounds from the Scope of Its Work ............................................. 63
`
`G.
`
`Secondary Considerations ................................................................... 65
`
`1.
`
`2.
`
`3.
`
`4.
`
`Commercial Success/Copying .................................................. 65
`
`Unexpected Results ................................................................... 66
`
`Long-Felt but Unmet Need ....................................................... 67
`
`Failure of Others ....................................................................... 69
`
`VI. CONCLUSION .............................................................................................. 70
`
`CLAIM LISTING APPENDIX ............................................................................... 71
`
`CERTIFICATE OF COMPLIANCE ....................................................................... 74
`
`CERTIFICATE OF SERVICE ................................................................................ 75
`
`
`
`ii
`
`

`

`TABLE OF AUTHORITIES
`
`Cases
`
`Eli Lilly and Co. v. Zenith Goldline Pharms., Inc.,
`471 F.3d 1369 (Fed. Cir. 2006) ............................................................................49
`
`Otsuka Pharm. Co. v. Sandoz, Inc.,
`678 F.3d 1280 (Fed. Cir. 2012) ............................................................... 27, 28, 30
`
`Pfizer Inc. v. Teva Pharm. USA, Inc.,
`555 F. App'x 961 (Fed. Cir. 2014) ........................................................... 26, 27, 46
`
`PPC Broadband, Inc. v. Corning Optical Commc'ns RF LLC,
`815 F.3d 734 (Fed. Cir. 2016)...............................................................................66
`
`Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd.,
`492 F.3d 1350 (Fed. Cir. 2007) ......................................................... 27, 28, 29, 47
`
`
`
`
`
`
`
`
`
`iii
`
`

`

`LIST OF EXHIBITS
`
`Document
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`
`2008
`
`2009
`
`2010
`
`2011
`
`2012
`
`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
`
`
`
`iv
`
`

`

`Exhibit
`No.
`
`Document
`
`2015
`
`2016
`2017
`
`2018
`
`2019
`
`2020
`
`2021
`
`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
`2023 U.S. Patent No.5,977,173 to Wos et al.
`Lee et al., "Pharmacological testing in the laser- induced monkey
`glaucoma model," Curr. Eye Res. 4(7):775-781 (1985)
`Transcript of Deposition of Mitchell deLong, Ph.D. (Feb. 13, 2018)
`Transcript of Deposition of Aron Rose, M.D. (Feb. 14, 2018)
`Alcon Canada Inc. v. Apotex Inc., 2014 FC 699 (Fed. Ct. CA, 2014)
`Supplemental Declaration of Timothy L. Macdonald, Ph.D.
`Supplemental Declaration of Robert D. Fechtner, M.D.
`Santen Pharmaceutical Co., Ltd. Third Quarter Financial Results for
`the Fiscal Year Ending March 31, 2018 [IFRS] (Consolidated),
`available at http://v4.eir-
`parts.net/v4Contents/View.aspx?cat=tdnet&sid=1551881, link
`provided at http://www.santen.com/en/news/2018.jsp
`Takagi et al., "Pharmacological characteristics of AFP-168
`(tafluprost), a new prostanoid FP receptor agonist, as an ocular
`hypotensive drug," Exp. Eye Res. 78:767-776 (2004)
`Zioptan® (tafluprost) Product Label, available at
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/202514s0
`03s004lbl.pdf
`JP-A-7070054 to Ueno Japan et al. (Patent Owner's Certified English
`Translation)
`Wang et al., "Effect of 8-iso prostaglandin E-2 on aqueous humor
`dynamics in monkeys," Arch. Ophthalmol. 116(9):1213-1216 (1998)
`
`2024
`
`2025
`2026
`2027
`2028
`2029
`
`2030
`
`2031
`
`2032
`
`2033
`
`2034
`
`
`
`v
`
`

