Paper No. 24
`IPR2017-01434
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`MICRO LABS LIMITED AND MICRO LABS USA INC.
`Petitioners,
`
`v.
`
`SANTEN PHARMACEUTICAL CO., LTD. AND ASAHI GLASS CO., LTD.
`Patent Owners.
`_____________
`
`Inter Partes Review No. IPR2017-01434
`U.S. Patent No. 5,886,035
`
`_____________
`
`
`PETITIONERS’ REPLY TO PATENT OWNER RESPONSE
`
`
`
`
`
`
`
`
`
`

`

`IPR2017-01434
`PETITIONERS’ REPLY TO PATENT OWNER RESPONSE
`
`
`TABLE OF CONTENTS
`
`TABLE OF AUTHORITIES .................................................................................... ii 
`LIST OF EXHIBITS ................................................................................................ iii 
`I.  INTRODUCTION ................................................................................................ 1 
`II.  A POSA WOULD HAVE BEEN MOTIVATED TO SELECT COMPOUND C
`AS A LEAD COMPOUND .................................................................................. 2 
`A. Patent Owner And Its Experts Overreach In Their Attempt To Incorrectly
`Characterize Compound C As Having “Unacceptable Hyperemia” That
`Would Have Taught Away From Compound C .............................................. 4 
`B.  PO and Its Experts Incorrectly Assert That There Is “An Initial Increase In
`IOP” For Compound C Based On A Misunderstanding of Klimko’s Data As
`Well As The Meaning of “An Initial Increase In IOP” ................................... 8 
`III. A POSA WOULD HAVE HAD A REASONABLE EXPECTATION THAT
`DIFLUORINATION OF THE C-15 POSITION WOULD SUCCESSFULLY
`IMPROVE COMPOUND C’S THERAPEUTIC PROFILE ............................. 14 
`A. Substituting The C-15 Hydroxyl Group With Fluorine Would Not Have
`Been Unpredictable, But Rather A Natural And Obvious Choice For A
`POSA ............................................................................................................. 14 
`B.  Ueno Japan Is Not Irrelevant Prior Art And Further Supports The
`Understanding Of The POSA That Difluorination Would Be Successful .... 17 
`IV. ALLEGED SECONDARY CONSIDERATIONS DO NOT OVERCOME THE
`STRONG SHOWING OF OBVIOUSNESS ...................................................... 18 
`A. Tafluprost Has Not Achieved Any Commercial Success ............................. 19 
`B.  There are No Unexpected Results for Tafluprost .......................................... 20 
`C.  There Was No Long-Felt But Unmet Need That Was Met by Tafluprost .... 21 
`D. There Has Not Been Failure of Others .......................................................... 21 
`E.  PO’s Alleged Secondary Considerations Evidence Are Not Commensurate
`In Scope With The Claims ............................................................................. 22 
`V. CONCLUSION ................................................................................................... 23 
`
`
`
`
`
`
`
`
`i
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`
`IPR2017-01434
`PETITIONERS’ REPLY TO PATENT OWNER RESPONSE
`
`TABLE OF AUTHORITIES
`
`Cases
`
`Page(s)
`
`Allergan, Inc. v. Apotex Inc.,
`
`754 F.3d 952 (Fed. Cir. 2015) .................................................................... 22, 23
`In re Applied Materials, Inc.,
`
`692 F.3d 1289 (Fed. Cir. 2012) ......................................................................... 19
`In re Clay,
`
`966 F.2d 656 (Fed. Cir. 1992) ........................................................................... 17
`Extreme Networks, Inc. v. Enterasys Networks, Inc.,
`
`395 F. App’x 709 (Fed. Cir. 2010) .................................................................... 11
`Galderma Laboratories, L.P. v. Tolmar, Inc.,
`
`737 F.3d 731 (Fed. Cir. 2013) ........................................................................... 20
`In re GPAC Inc.,
`
`57 F.3d 1573 (Fed. Cir. 1995) ........................................................................... 18
`In re Greenfield,
`
`571 F.2d 1185, 1189 (C.C.P.A. 1978) .............................................................. 22
`In re Hogan,
`
`559 F.2d 595 (C.C.P.A. 1977) ........................................................................... 16
`Institut Pasteur & Universite Pierre Et Marie Curie v. Focarino,
`
`738 F.3d 1337 (Fed. Cir. 2013) ......................................................................... 18
`Line Rothman v. Target Corp.,
`
`556 F.3d 1310 (Fed. Cir. 2009) ......................................................................... 19
`Merck & Co. v. Biocraft Labs. Inc.,
`
`874 F.2d 804 (Fed. Cir. 1989) ........................................................................... 18
`Novo Nordisk A/S v. Caraco Pharmaceutical Laboratories, Ltd.,
`
`719 F.3d 1346 (Fed. Cir. 2013) ......................................................................... 19
`Otsuka Pharm. Co. v. Sandoz, Inc.,
`
`678 F.3d 1280 (Fed. Cir. 2012) ........................................................................... 2
`Santarus, Inc. v. Par Pharm., Inc.,
`
`720 F. Supp. 2d 427 (D. Del. 2010) ........................................................... 19, 20
`Thomas & Betts Corp. v. Litton Sys., Inc.,
`
`720 F.2d 1572 (Fed. Cir. 1983) ........................................................................ 16
`
`ii
`
`

