`U.S. Patent No. 8,293,742
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`SLAYBACK PHARMA LLC
`
`Petitioner
`
`v.
`
`EYE THERAPIES LLC
`
`Patent Owner
`
`
`Case No. IPR2022-00142
`U.S. Patent No. 8,293,742
`
`
`PETITIONER’S REPLY
`
`
`
`TABLE OF CONTENTS
`
`
`I.
`II.
`
`INTRODUCTION ........................................................................................... 1
`CLAIM CONSTRUCTION ............................................................................ 1
`A. Ocular Condition ................................................................................... 1
`B.
`“About 0.025%” .................................................................................... 2
`III. THE ’553 PATENT ANTICIPATES CLAIMS 1 AND 2 .............................. 7
`IV. THE CHALLENGED CLAIMS ARE OBVIOUS ......................................... 9
`A.
`The Prior Art Taught Toward Brimonidine, Not Away ...................... 10
`B. A POSA Would Not Have Understood Brimonidine’s Ability to
`Reduce Redness to Be Concentration Dependent ............................... 15
`POSA Would Have Been Motivated to Use pH Within the Claimed
`Range ................................................................................................... 17
`1.
`There Was No Recognized “Progression” Toward Higher pH 18
`2.
`Eye Redness Relievers Work on the Surface of the Eye .......... 19
`3.
`There Is a Range of pH That Is Tolerable to Patients ............... 20
`D. A POSA Would Have Been Able to Make the Claimed Formulations
`With Routine Skill ............................................................................... 21
`Claims 4-6 Are Also Obvious ............................................................. 22
`Secondary Considerations Are Insufficient to Overcome an
`Obviousness Finding ........................................................................... 22
`
`C.
`
`E.
`F.
`
`
`
`
`
`
`
`
`Case IPR2022-00142
`U.S. Patent No. 8,293,742
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`ABT Sys., LLC v. Emerson Elec. Co.,
`797 F.3d 1350 (Fed. Cir. 2015) .......................................................................... 24
`Amgen Inc. v. Hoeschst Marion Roussel, Inc.,
`314 F.3d 1313 (Fed. Cir. 2003) ...................................................................... 9, 11
`Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc.,
`752 F.3d 967 (Fed. Cir. 2014) ............................................................................ 24
`C.R. Bard, Inc. v. Medline Indus., Inc.,
`No. 2020-1900, 2021 WL 3574043 (Fed. Cir. Aug. 13, 2021) .................... 12, 13
`Ethicon Endo-Surgery, Inc. v. Covidien LP,
`812 F.3d 1023 (Fed. Cir. 2016) .................................................................... 25, 26
`Fox Factory, Inc. v. SRAM, LLC,
`944 F.3d 1366 (Fed. Cir. 2019) .......................................................................... 23
`In re Fulton,
`391 F.3d 1195 (Fed. Cir. 2004) .......................................................................... 17
`Hill-Rom Serv., Inc. v. Stryker Corp.,
`755 F.3d 1367 (Fed. Cir. 2014) ............................................................................ 2
`Micron Tech., Inc. v. Lone Star Silicon Innovations LLC,
`IPR2017-01562, 2018 WL 6602102 (P.T.A.B. Dec. 13, 2018) ........................... 3
`Microsoft Corp. v. Mira Advanced Tech., Inc.,
`IPR2017-01411, 2018 WL 6204170 (P.T.A.B. Nov. 27, 2018) ........................... 3
`Ormco Corp. v. Align Tech., Inc.,
`463 F.3d 1299 (Fed. Cir. 2006) .......................................................................... 23
`Ortho-McNeil Pharm., Inc. v. Caraco Pharm. Lab’ys,
