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
`
`____________
`
`
`DECLARATION OF TIMOTHY L. MACDONALD, PH.D.
`
`
`
`
`
`IPR Page 1/97
`
`Santen/Asahi Glass Exhibit 2001
`Micro Labs v. Santen Pharm. and Asahi Glass
`IPR2017-01434
`
`
`
`____________
`
`
`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
`
`____________
`
`
`DECLARATION OF TIMOTHY L. MACDONALD, PH.D.
`
`
`
`
`
`IPR Page 1/97
`
`Santen/Asahi Glass Exhibit 2001
`Micro Labs v. Santen Pharm. and Asahi Glass
`IPR2017-01434
`
`
`
`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`II.
`
`QUALIFICATIONS ........................................................................................ 1
`
`III.
`
`SUMMARY OF OPINIONS ........................................................................... 3
`
`IV. STATE OF THE ART AS OF THE PRIORITY DATE
`OF THE '035 PATENT, DECEMBER 26, 1996 ............................................ 6
`
`V.
`
`SUMMARY OF THE '035 PATENT............................................................ 16
`
`VI. PROSECUTION HISTORY FOR THE '035 PATENT ............................... 24
`
`VII. LEVEL OF ORDINARY SKILL IN THE ART ........................................... 27
`
`VIII. CLAIM CONSTRUCTION .......................................................................... 29
`
`IX. OBVIOUSNESS ANALYSIS ....................................................................... 30
`
`A.
`
`The Claimed Tafluprost Compound Would Not
`Have Been Obvious to a POSITA as of December 26, 1996 ............. 33
`
`1.
`
`2.
`
`3.
`
`4.
`
`A POSITA Would Not Have Considered
`Compound C of Klimko as a Lead Compound ........................ 37
`
`It Would Not Have Been Obvious to Modify
`Compound C of Klimko by C15 Fluorination .......................... 49
`
`It Would Not Have Been Obvious
`to Difluorinate Compound C of Klimko ................................... 54
`
`Klimko's Own Inventors Specifically Excluded C15
`Difluorinated Compounds from the Scope of Their Work ....... 61
`
`X.
`
`SECONDARY CONSIDERATIONS ........................................................... 64
`
`
`
`i
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`IPR Page 2/97
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`I, Timothy L. Macdonald, Ph.D., declare and state as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I am Professor of Chemistry, and former Chair of Chemistry, at the
`
`University of Virginia ("UVA"). I also hold a secondary appointment as Professor
`
`of Pharmacology at UVA.
`
`2.
`
`I have been retained on behalf of Patent Owners Santen
`
`Pharmaceutical Co., Ltd. and Asahi Glass Co., Ltd. (together, "Patent Owner") as
`
`an independent expert consultant in the above-referenced inter partes review
`
`("IPR") proceeding, to provide information and opinions on the teachings of the
`
`prior art and the state of the art, as relevant to the issued claims of U.S. Patent No.
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`5,886,035 ("the '035 Patent"). Ex. 1001.
`
`3.
`
`I am being compensated for my time spent in connection with this
`
`matter at my usual rate of $550 per hour. My compensation is in no way
`
`contingent on the outcome of this case.
`
`II. QUALIFICATIONS
`
`4. My full curriculum vitae is attached as Exhibit A to this Declaration,
`
`but I have summarized below some of the relevant aspects in relation to the issues
`
`in this proceeding.
`
`5.
`
`I have approximately 40 years of academic and professional
`
`experience in the field of medicinal chemistry, and over 20 years of overlapping
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`1
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`IPR Page 3/97
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`
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`experience in the field of molecular pharmacology. I received a Bachelor of
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`Science degree with Honors in 1971 from the University of California, Los
`
`Angeles. In 1975, I received a Ph.D. in synthetic organic chemistry from
`
`Columbia University, followed by a postdoctoral fellowship at Stanford University
`
`from 1975 to 1977 (also in synthetic organic chemistry). I held the position of
`
`Assistant Professor of Chemistry at Vanderbilt University from 1977 to 1982.