`

`Exhibit
`No.
`
`Document
`
`2035
`
`2036
`
`2037
`
`2038
`
`2039
`
`2040
`
`2041
`
`2042
`
`2043
`
`2044
`
`2045
`
`2046
`
`Aung et al., "A randomized double-masked crossover study comparing
`latanoprost 0.005% with unoprostone 0.12% in patients with primary
`open-angle glaucoma and ocular hypertension," Am. J. Ophthalmol.
`131(5):636-642 (2001)
`Aung et al., "Additive effect of unoprostone and latanoprost in patients
`with elevated intraocular pressure," Br. J. Ophthalmol. 86:75–79
`(2002)
`Xalatan® (latanoprost) Product Label, available at
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020597s0
`51lbl.pdf
`Lumigan® (bimatoprost) 0.03% Product Label, available at
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021275s0
`27lbl.pdf
`Lumigan® (bimatoprost) 0.01% Product Label, available at
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022184s0
`06lbl.pdf
`Travatan® (travoprost) Product Label, available at
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021257s0
`25lbl.pdf
`Travatan Z® (travoprost) Product Label, available at
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021994s0
`12lbl.pdf
`Rescula® (isopropyl unoprostone) Product Label, available at
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021214s0
`06s007lbl.pdf
`Iopidine® (apraclonidine) Product Label, available at
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020258s0
`30lbl.pdf
`Tapros Medication Guide, available at http://www.rad-
`ar.or.jp/siori/english/kekka.cgi?n=33409
`Complaint, Santen Pharmaceutical Co., Ltd., Asahi Glass Co., Ltd.,
`and Oak Pharmaceuticals, Inc. v. Micro Labs Limited and Micro Labs
`USA Inc., Case No. 16-cv-353 (D. Del.), Dkt. 1, filed May 13, 2016
`Complaint, Santen Pharmaceutical Co., Ltd., Asahi Glass Co., Ltd.,
`and Oak Pharmaceuticals, Inc. v. Sandoz Inc., Case No. 16-cv-354 (D.
`Del.), Dkt. 1, filed May 13, 2016
`
`
`
`vi
`
`

`

`Exhibit
`No.
`
`2047
`
`2048
`
`Document
`
`Dunitz et al., "Organic Fluorine Hardly Ever Accepts Hydrogen
`Bonds," Chem. Eur. J. 3(1):89-98 (1997)
`Carey and Sundberg, "3: Conformational, Steric, and Stereoelectronic
`Effects," in Advanced Organic Chemistry, Part A: Structure and
`Mechanism (2nd ed. 1984)
`
`
`
`
`
`
`
`vii
`
`

`

`
`
`I.
`
`INTRODUCTION
`
`Patent Owners Santen Pharmaceutical Co., Ltd. and Asahi Glass Co., Ltd.
`
`(together, "Patent Owner") submit this Patent Owner 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 that any claim of the '035 Patent is unpatentable.
`
`The claims of the '035 Patent are generally directed to a genus of compounds
`
`(and particular species) which includes tafluprost - the active ingredient of, for
`
`example, Zioptan® and Tapros 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 ("PGF2α") isopropyl ester ("IE"), where each carbon of the
`
`skeleton is numbered sequentially, beginning with C1:
`
`
`
`1
`
`

`

`
`
`
`
`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).
`
`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):
`
`
`
`
`
`2
`
`

`

`
`
`
`
`
`
`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
`
`the naturally-occurring PGF2α prostaglandin (which was believed to be critical for
`
`IOP-lowering activity). In fact, Petitioner's expert, Dr. deLong, admitted that he
`
`was not aware of any C15-difluorinated PGF2α analogs for glaucoma or ocular
`
`hypertension prior to December 26, 1996. Ex.2025, 186:17-23. 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
`
`
`
`3
`
`

`

`
`
`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), i.e., 16-phenoxy-17,18,19,20-tetranor PGF2α isopropyl ester. As,
`
`Petitioner's expert, Dr. deLong, conceded at deposition, the structure of tafluprost
`
`dictated Petitioner's selection of Compound C as lead compound - made in
`
`hindsight. Ex.2025, 79:6-22. But, Klimko does not direct 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, 3:39-44 (underlining in
`
`original). And yet, Petitioner's experts, Drs. deLong and Rose, did not address this
`
`clear teaching away in their declarations.1 In any event, Petitioner's experts freely
`
`admitted at deposition that Klimko was written to teach away from Compound C.
`
`Ex.2025, 141:23-142:3, 143:11-18; Ex.2026, 60:22-61:5, 87:8-17. Incredibly,
`
`Petitioner's experts now take the position that they disagree with the express
`
`
`1 Any new arguments in this respect are improper.
`
`
`
`4
`
`

`

`
`
`conclusions of Klimko - their own primary prior art reference. Ex.2025, 61:25-
`
`62:15, 63:7-15; Ex.2026, 61:9-62:8.
`
`Dr. deLong's opinions in this proceeding should be accorded no weight.
`
`Although Dr. deLong now claims to disagree with Klimko's teaching away from
`
`Compound C, he maintained the opposite position on behalf of Alcon (the assignee
`
`of Klimko). Specifically, in a previous Canadian proceeding involving a
`
`counterpart of Klimko (with identical disclosure), Dr. deLong adopted Klimko's
`
`express teaching. Dr. deLong opined that Compound C "showed what appears to
`
`be an unacceptable degree of hyperemia and was not advanced for further
`
`testing." Ex.2027, ¶314 (emphasis added). He unequivocally took the position
`
`that there "was very little, if any motive, to test any phenoxy prostaglandin
`
`compounds, given the prior art information available." Id., ¶434 (emphasis
`
`added).
`
`The medicinal chemistry of prostaglandins was highly unpredictable as of
`
`December 26, 1996 (and remains so today); there is a wide range of distinct
`
`biological activities and side effects without known, direct correlation to structure.
`
`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
`
`
`
`5
`
`