`476 F.3d 1321 (Fed. Cir. 2007) ............................................................................ 4
`Par Pharm., Inc. v. Hospira, Inc.,
`835 F. App’x 578 (Fed. Cir. 2020) ....................................................................... 4
`
`
`
`
`
`Case IPR2022-00142
`U.S. Patent No. 8,293,742
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) .................................................................... 17, 24
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .......................................................................... 22
`Schering Corp v. Geneva Pharms.,
`339 F.3d 1373 (Fed. Cir. 2003) ........................................................................ 8, 9
`Vitronics Corp. v. Conceptronic, Inc.,
`90 F.3d 1576 (Fed. Cir. 1996) .............................................................................. 6
`
`
`
`
`
`
`
`
`Exhibit
`
`1001
`
`1002
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`EXHIBIT LIST
`
`Description
`U.S. Patent No. 8,293,742 (filed July 27, 2009) (issued Oct. 23, 2012)
`(’742 Patent)
`Expert Declaration of Neal A. Sher, M.D. (Sher)
`Expert Declaration of Paul A. Laskar, Ph.D. (Laskar)
`U.S. Patent No. 6,294,553 (filed Feb. 14, 2001) (issued Sep. 25, 2001)
`(’553 patent)
`Walters, Thomas R., et al. “A Pilot Study of Life Efficacy and Safety of
`AGN 190342-Lf 0.02% And 0.08% In Patients with Elevated Intraocular
`Pressure.” Association for Research in Vision and Ophthalmology, vol. 32,
`no. 4, 15 Mar. 1991, p. 988 (Walters 1991)
`Norden, Richard A. “Effect of Prophylactic Brimonidine or Bleeding
`Complications and Flap Adherence after Laser in Situ Keratomileusis.”
`Journal of Refractive Surgery, vol. 18, no. 4, 2002, pp. 468–471 (Norden
`2002)
`U.S. Patent 6,242,442 (filed Dec. 7, 1999) (issued June 5, 2001) (’442
`patent)
`“ALPHAGAN® (brimonidine tartrate ophthalmic solution) 0.2%.”
`Physicians’ Desk Reference, 52th ed., Medical Economics Company, Inc.,
`1998, p. 487 (Alphagan® Label 1998)
`53 Fed. Reg. 7076-7093 (Mar. 4, 1988) (Federal Register 1988)
`U.S. Application 12/460,941 filed July 27, 2009, downloaded from PAIR
`(’941 Application)
`U.S. Provisional Application 61/207,481 filed February 12, 2009,
`downloaded from PAIR (’481 Provisional)
`
`
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`Case IPR2022-00142
`U.S. Patent No. 8,293,742
`U.S. Provisional Application 61/203,120 filed December 18, 2008,
`downloaded from PAIR (’120 Provisional)
`U.S. Provisional Application 61/192,777 filed September 22, 2008,
`downloaded from PAIR (’777 Provisional)
`U.S. Provisional Application 61/137,714 filed August 1, 2008,
`downloaded from PAIR (’714 Provisional)
`Timmermans, et al., “Structure-Activity Relationships in Clonidine-Like
`Imidazolines and Related Compounds,” Progress in Pharmacology, edited
`by H. Grobecker et al., vol. 3, No. 1, Gustav Fischer Verlag, New York,
`NY, 1980 (Timmermans 1980)
`Griffith, Robert K. “Adrenergics and Adrenergic- Blocking Agents.”
`Burger's Medicinal Chemistry and Drug Discovery, edited by Donald J.
`Abraham, 6th ed., vol. 6, John Wiley & Sons, Inc., New York, NY, 2003,
`pp. 2–37 (Griffith 2003)
`Wickberg-Matsson, Anna, and Ulf Simonsen. “Potent α2A-Adrenoceptor–
`Mediated Vasoconstriction by Brimonidine in Porcine Ciliary Arteries.”
`Investigative Ophthalmology & Visual Science, vol. 42, no. 9, Aug. 2001,
`pp. 2049–2055 (Wikberg 2001)
`Robin, Alan L., and Yochanan Burnstein. “Selectivity of Site of Action
`and Systemic Effects of Topical Alpha Agonists.” Current Opinion in
`Ophthalmology, vol. 9, no. 2, 1998, pp. 30–33 (Robin 1998)
`Lachkar, Yves, and Surinda Dhanjill. “Effect of Brimonidine Tartrate on
`Ocular Hemodynamic Measurements.” Archives of Ophthalmology, vol.