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`Beginning with my appointment at Vanderbilt, my research was further specialized
`
`in medicinal chemistry. From 1982-1988, I held the position of a tenured
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`Associate Professor of Chemistry at UVA, and I have been a full Professor of
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`Chemistry from 1988 to the present time (with a secondary appointment as
`
`Professor of Pharmacology from 2003 to the present time). During my tenure as
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`Professor at UVA, I have mentored 63 Ph.D. students and approximately 35
`
`postdoctoral fellows, and I served as Chair of Chemistry from 1997 to 2003.
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`6.
`
`I have authored or co-authored more than 200 scientific publications.
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`I am also a named inventor on over 50 issued US patents (and several pending
`
`applications), and I am a founder of 6 biotechnology spin-out companies based on
`
`my research at UVA. I have served as a medicinal chemistry consultant to many
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`pharmaceutical companies, including Allergan, Biogen Idec, Abbott, Wyeth and
`
`SmithKline French, as well as several biotechnology companies.
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`2
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`7.
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`A major focus of my research has been the characterization of lipid
`
`signaling systems that include lipid mediators and their receptors. My research has
`
`involved synthesis of analogs of naturally-occurring lipid compounds (including
`
`agonists and antagonists), and the investigation of structure-activity relationships
`
`("SAR") and molecular pharmacology with respect to such compounds.
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`8. My expertise is generally applicable to lipid signaling systems,
`
`including prostaglandins and prostaglandin receptors. In that regard, for nearly 30
`
`years (approximately 1988-2015), I served as a technical consultant to Allergan (a
`
`leader in the eye care field), and in that capacity, I provided my expertise in
`
`medicinal chemistry and molecular pharmacology in connection with the discovery
`
`and evaluation of novel compounds, including prostaglandin analogs for the
`
`treatment of glaucoma and ocular hypertension. Notably, my work with Allergan
`
`often involved reviewing and evaluating intraocular pressure ("IOP")-lowering and
`
`side effect data from animal studies involving IOP-lowering agents, including
`
`prostaglandin analogs. I have also testified on behalf of Allergan in several patent
`
`litigations involving Lumigan® (bimatoprost) as an expert in medicinal chemistry
`
`and molecular pharmacology.
`
`III. SUMMARY OF OPINIONS
`
`9. My opinions in this Declaration are based on documents I have
`
`reviewed in connection with this proceeding, and are further informed by my
`
`3
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`knowledge and experience, including my decades of experience in medicinal
`
`chemistry and molecular pharmacology. A list of the documents and materials that
`
`I considered in connection with the development of my opinions set forth in this
`
`declaration is attached hereto as Exhibit B.
`
`10.
`
`In my opinion, the claims of the '035 Patent are generally directed to a
`
`genus (and particular species) of 15,15-difluoro-15-deoxy-PGF2α analogs, in which
`
`the omega chain is terminated by an aryloxyalkyl group, as well as medicines
`
`containing one of the claimed compounds as an active ingredient (including
`
`medicines for preventing or treating glaucoma or ocular hypertension). Therefore,
`
`in my opinion, a person of ordinary skill in the art ("POSITA") would have been an
`
`individual or a team with a Ph.D. degree in medicinal or organic chemistry, 3 years
`
`of work experience in medicinal chemistry, and sufficient familiarity interpreting
`
`or evaluating studies that use animal models to test for IOP reducing activity and
`
`side effects of compounds having the potential to treat glaucoma or ocular
`
`hypertension.
`
`11.
`
`In my opinion, claims 1-14 of the '035 Patent do not contain any terms
`
`that require construction by the Board.
`
`12.
`
`In my opinion, claims 1-14 of the '035 Patent would not have been
`
`obvious as of December 26, 1996 over Klimko (Ex. 1003) in view of Kishi (Ex.
`
`1005) and Ueno Japan (Ex. 1006).
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`4
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`13.
`
`In my opinion, claims 1-14 of the '035 Patent would not have been
`
`obvious as of December 26, 1996 over Klimko (Ex. 1003) in view of Kishi (Ex.
`
`1005), Ueno Japan (Ex. 1006) and Bezuglov 1982 (Ex. 1007) and/or Bezuglov
`
`1986 (Ex. 1008).
`
`14.