`

`
`
`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.
`
`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
`
`
`
`6
`
`

`

`
`
`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 the
`
`unpatentability of 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 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., ¶¶16-17.
`
`
`
`7
`
`

`

`
`
`Since at least as early as 1977, researchers investigated the potential use of
`
`prostaglandins to reduce IOP. Ex.2001, ¶18 (citing Ex.2003); Ex.2002, ¶18 (citing
`
`Ex.2003; Ex.2011; Ex.2013; Ex.2014). 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. Ex.2001, ¶18 (citing
`
`Ex.2004); Ex.2002, ¶20. A second drug, Rescula® (isopropyl unoprostone), 2
`
`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. Ex.2001, ¶18 (citing Ex.2006, 23).
`
`
`2 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).
`
`3 Except for citations to patents, patent publications and transcripts (which refer to
`
`the originally-published column/page and line numbers), and to paragraph numbers
`
`where applicable, this Response cites to the IPR page numbers added at the bottom
`
`of each Exhibit.
`
`
`
`8
`
`

`

`
`
`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, 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, 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
`
`preferentially bind DP, EP, FP and IP receptors, respectively. Id. (citing
`
`Ex.2007, 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
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`9
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`
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`double bond between C13 and C14. Id., ¶21 (citing Ex.1026, 1-2). 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
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`smooth muscle of circulatory, respiratory and gastrointestinal systems, aggregation
`
`or disaggregation of platelets, uterine contraction, regulation of hormones,
`
`regulation of inflammation, regulation of gastric acid, bicarbonate and mucus
`
`secretion, and regulation of mucosal integrity). Id., ¶22 (citing Ex.2008, 5-11;
`
`Ex.2007, 2).
`
`And yet, certain structural similarities among the prostaglandins (i.e., the
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`prostanoic acid skeleton, C15 hydroxyl, C13-C14 trans double bond, and some
`
`shared functional groups on the cyclopentane ring) are associated with
`
`
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`10
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`
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`promiscuous, overlapping binding of multiple receptors to varying degrees - and
`
`trigger undesirable side effects. Id., ¶23 (citing Ex.2009, 2; Ex.2010, 1); Ex.2025,
`
`45:9-16, 213:15-24; Ex.2023, 1:67-2:6. Even binding to the same receptor, but in
`
`different tissues, can cause side effects. Ex.2025, 213:25-214:16.
`
`As of December 26, 1996, medicinal chemistry was a highly unpredictable
`
`art, and it remains so to this day. Ex.2001, ¶¶24, 101. 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., ¶24 (citing Ex.2010, 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 irritation and pain, and headaches. Id.
`
`(citing Ex.2011, 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
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`
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`11
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`
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`intended to reduce IOP. Id. (citing Ex.2003, 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, 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
`
`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, 7.
`
`
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`12
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`
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`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, 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, 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:4
`
`
`4 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.
`
`
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`13
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`

`

`
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`Id. (citing Ex.2009, 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.
`
`As of December 26, 1996, isopropyl unoprostone was the only other
`
`commercially-available drug for IOP-reduction, but was not available in most (if
`
`any) countries outside of Japan, including the US or Europe. Id., ¶29. Isopropyl
`
`unoprostone is 13,14-dihydro-15-keto-20-ethyl-PGF2α-IE:
`
`
`
`Id. (citing Ex.2006, 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, 5, 8). Also, compared to latanoprost, isopropyl
`
`unoprostone was less effective and at least 20 times less potent. Id. (citing
`
`Ex.2015, 6; Ex.2016).
`
`
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`14
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`
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`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
`
`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, 2:16-
`
`18, 2:65-67; see also id., 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-
`
`
`
`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., 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
`
`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., 1:11-
`
`18. As a result, research into prostaglandin derivatives for the treatment of
`
`glaucoma focused on achieving a suitable side effect profile. Id., 1:18-21.
`
`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., 1:31-43. With respect to
`
`side effects, latanoprost was known to induce melanin production, causing "iridial
`
`pigmentation," i.e., discoloration of the iris of the eye. Id., 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., 1:44-47.
`
`
`
`16
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`
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`The inventors