`

`
`
`
`
`Exhibit
`No.
`1001
`
`1002
`1003
`1004
`1005
`1006
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`1013
`
`1014
`
`1015
`1016
`
`IPR2017-01434
`PETITIONERS’ REPLY TO PATENT OWNER RESPONSE
`
`LIST OF EXHIBITS
`Document
`
`U.S. Patent No. 5,886,035 to Shirasawa et al. (issued March 23,
`1999).
`File History of U.S. Patent No. 5,886,035.
`EP0639563A2 to Klimko et al. (published February 22, 1995).
`EP0471856A1 to Kishi et al. (published February 26, 1992).
`U.S. Patent No. 5,292,754 to Kishi et al. (issued March 8, 1994).
`JP-A-7070054 to Ueno Japan et al. (published March 14, 1995).
`Bezuglov, V. V. & L. D. Bergelson, “Fluoroprostaglandins—A
`New Class of Biologically Active Analogues of Natural
`Prostaglandins” in Lipids of Biological Membranes (L.D.
`Bergelson, ed., 1982).
`Bezuglov, Vladimir V. “Fluorodeoxy Prostaglandins, Synthesis and
`Perspectives” in Prostaglandins and Cardiovascular Diseases
`(Takayuki Ozawa et al. eds., 1986).
`Camras et al. “Reduction of intraocular pressure in normal and
`glaucomatous primate (Aotus trivirgatus) eyes by topically applied
`PGF2α,” Curr. Eye Res. 1:205–209 (1981).
`Stjernschantz, J.W. “From PGF2α-Isopropyl Ester to Latanoprost: A
`Review of the Development of Xalatan,” Investig. Ophthal. & Vis.
`Sci. 42(6):1134–1145 (2001).
`Nixon, D. “Hyperemia in Glaucoma Patients,” (2008) available
`online at http://www.medscape.org/viewarticle/577054.
`PCT/US97/20671 to Klimko et al. (published May 22, 1998).
`U.S. Provisional Patent Application No. 60/030,519 to Klimko et al.
`(made accessible as of May 22, 1998).
`Alm, A. 1989 “Progress in Clin. and Biological Research,” pp. 447–
`458.
`Stjernschantz, J. 1992 Drugs of the Future 691–704.
`Product Details for NDA 020597 (XALATAN) available online at
`https://www.accessdata.fda.gov/scripts/cder/ob/results_product.cfm
`?Appl_Type=N&Appl_No=020597.
`
`iii
`
`