`
`In my opinion, without the benefit of improper hindsight, a POSITA
`
`as of December 26, 1996 would not have considered Compound C of Klimko to be
`
`a suitable lead compound. Klimko expressly teaches away from selection of
`
`Compound C as a lead compound. Accordingly, I disagree with both grounds of
`
`Petitioner's obviousness argument, each of which requires the selection of
`
`Compound C as a lead compound and its modification to obtain the claimed
`
`tafluprost compound.
`
`15.
`
`In my opinion, even if Compound C had been considered a suitable
`
`lead compound as of December 26, 1996 (which it was not), it would not have
`
`been obvious to follow the elaborate and unpredictable development path proposed
`
`by Petitioner.
`
`16.
`
`In my opinion, even if a POSITA had decided to pursue Petitioner's
`
`proposed development path toward a fluorinated Compound C, a POSITA would
`
`not have been motivated with a reasonable expectation of success to include two
`
`fluorines at the C15 position of Compound C.
`
`5
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`17.
`
`In my opinion, Klimko '671 is not representative of the state of the art
`
`as of December 26, 1996 (as it was not yet published), but its explicit exclusion of
`
`C15 difluorination from its scope does establish that it would not have been
`
`obvious to C15 difluorinate Compound C of Klimko.
`
`IV. STATE OF THE ART AS OF THE PRIORITY DATE
`OF THE '035 PATENT, DECEMBER 26, 1996
`
`18. Since at least as early as 1977, researchers had been investigating the
`
`potential use of a class of compounds, called prostaglandins (described below), to
`
`reduce IOP for the treatment of glaucoma and ocular hypertension. 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) ("Camras
`
`1977") (Ex. 2003). However, as of December 26, 1996 (nearly two decades later),
`
`only two prostaglandin analogs had made it to market. Xalatan® (latanoprost),
`
`developed by Pharmacia & Upjohn, was approved earlier in 1996 in the US, but
`
`only as second-line treatment. "Pharmacia Cleared To Market Xalatan, Drug for
`
`Glaucoma," Wall St. J. B7 (June 7, 1996) ("Xalatan 1996") (Ex. 2004). A second
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`drug, isopropyl unoprostone (eventually marketed as Rescula®),1 developed by R-
`
`
`1 In recent years, it has been determined that isopropyl unoprostone is not even a
`
`prostaglandin analog; it is now considered to be a "docosanoid" (a derivative of
`
`docosahexaenoic acid) that exhibits virtually no binding to prostaglandin receptor.
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`6
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`Tech Ueno, had been marketed in Japan since 1994, but there was limited
`
`experience with the drug outside the Japanese market. Linden and Alm,
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`"Prostaglandin Analogues in the Treatment of Glaucoma," Drug Aging, 14(5):387-
`
`398 (1999) ("Linden 1999") (Ex. 2006) at 2.
`
`19. Prostaglandins are lipid compounds with the 20-carbon skeleton of
`
`prostanoic acid, which includes an alpha chain (α-chain), a cyclopentane ring, and
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`an omega chain (ω-chain):
`
`Nelson, "Prostaglandin Nomenclature," J. Med. Chem. 17(9):911-918 (1974)
`
`("Nelson 1974") (Ex. 1026) at 1. As illustrated above, it was known that each
`
`carbon of the skeleton was numbered sequentially, C1 through C20. Id.
`
`
`
`
`Fung and Whitson, "An evidence-based review of unoprostone isopropyl
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`ophthalmic solution 0.15% for glaucoma: place in therapy," Clin. Ophthalmol.
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`8:543-554 (2014) (Ex. 2005) at 2.
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`7
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`20. As of December 26, 1996, prostaglandins had been broken down into
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`subclasses, A through J, based on the functional groups of the cyclopentane ring,
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`e.g.:
`
`
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`Id. at 1-2. (In the case of PGF, the stereochemistry of the hydroxyl (-OH) group at
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`the C9 position was indicated by an α or β designation. Id.) It was known in the
`
`art at that time that the small structural differences above lead to preferential
`
`binding to different classes of receptors. For example, PGD, PGE, PGF and PGI
`
`were known to preferentially bind DP, EP, FP and IP receptors, respectively.
`
`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) ("Coleman 1994") (Ex.
`
`2007) at 3.
`
`21. As of December 26, 1996, naturally-occurring prostaglandins were
`
`known to contain a hydroxyl group at the C15 position, as well as a trans double
`
`bond between C13 and C14. Nelson 1974 (Ex. 1026) at 1-2. (PGG was the lone
`
`exception, as it was known to contain a C15 hydroperoxyl (-O-OH) group, rather
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`8
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`than a C15 hydroxyl; but it was believed to be quickly converted in vivo to PGH.
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`Id.) Prostaglandins were further classified by the numbers 1 through 3,
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`representing the number of double bonds, e.g., PGE1 (1 double bond) or PGF2α (2
`
`double bonds). Id. For example, PGF2α was known to have the following
`
`structure, containing the requisite C15 hydroxyl and C13-C14 double bond, as well
`
`as a second cis double bond at the C5-C6 position:
`
`
`
`22.
`
`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,
`
`regulation of inflammation, regulation of gastric acid, bicarbonate and mucus
`
`secretion, and regulation of mucosal integrity). Konturek and Pawlik, "Physiology
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`9
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`and pharmacology of prostaglandins," Dig. Dis. Sci. 31(2 Suppl):6S-19S (1986)
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`(Ex. 2008) at 5-11; Coleman 1994 (Ex. 2007) at 2.
`
`23. At the same time, the biological activities of the various
`
`prostaglandins were known to overlap to varying degrees. In that regard,
`
`prostaglandins were known to be promiscuous molecules that can bind multiple
`
`receptors to varying degrees - causing side effects - likely because of certain
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`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). Stjernschantz and Alm, "Latanoprost as a new horizon in
`
`the medical management of glaucoma," Curr. Opin. Ophthalmol. 7(2):11-17
`
`(1996) ("Stjernschantz 1996") (Ex. 2009) at 2 ("Naturally occurring prostaglandins
`
`tend to spill over on many different prostanoid receptors resulting in a mixed
`
`pharmacological response. For instance the ocular irritating effect of PGF2α is
`
`probably at least partly due to the fact that this prostaglandin is a relatively
`
`effective agonist also on several of the EP receptors."); see also Collins and Djuric,
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`"Synthesis of Therapeutically Useful Prostaglandin and Prostacyclin Analogs,"
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`Chem. Rev. 93:1533-1564 (1993) ("Collins 1993") (Ex. 2010) at 1 ("The side
`
`effects observed with PGs are due to their multiple pharmacological and
`
`physiological activities all of which may be manifested when the body is exposed
`
`to them systemically."). Further complicating matters is the fact that another
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`10
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`related group of compounds, thromboxanes, bind the prostaglandins' receptors, and
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`vice-versa. Coleman 1994 (Ex. 2007) at 2.
`
`24. As of December 26, 1996, medicinal chemistry was a highly
`
`unpredictable art, and it remains so to this day. This is especially true with respect
`
`to prostaglandins - a large class of compounds with very different, but overlapping,
`
`receptor profiles, which generate various distinct biological activities. Collins
`
`1993 (Ex. 2010) at 1-2.
`
`25. The complex relationship between chemical structure and biological
`
`activity (SAR) of the prostaglandins was reflected in slow progress toward a useful
`
`prostaglandin-based compound for the reduction of IOP in patients with glaucoma
`
`and ocular hypertension. As of 1977, researchers were already aware, based on
`
`animal studies, of the potential IOP-reducing activity of prostaglandins. Camras
`
`1977 (Ex. 2003). And, by 1985, it had been demonstrated that PGF2α could lower
`
`IOP in humans. Giuffrè, "The effects of prostaglandin F2α in the human eye,"
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`Graefe's Arch. Clin. Exp. Ophthalmol. 222:139-141 (1985) (Ex. 2011). However,
`
`administration of PGF2α also caused severe side effects, including conjuctival
`
`hyperemia (eye redness), eye irritation and pain, and headaches. Id. at 1, 3. Such
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`side effects made prostaglandins an unattractive therapeutic option. There had also
`
`been concern regarding the initial increase in IOP after administration of
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`prostaglandins, an unacceptable outcome for a drug intended to reduce IOP. See,
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`11
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`IPR Page 13/97
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`e.g., Camras 1977 (Ex. 2003) at 1 ("the well-known initial hypertensive phase").
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`This led to intensive research to develop a prostaglandin analog that could
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`significantly reduce IOP while minimizing side effects.