`

`
`
`Exhibit
`No.
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`1026
`
`1027
`1028
`1029
`
`1030
`
`IPR2017-01434
`PETITIONERS’ REPLY TO PATENT OWNER RESPONSE
`
`Document
`
`Patent and Exclusivity for: N202514 (ZIOPTAN) available online at
`https://www.accessdata.fda.gov/scripts/cder/ob/patent_info.cfm?Pro
`duct_No=001&Appl_No=202514&Appl_type=N.
`Lee, P.Y. et al., “The effect of prostaglandin F2 alpha on intraocular
`pressure in normotensive human subjects,” Invest. Ophthalmol. Vis.
`Sci. Oct. 29(10):1474–1477 (1988).
`Camras, C.B. et al., “Maintained reduction of intraocular pressure
`by prostaglandin F2 alpha-1-isopropyl ester applied in multiple
`doses in ocular hypertensive and glaucoma patients,”
`Ophthalmology Sep. 96(9):1329–1337 (1989).
`Nilsson, S.F. et al., “Increased uveoscleral outflow as a possible
`mechanism of ocular hypotension caused by prostaglandin F2
`alpha-1-isopropylester in the cynomolgus monkey,” Exp. Eye Res.
`May 48(5):707–716 (1989).
`Pederson, J.E. et al., “Laser-induced primate glaucoma. I.
`Progression of cupping,” Arch. Ophthalmol. Nov. 102(11):1689–92
`(1984).
`Radius, R.L. et al., “Laser-induced primate glaucoma. II.
`Histopathology,” Arch. Ophthalmol. Nov. 102(11):1693–8 (1984).
`Lee, P.Y. et al., “Pharmacological testing in the laser-induced
`monkey glaucoma model,” Curr. Eye Res. Jul. 4(7):775–81 (1985).
`Bito, L.Z. “Species differences in the responses of the eye to
`irritation and trauma: a hypothesis of divergence in ocular defense
`mechanisms, and the choice of experimental animals for eye
`research,” Exp. Eye Res. Dec. 39(6):807–29 (1984).
`U.S. Patent No. 3,914,265 to Middleton (issued October 21, 1975).
`Nelson, N.A. “Prostaglandin Nomenclature,” J. Med. Chem.
`17(9):911–918 (1974).
`Declaration of Mitchel deLong, Ph.D
`Declaration of Aron D. Rose, M.D.
`Exhibit 1006 (JP-A-7070054 to Ueno Japan et al. (published March
`14, 1995) (“Ueno”)) with affidavits in compliance with 37 C.F.R.
`§§ 42.63(b) and 1.68, as required by the Board in its November 29,
`2017 Order (Paper No. 11), pp. 5–6, n.1.
`Exhibit 1007 (Bezuglov, V. V. & L. D. Bergelson,
`“Fluoroprostaglandins—A New Class of Biologically Active
`
`iv
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`

`

`IPR2017-01434
`PETITIONERS’ REPLY TO PATENT OWNER RESPONSE
`
`Document
`
`
`
`Exhibit
`No.
`
`1031
`1032
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`Analogues of Natural Prostaglandins” in Lipids of Biological
`Membranes (L.D. Bergelson, ed., 1982) (“Bezuglov 1982”)) with
`affidavits in compliance with 37 C.F.R. §§ 42.63(b) and 1.68, as
`required by the Board in its November 29, 2017 Order (Paper No.
`11), p. 6, n.2.
`Supplemental Declaration of Mitchell A. deLong, Ph.D.
`Supplemental Declaration of Aron D. Rose, M.D.
`Kerstetter, J.R. et al., “Prostaglandin F2α-1-Isopropylester Lowers
`Intraocular Pressure Without Decreasing Aqueous Humor Flow,”
`American Journal of Ophthalmology, Vol. 105, No. 1, 30–34
`(1988).
`Villumsen, Jorgen et al., “Prostaglandin F2α-isopropylester eye
`drops: effect on intraocular pressure in open-angle glaucoma,” Br. J.
`Opthalmol. 73:975–979 (1989).
`U.S. Patent No. 5,296,504 to Stjernschantz et al., issued March 22,
`1994.
`Alm A., “Latanoprost in the treatment of glaucoma,” Clin.
`Ophthalmol., 8:1967-85 (2014).
`Alan Robin, MD, “Two new options will make glaucoma therapy
`safer,” Primary Care Optometry News, July 1996.
`1038 Mishima, Hiromu K., et al., “Circadian Intraocular Pressure
`Management with Latanoprost: Diurnal and Nocturnal Intraocular
`Pressure Reduction and Increased Uveoscleral Outflow,” Survey of
`Ophthalmology, vol. 41:2 (Feb. 1997).
`Camras et al., “Latanoprost, a Prostaglandin Analog, for Glaucoma
`Therapy: efficacy and safety after 1 year of treatment in 198
`patients,” Ophthalmology, 103:1916–1924 (November 1996).
`Camras C.B. et al., “Comparison of latanoprost and timolol in
`patients with ocular hypertension and glaucoma: a six-month,
`masked, multicenter trial in the United States,” Ophthalmology,
`103(1):138-47 (January 1996).
`Konstas, Anatasios G P et al. “Twenty-four hour efficacy with
`preservative free tafluprost compared with latanoprost in patients
`with primary open angle glaucoma or ocular hypertension,” Br. J.
`Opthalmol., 97:1510–1515 (2013).
`Ikeda, Yoko et al. “Comparison study of intraocular pressure
`reduction efficacy and safety between latanoprost and tafluprost in
`
`1039
`
`1040
`
`1041
`
`1042
`
`v
`
`

`

`
`
`Exhibit
`No.
`
`1043
`
`1044
`
`1045
`
`1046
`
`1047
`
`1048
`
`1049
`
`1050
`
`1051
`
`1052
`
`1053
`
`IPR2017-01434
`PETITIONERS’ REPLY TO PATENT OWNER RESPONSE
`
`Document
`
`Japanese with normal-tension glaucoma,” Clinical
`Ophthalmology,10:1633–1637 (2016).
`Fogagnolo, Paolo et al. “A 1-Year Randomized Study of the
`Clinical and Confocal Effects of Tafluprost and Latanoprost in
`Newly Diagnosed Glaucoma Patients,” Adv. Ther., 32:356–369
`(2015).
`Lee P-Y et al., “Effect of prostaglandin F2α on aqueous humor
`dynamics of rabbit, cat, and monkey,” Invest Ophthalmol Vis Sci,
`25:1087–1093 (1984).
`Patel S.S. et al., “Latanoprost: A Review of its Pharmacological
`Properties, Clinical Efficacy and Tolerability in the Management of
`Primary Open-Angle. Glaucoma and Ocular Hypertension,” Drugs
`Aging, 9(5):363–78 (November 1996).
`Husain S. et al., “Latanoprost-Induced Changes in Rat Intraocular
`Pressure: Direct or Indirect?” J. Ocul. Pharmacol. Ther., 24(4):367–
`372 (2008).
`Resul B. et al., “Phenyl-Substituted Prostaglandins: Potent and
`Selective Antiglaucoma Agents,” J. Med. Chem., 36:243–248
`(1993).
`Skuballa W. et al., “15, 15-Ketals of Natural
`Prostaglandins and Prostaglandin Analogues. Synthesis and
`Biological Activities,” J. Med. Chem. 21:443-447 (1978).
`Bito L.Z., “Comparison of the Ocular Hypotensive Efficacy of
`Eicosanoids and Related Compounds,” Exp. Eye Res., 38(2):181–94
`(1984).
`Judith A.K. Howard et al., “How Good is Fluorine as a
`Hydrogen Bond Acceptor?” Tetrahedron, 52:12613–12622 (Sept.
`1996).
`deLong M.A., “Seminar on Lipophilicity including
`a method for estimating the logP of organic compounds,” Lecture
`notes follow circa 1989, Stanford University.
`Latanoprost DrugBank Profile, available at
`https://www.drugbank.ca/drugs/DB00654 (last visited May 31,
`2018).
`Santen Pharmaceutical Co., Ltd. Annual Report 2013, available at
`http://www.santen.com/en/ir/document/pdf/ar2013e.pdf (last visited
`June 1, 2018).
`
`vi
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`IPR2017-01434
`PETITIONERS’ REPLY TO PATENT OWNER RESPONSE
`
`Document
`
`Santen Pharmaceutical Co., Ltd. Data Book Year Ended March 31,
`2016, available at
`http://www.santen.com/en/ir/document/pdf/db2016.pdf (last visited
`June 1, 2018).
`GlobalData Healthcare, “Global glaucoma market to reach $3.8bn
`by 2026,” (Feb. 1, 2018), available at
`https://www.globaldata.com/global-glaucoma-marketreach-
`3-8bn-2026/ (last visited May 31, 2018).
`Aerie Pharmaceuticals, Inc. Form 8-K (January 8, 2018), available
`at http://investors.aeriepharma.com/static-files/5b1e29b1-da32-
`4ac9-b96a-cf22116b877b (last visited June 1, 2018).
`Aerie Pharmaceuticals, Inc. Form 8-K (September 12, 2017),
`available at http://investors.aeriepharma.com/static-files/3ee6b361-
`bc0a-4d15-a5d5-0203450c2f4e (last visited June 1, 2018).
`Santen Pharmaceutical Co., Ltd. Data Book Year Ended March 31,
`2015, available at
`http://www.santen.com/en/ir/document/pdf/db2015.pdf (last visited
`June 1, 2018).
`Santen Pharmaceutical Co., Ltd. Data Book Year Ended March 31,
`2017, available at
`http://www.santen.com/en/ir/document/pdf/db2017.pdf (last visited
`June 1, 2018).
`Santen Pharmaceutical Co., Ltd. Annual Report 2014, available at
`http://www.santen.com/en/ir/document/pdf/ar2014e.pdf (last visited
`June 1, 2018).
`U.S. Patent No. 4,599,353 to Bito L.Z., issued July 8, 1986.
`
`
`
`Exhibit
`No.
`1054
`
`1055
`
`1056
`
`1057
`
`1058
`
`1059
`
`1060
`
`1061
`
`
`
`vii
`
`