`
`26. Subsequent efforts unsuccessfully focused on esterification of PGF2α,
`
`a modification that had been previously shown to increase potency. For example,
`
`researchers investigated the following isopropyl ester (indicated in red) of PGF2α
`
`("PGF2α-IE"):
`
`
`
`See, e.g., 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) (Ex. 2012). It was found that the
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`enhanced potency of PGF2α-IE was due to enhanced penetration of the compound
`
`into the eye. Id. at 7. It was also found that PGF2α-IE acted as a pro-drug, and was
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`converted inside the eye to the active, free-acid form of PGF2α. Id. However,
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`12
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`while PGF2α-IE analog provided enhanced bioavailability and IOP-lowering
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`activity, it did not eliminate the side effects that plagued the naturally-occurring
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`PGF2α compound: "The use of very low doses of PGF2α, made possible with the
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`increased lipid solubility of the ester, did not cause a sufficiently efficient
`
`separation of effect and subjective side effects." Villumsen and Alm,
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`"Prostaglandin F2α-isopropylester eye drops: effects in normal human eyes," Br. J.
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`Ophthalmol. 73:419-26 (1989) (Ex. 2013) at 7.
`
`27. 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. Villumsen and Alm, "Ocular effects of two
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`different prostaglandin F2α esters: a doublemasked cross-over study on
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`normotensive eyes," Acta Ophthalmol. 68:341-343 (1990) (Ex. 2014). The hope
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`had been that the prostaglandin analog would exhibit decreased activity until the
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`compound had penetrated the eye, resulting in decreased side effects. Id. at 1.
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`However, again, the researchers observed that the new compound did not
`
`"provide[] a better separation between effect [on IOP] and side effects than PGF2α-
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`IE." Id. at 3. The researchers expressly noted that "[o]ur results indicate that more
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`radical changes of the parent molecule may be necessary to achieve this goal." Id.
`
`28. As explained above, as of December 26, 1996, the only two
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`compounds that had advanced to the point of being approved for reduction of IOP
`
`13
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`
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`were Xalatan® (latanoprost) and isopropyl unoprostone. Latanoprost is 13,14-
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`dihydro-17-phenyl-18,19,20-trinor-PGF2α-IE (where 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):
`
`
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`Stjernschantz 1996 (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
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`bond (rather than a double bond). Latanoprost was heralded as an improvement
`
`over PGF2α and PGF2α-IE, with less eye irritation and hyperemia, while
`
`maintaining significant IOP-lowering activity. Nevertheless, latanoprost was
`
`known to exhibit other significant side effects, e.g., iridial pigmentation
`
`(discoloration of the iris of the eye). Xalatan 1996 (Ex. 2004).
`
`29. As of December 26, 1996, the only other commercially-available drug
`
`for IOP-reduction was isopropyl unoprostone, which was not widely available
`
`14
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`outside of Japan. Isopropyl unoprostone is 13,14-dihydro-15-keto-20-ethyl-
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`PGF2α-IE:
`
`
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`Linden 1999 (Ex. 2006) at 4. Isopropyl unoprostone takes a very different
`
`approach, structurally, than latanoprost. There is no 17-phenyl group; instead the
`
`ω-chain is lengthened by 2 carbons. Moreover, the C15 hydroxyl is converted to a
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`ketone. Indeed, it had been reported that isopropyl unoprostone targeted a
`
`different receptor than latanoprost; whereas latanoprost targeted the FP receptor,
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`isopropyl unoprostone had very little affinity for that receptor. Id. at 5
`
`("Latanoprost is a more selective FP-receptor agonist than PGF2α . . ."), 8 ("In
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`contrast to latanoprost, it has been reported that unoprostone only has a weak
`
`agonist activity for FP-receptors . . ."). Also, compared to latanoprost, isopropyl
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`unoprostone was less effective and at least 20 times less potent. Camras and Alm,
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`"Initial Clinical Studies with Prostaglandins and Their Analogues," Surv.
`
`15
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`
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`Ophthalmol. 41(Suppl. 2):S61-S68 (1997) (Ex. 2015) at 6 (citing Camras,
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`"Prostaglandins," in The Glaucomas 69:1449-1461 (1996) (Ex. 2016)).