`

` Case IPR2017-01434
`Patent 5,886,035
`
`I.
`
`INTRODUCTION
`On November 29, 2017, the Board issued a decision to institute inter partes
`
`review of U.S. Patent No. 5,886,035 (“the ’035 patent”). The Board found that
`
`Petitioners demonstrated a reasonable likelihood of showing that claims 1–14
`
`would have been obvious over the combined teachings of (1) Klimko, Kishi, and
`
`Ueno Japan or (2) Klimko, Kishi, Ueno Japan, and Bezuglov 1982 and/or
`
`Bezuglov 1986.
`
`In view of the prior art, a Person of Ordinary Skill in the Art (“POSA”)
`
`would have (i) selected compound C as a lead compound for further development
`
`for treatment of glaucoma and elevated IOP based on its superior and long-lasting
`
`IOP-reducing efficacy; (ii) been motivated to substitute the C-15 hydroxyl group
`
`with two fluorine atoms to improve compound C’s therapeutic profile; and (iii) had
`
`a reasonable expectation that difluorination at the C-15 position of compound C
`
`would successfully improve its therapeutic profile. Faced with a compelling case
`
`of obviousness, Patent Owner (“PO”) ignores unfavorable data in the prior art,
`
`instead resting its argument precariously on a few self-serving statements from the
`
`Klimko patent application, which sought to distinguish prior art compounds
`
`including compound C. However, PO’s arguments mischaracterize the prior art
`
`and run contrary to the established common knowledge in the prostaglandin field
`
`that would have been applied by a POSA.
`
`1
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`

` Case IPR2017-01434
`Patent 5,886,035
`There are no secondary considerations that can overcome this strong prima
`
`facie case of obviousness, as explained in this Reply and Petitioners’ expert
`
`declarations from Mitchell deLong, Ph.D. and Aron Rose., M.D. PO’s purported
`
`secondary considerations of non-obviousness bear no nexus to, and are not
`
`commensurate in scope with, any of the claims.
`
`II. A POSA WOULD HAVE BEEN MOTIVATED TO SELECT
`COMPOUND C AS A LEAD COMPOUND
`A POSA would have been motivated to select compound C as a lead
`
`compound based on Klimko’s disclosure because it shows a longer duration of
`
`action for compound C, which advantageously allows for once-per-day dosing,
`
`combined with IOP-lowering efficacy that is superior to the commercially
`
`available prostaglandin latanoprost (compound E of Klimko).1 Klimko’s data
`
`shows that compound C has longer-lasting efficacy than the comparison
`
`compounds A, B and D. (Ex. 1031, ¶¶ 10–16, 75; Ex. 1032, ¶¶ 48–53.) Long-
`
`lasting efficacy is an important consideration in the selection of an appropriate lead
`
`compound for treatment of glaucoma or elevated IOP because it suggests to the
`
`POSA the advantage of once-daily dosing. (Id.; see also Otsuka Pharm. Co. v.
`
`Sandoz, Inc., 678 F.3d 1280, 1292 (Fed. Cir. 2012) (“In determining whether a
`
`
`1 Latanoprost (Xalatan®) quickly became the gold standard in treatment of elevated
`
`IOP and glaucoma after its approval by the FDA in June 1996. (Ex. 1032, ¶ 24.)
`
`2
`
`

`

` Case IPR2017-01434
`Patent 5,886,035
`chemist would have selected a prior art compound as a lead, the analysis is guided
`
`by evidence of the compound’s pertinent properties. Such properties may include
`
`positive attributes such as activity and potency….”).)
`
`In Klimko, the POSA would readily recognize from Table 4 and Figure 2
`
`that compound C’s percent IOP reduction is better than all of the other compounds
`
`at the furthest time point following administration of a dose. (Ex. 1031, ¶ 12.)
`
`Specifically, compound C shows greater percent IOP reduction (30.2±4.4%) than
`
`all of the other compounds at 16 hours after the fourth dose (16/4) — i.e., at the
`
`greatest elapsed time between any two given doses of the same compound. (Id.)
`
`Compound C’s longer duration of action as compared to compounds A, B
`
`and D is further confirmed by the observable trend at 2, 4 and 6 hours after
`
`administration of the fifth dose, which shows that all of the compounds with the
`
`exception of compound C reach their peak percent IOP-reduction early, at only 2
`
`or 4 hours after dosing, and have reduced effectiveness at 4 to 6 hours after dosing.
`
`This is in marked contrast to compound C, which does not show reduced
`
`effectiveness over the same period of 4 to 6 hours, but instead shows a downward
`
`trend in IOP, thus suggesting that it continues to lower IOP more than 6 hours after
`
`dosing. (Ex. 1031, ¶¶ 12–16; Ex. 1032, ¶¶ 50–52.)
`
`Based on the percent IOP reduction at the furthest time point following
`
`administration of a dose (i.e., 16 hours after the fourth dose), and also the
`
`3
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`

` Case IPR2017-01434
`Patent 5,886,035
`observable trend discussed above for the percent IOP reduction for the time points
`
`following the fifth dose, a POSA would have a reasonable expectation that dosing
`
`a patient once per day with compound C would successfully and effectively treat
`
`elevated IOP and glaucoma.
`
`A.
`
`Patent Owner And Its Experts Overreach In Their Attempt To
`Incorrectly Characterize Compound C As Having “Unacceptable
`Hyperemia” That Would Have Taught Away From Compound C
`PO’s reliance on hyperemia as a reason not to select compound C is
`
`misplaced because hyperemia was primarily considered a minor cosmetic side
`
`effect in December 1996. (Ex. 1031, ¶ 73; Ex. 1032, ¶¶ 31, 35, and 44.)
`
`Prostaglandin analogs were generally known to be associated with a high incidence
`
`of conjunctival hyperemia (i.e., redness of the eye) (see, e.g., Ex. 1011 at 2), but a
`
`moderate degree of hyperemia would not have, and in fact has not, dissuaded
`
`researchers from pursuing promising prostaglandin analogs as lead compounds for
`
`developing an improved treatment for glaucoma and/or elevated IOP. (Ex. 1031,
`
`¶¶ 25–27; Ex. 1032, ¶¶ 42–47.) For example, both prostaglandin analogs
`
`bimatoprost and travoprost, despite exhibiting more observed incidences of
`
`conjunctival hyperemia when compared to latanoprost, still became commercially-
`
`available drugs that are FDA approved for treating glaucoma and elevated IOP.
`
`(Ex. 1031, ¶ 26; Ex. 1032, ¶ 61.)
`
`4
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`