`
`30. 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:
`
`Neither of the commercially available prostaglandin analogs as of December 26,
`
`1996 was fluorinated (let alone difluorinated, and at the C15 position specifically),
`
`neither contained a 16-phenoxy group, and neither contained a C13-C14 double
`
`
`
`bond.
`
`V.
`
`SUMMARY OF THE '035 PATENT
`
`31. 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
`
`16
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`IPR Page 18/97
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`
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`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.
`
`32. 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. Therefore, achieving a suitable side effect profile was a major goal of
`
`the research into prostaglandin derivatives for the treatment of glaucoma. Id. at
`
`1:18-21. Although latanoprost had been licensed as of December 26, 1996 for the
`
`treatment of glaucoma and ocular hypertension, it still caused certain undesirable
`
`side effects, and there was room for improvement in the duration of efficacy. Id. at
`
`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. at 1:40-43. "For this reason, extensive research has been conducted both at
`
`17
`
`IPR Page 19/97
`
`
`
`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.
`
`33. 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.
`
`34.
`
`In addition to C15 difluorination, the inventors also emphasized a
`
`preference for omega chains other than the one present on naturally-occurring
`
`prostaglandin: "[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." 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-
`
`18
`
`IPR Page 20/97
`
`
`
`15,15-difluoro-17,18,19,20-tetranorprostaglandin F2α, isopropyl ester") (emphasis
`
`added).
`
`35.
`
`In Example 23, the inventors compared latanoprost against four
`
`compounds of the '035 Patent (referred to as Compounds A-D), with respect to
`
`IOP-lowering and melanogenesis. Id. at 28:1-30:67. The '035 Patent compounds
`
`included 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.
`
`36. The IOP-lowering efficacy of the tested compounds, after a single
`
`administration to macaques, was reported in Table 1:
`
`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-
`
`
`
`19
`
`IPR Page 21/97
`
`
`
`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.
`
`37. With respect to IOP-lowering efficacy after a two week repeated
`
`application test in macaques, the results were reported in Table 2:
`
`
`
`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
`
`20
`
`IPR Page 22/97
`
`
`
`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.
`
`38. 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
`
`Compound A have the same free acid form, results are only presented for
`
`Compound A. Id. at 30:35-37, 30:40-41. The results were presented in Table 3:
`
`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
`
`21
`
`IPR Page 23/97
`
`
`
`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.
`
`39. Overall, "[t]he results of the pharmacological tests clearly indicate
`
`that the compounds of the present invention are useful as long-lasting therapeutic
`
`medicines for glaucoma, are hardly irritant to the eye and have little effect on
`
`melanogenesis." Id. at 30:64-67.
`
`40. 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,
`
`22
`
`IPR Page 24/97
`
`
`
`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.
`
`Id. at 31:2-26.
`
`41. Dependent claims 2 and 3 further narrow the genus of claim 1, with
`
`claim 3 reciting only three specific compounds, including the tafluprost compound:
`
`3. The compound according to claim 1, which is 16-phenoxy-15-
`
`deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglandin F2α, 16-
`
`(3-chlorophenoxy)-15-deoxy-15,15-difluoro-17,18,19,20-
`
`tetranorprostaglandin F2α, 16-phenoxy-15-deoxy-15,15-difluoro-
`
`13,14-dihydro-17,18,19,20-tetranorprostaglandin F2α or an alkyl
`
`ester or a salt thereof.
`
`Id. at 31:27-32:3 (emphasis added).
`
`42. Dependent claims 4-11 are directed to "[a] medicine containing the
`
`compound according to claim 1 as an active ingredient." Id. at 32:4-21. Claim 5
`
`limits the medicine to "a preventive or therapeutic medicine for an eye disease,"
`
`23
`
`IPR Page 25/97
`
`
`
`and claim 6 further limits the eye disease to "glaucoma or ocular hypertension."
`
`Id. at 32:6-9. Claims 7-11 narrow the genus of claim 1 that is included in the
`
`medicine. Id. at 32:10-21.
`
`43. The second of two independent claims - claim 12 - recites a medicine
`
`with one of three specific compounds, including tafluprost:
`
`12. A medicine containing 16-phenoxy-15-deoxy-15,15-difluoro-
`
`17,18,19,20-tetranorpro
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