` Case IPR2017-01434
`Patent 5,886,035
`Contrary to PO’s exaggerated claims of “unacceptable hyperemia,” Klimko
`
`and Stjernshantz’s data show only moderate hyperemia for compound C. (Ex.
`
`1031, ¶¶ 22, 25; Ex. 1032, ¶¶ 31, 44, 46). Specifically, Klimko did not report a
`
`score of “4” (indicating severe hyperemia) on a scale from 0 to 4 for any of the
`
`guinea pigs tested for hyperemia in Klimko. In fact, Klimko reported a score of
`
`“2” (indicating only mild/modest hyperemia) for the majority (62 percent) of
`
`subjects dosed with compound C at 0.3 µg (Ex. 1003 at p.17, Table 3). Moderate
`
`hyperemia is not the same as “severe hyperemia,” and would not discourage the
`
`POSA from selecting compound C as a lead compound, especially considering its
`
`benefits. (Ex. 1031, ¶¶ 26, 73; Ex. 1032, ¶¶ 46, 49.) Accordingly, a POSA would
`
`not conclude that compound C displays “unacceptable hyperemia.”
`
` Referencing Stjernschantz’s data, PO and its experts erroneously claim that
`
`compound C displays a “high degree of hyperemia,” relying on comparing
`
`compound C’s hyperemia score of 2.3±0.3 on a scale from 0 to 4, at a dose of 0.5
`
`µg, with the hyperemia scores of other compounds at different doses, including
`
`PGF2α-IE at a dose of 0.1 µg, for which Stjernschantz reports a hyperemia score of
`
`2.8±0.3. (PO Br. at 30–31.) Neither PO nor its experts explains why this is a
`
`proper comparison when the dose of compound C was five times greater than the
`
`dose of PGF2α-IE. (Ex. 2017 at 15 (Table IV: PGF2α-IE in the top row, Compound
`
`C of Klimko at the bottom).) (Ex. 1032, ¶ 31.) Further, PO’s assertion is
`
`5
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` Case IPR2017-01434
`Patent 5,886,035
`inconsistent with Stjernschantz. Dr. Stjernschantz, who Dr. Macdonald describes
`
`as “an expert in the field who developed latanoprost,” characterized a closer
`
`hyperemia score of 2.0±0.3 as “only modest” hyperemia. (Ex. 1031, ¶ 22 (citing
`
`Ex. 2017 at p.10, ll.57–58, p.16 (Compound 2 of Table V)); Ex. 1032, ¶ 31.)
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`Accordingly, a POSA would consider a score of 2.3 as only modest hyperemia.
`
`(Ex. 1031, ¶ 27; Ex. 1032, ¶¶ 31, 46.) PO and its experts overreach in their attempt
`
`to incorrectly characterize compound C as having “unacceptable hyperemia” that
`
`would have taught away from compound C.
`
`Unlike Klimko, which was drafted to distinguish over the prior art
`
`(including compound C), Stjernschantz did not characterize compound C as having
`
`an “unacceptable therapeutic profile.” To the contrary, Stjernschantz teaches that
`
`compound C “effectively lowers the intraocular pressure studied in cats,” (Ex.
`
`2017 at 11, ll.8–9), and exhibits little or no ocular irritation. (Ex. 2017 at 10, ll.32–
`
`38.) PO and its experts conveniently avoid mentioning compound C’s low degree
`
`of ocular irritation, despite that irritation is more serious than hyperemia. (Ex.
`
`1031, ¶ 23; Ex. 1032, ¶¶ 23, 34–35.) Ocular irritation is more serious than
`
`hyperemia because hyperemia, i.e., redness of the eye, is a cosmetic side effect that
`
`fades after a few hours, whereas irritation causes the patient physical discomfort.
`
`(Id.) Therefore, a POSA would have considered such teaching from Stjernschantz
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`as favorable for compound C, rather than conveniently dismissing it as PO and its
`
`experts did.
`
`PO attempts to attack Dr. deLong’s credibility by relying on a Canadian
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`court decision wherein he characterized compound C as showing “what appears to
`
`be an unacceptable degree of hyperemia,” based on data reported in Stjernschantz.
`
`(PO Br. at 47–51; Ex. 2051 at 33.) PO’s attempted attack is meritless. The
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`relevant priority date of the Canadian counterpart to Klimko was August 3, 1993
`
`(Ex. 2051 at 4, ¶ 20), which is several years before the later December 1996
`
`priority date for the ’035 patent that is at issue here. As Drs. deLong and Rose
`
`explain, by at least late 1996, doctors and researchers understood that modest
`
`prostaglandin-induced hyperemia was only a minor cosmetic concern. (Ex. 1031,
`
`¶¶ 72–73; Ex. 1032, ¶¶ 31, 35, and 44.) In addition, as of August 3, 1993, the
`
`POSA would neither have had the benefit of Klimko as a prior art reference, nor
`
`knowledge that another prostaglandin analog—latanoprost—had been FDA
`
`approved and was well-received by patients despite producing modest hyperemia.
`
`(Ex. 1031, ¶ 73.) The POSA in 1993 also would not have had (as s/he does in this
`
`case) the benefit of Kishi’s teaching that certain side effects, including hyperemia,
`
`could be reduced or eliminated by modifying the C-15 hydroxyl. (Ex. 1031, ¶ 74.)
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`A POSA would recognize compound C as a lead compound because it
`
`clearly exhibits superior and longer-lasting IOP-reducing efficacy accompanied by
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`only a mild/moderate hyperemia. The fact that compound C has also been shown
`
`to cause little to no ocular irritation would have further motivated a POSA to select
`
`it as a lead compound. Moreover, in view of the teaching in Kishi, a POSA would
`
`reasonably expect that replacing the hydroxyl group at the C-15 position of
`
`compound C (1) reduces side effects, including hyperemia, and (2) eliminates any
`
`initial increase in IOP. Kishi further teaches a POSA that removal of the C-15
`
`hydroxyl makes prostaglandins less “chemically and biologically labile,” and thus
`
`protects them from metabolic degradation. (Ex. 1027-28 at ¶ 74; Ex. 1005-1 at
`
`1:50–56.)
`
`B.
`
`PO and Its Experts Incorrectly Assert That There Is “An Initial
`Increase In IOP” For Compound C Based On A
`Misunderstanding of Klimko’s Data As Well As The Meaning of
`“An Initial Increase In IOP”
`PO and its expert Dr. Macdonald claim that, because there was less of a
`
`decrease in IOP immediately after the fourth dose of compound C as compared to
`
`the treated IOP level, there is an “unacceptable initial increase in IOP with
`
`compound C.” (Ex. 2001, ¶ 87.) But this claim is baseless and scientifically
`
`wrong. As Dr. deLong explains in his declaration, Dr. Macdonald’s flawed
`
`understanding of what is meant by an initial increase in IOP is not only
`
`unsupported by the prior art reference he relies on, but also inconsistent with the
`
`accepted understanding in the art. (Ex. 1031, ¶¶ 30–35.)
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`In December 1996, researchers in the art used the term “initial increase” to
`
`refer to an increase in IOP (known as an initial hypertensive effect) as compared to
`
`either the baseline IOP of the treated eye of the subject or the simultaneously-
`
`measured IOP of the control (untreated) eye shortly after administration a dose of a
`
`prostaglandin, usually within 2 hours. (Ex. 1031, ¶¶ 30–35; Ex. 1032, ¶¶ 36–41.)
`
`This is the only correct interpretation of “an initial increase in IOP” because it is
`
`the only interpretation that is supported by the literature cited by both parties’
`
`experts. (Ex. 2028, ¶ 7 (citing Ex. 2003); Ex. 1031, ¶¶ 30–35 (citing Exs. 2003,
`
`1009, 1044).) This interpretation also makes sense because it explains why “an
`
`initial increase in IOP” could be a concern to a POSA. An IOP rising above the
`
`baseline IOP or above the IOP of a control untreated eye could potentially
`
`exacerbate a patient’s eye condition.
`
`An initial increase in IOP, however, is not what happened with any of the
`
`compounds tested in Klimko including compound C. All of the IOP measurements
`
`taken following administration of all of the compounds (A, B, C, D and E) reported
`
`by Klimko in Fig. 2 and Table IV are substantially below baseline. Specifically as
`
`to compound C, at no point does it fail to reduce IOP below baseline. Dr. deLong
`
`illustrated this point by replotting Klimko’s data to show IOP at measured time
`
`points by Klimko after the fifth dose relative to baseline:
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`
`
`
`PO also erroneously cites an alleged initial increase in IOP in Stjernschantz (for
`
`which Stjernschnantz reports no statistical significance). But the IOP reduction
`
`data in Stjernschantz (referenced in Klimko) does not suggest to a POSA that
`
`compound C caused an initial increase in IOP because the IOP of both the control
`
`group (group “C”) and the experimental group (group “E”) increased. As
`
`explained by Drs. deLong and Rose, there can be no finding of an initial increase
`
`in IOP when an increase in IOP is observed in both the control group and the
`
`experimental group after administration. (Ex. 1031, ¶¶ 30–39; Ex. 1032, ¶¶ 36–
`
`41.) PO relies on a reference (Ex. 2034) that reaches a similar conclusion based on
`
`data showing that both the control and experimental group IOP increased after
`
`administration. (Ex. 1031, ¶ 41.) Since the control (untreated) group in that study
`
`also exhibited an unexplained increase in IOP, the rise in IOP for both groups
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`Patent 5,886,035
`suggests that any initial increase in IOP for the experimental group is due to
`
`reasons other than the administration of compound C. (Ex. 1031, ¶ 38 (citing Ex.
`
`2034).) Therefore, a POSA would not be concerned about any alleged “initial
`
`increase in IOP” of compound C.
`
`
`
`Dr. Macdonald’s misapprehension of what “an initial increase in IOP”
`
`means, which is a basic concept that is well-understood in the relevant field,
`
`highlights his lack of relevant experience. (Supra Sec. II.B.) Dr. Macdonald’s
`
`field of expertise is not in developing prostaglandin analogs for the treatment of
`
`glaucoma or ocular hypertension, but rather lipid signaling molecular biology.2
`
`(Ex. 2001, Ex. A.) Although Dr. Macdonald is a medicinal chemist and molecular
`
`pharmacologist, neither of these credentials in and of themselves qualify him as an
`
`expert in the relevant field for the invention claimed in the ’035 patent. Extreme
`
`Networks, Inc. v. Enterasys Networks, Inc., 395 F. App’x 709, 715 (Fed. Cir. 2010)
`
`
`2 It is telling that despite allegedly nearly 30 years of serving as a technical
`
`consultant on the discovery and evaluation of novel compounds, including
`
`prostaglandin analogs, none of Dr. Macdonald’s over 200 scientific publications
`
`and more than 50 issued US patents is in the area of prostaglandin analogs, let
`
`alone the use of prostaglandin analogs in the treatment of glaucoma or ocular
`
`hypertension. (Ex. 1031, ¶ 9 (citing Ex. 2001, ¶ 8; Ex. A).)
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`(“General experience in a related field may not suffice when experience and skill
`
`in specific product design are necessary to resolve patent issues.”). On the other
`
`hand, Petitioners’ expert Dr. deLong is a medicinal chemist with decades of
`
`specific experience in developing prostaglandin derivative compounds for
`
`treatment of glaucoma or ocular hypertension. (Ex. 1027, Appendix B at 63–69.)
`
`His experience is in both industry and academia, and extends to formulating and
`
`evaluating ophthalmic compositions in various animal models for use in such
`
`treatment. (Ex. 1027, ¶ 5; Appendix B.) In an effort to compensate for Dr.
`
`Macdonald’s lack of relevant expertise and experience, PO conveniently and
`
`erroneously asserts that the POSA need not have “at least several years of
`
`experience researchi