`116, no. 12, Dec. 1998, pp. 1591–1594 (Lachkar 1998)
`Carlsson, Anthony M, et al. “The Effect of Brimonidine Tartrate on
`Retinal Blood Flow in Patients with Ocular Hypertension.” American
`
`1019
`
`1017
`
`1018
`
`1020
`
`
`
`
`
`1021
`
`1022
`
`1023
`
`1024
`
`Case IPR2022-00142
`U.S. Patent No. 8,293,742
`Journal of Ophthalmology, vol. 129, no. 3, Mar. 2000, pp. 297–301
`(Carlsson 2000)
`David, R. “Brimonidine (Alphagan®): A Clinical Profile Four Years after
`Launch.” European Journal of Ophthalmology, vol. 11, no. 2_suppl, 2001,
`pp. S72–S77 (David 2001)
`Schuman, Joel S., et al. “A 1-Year Study of Brimonidine Twice Daily In
`Glaucoma and Ocular Hypertension.” Archives of Ophthalmology, vol.
`115, no. 7, July 1997, pp. 847-852 (Schuman 1997)
`Scruggs, Jennifer T., et al. “The Teardrop Sign: A Rare Dermatological
`Reaction to Brimonidine.” British Journal of Ophthalmology, vol. 84, no.
`6, 2000, pp. 671–672 (Scruggs 2000)
`File Wrapper, U.S. Application 12/460,941 filed July 27, 2009,
`downloaded from PAIR
`Pasquali, Theodore A., et al. “Dilute Brimonidine to Improve Patient
`Comfort and Subconjunctival Hemorrhage After Lasik.” Journal of
`Refractive Surgery, vol. 29, no. 7, 2013, pp. 469–475 (Pasquali 2013)
`Murphy, P. J., et al. “How Red Is a White Eye? Clinical Grading of
`Normal Conjunctival Hyperaemia.” Eye, vol. 21, no. 5, 2006, pp. 633–638
`(Murphy 2007)
`Derick, Robert J., et al. “Brimonidine Tartrate.” Ophthalmology, vol. 104,
`no. 1, Jan. 1997, pp. 131–136 (Derick 1997)
`Burke, James, et al. “Adrenergic and Imidazoline Receptor-Mediated
`Responses to UK-14,304-18 (Brimonidine) in Rabbits and, Monkeys.” The
`Imidazoline Receptor: Pharmacology, Functions, Ligands and Relevance
`to Biology and Medicine, edited by Donald J. Reis, et al., Vol. 763, The
`
`1027
`
`1025
`
`1026
`
`1028
`
`
`
`
`
`1029
`
`1030
`
`1031
`
`Case IPR2022-00142
`U.S. Patent No. 8,293,742
`New York Academy of Sciences, New York, NY, 1995, pp. 78–95. (Burke
`1995)
`David, Robert, et al. “Brimonidine in the Prevention of Intraocular
`Pressure Elevation Following Argon Laser Trabeculoplasty,” Archives of
`Ophthalmology, vol. 111, No. 10, Oct. 1993, pp. 1387–1390 (David 1993)
`U.S. Patent Application Publication No. 2005/0244463 (filed Apr. 30,
`2004) (published Nov. 3, 2005) (US 2005/0244463)
`United States, Center for Drug Evaluation and Research, and Joanne
`Holmes. NDA 20-613 AlphaganTM (Brimonidine Ophthalmic Solution)
`0.2% Sterile, vol. 1, U.S. Food and Drug Administration, 1985, pp. 1–286.
`(CDER Records 20613)
`Rahman, Mamum Q., et al. “Brimonidine for Glaucoma.” Expert Opinion
`Drug Safety, vol. 9, no. 3, 2010, pp. 483–491 (Rahman 2010)
`U.S. Patent No. 6,562,873 (filed July 10, 2001) (issued May 13, 2003)
`(’873 patent)
`Chien, Du-Shieng, et al. “Corneal and Conjunctival/Scleral Penetration of
`P-Aminoclonidine, AGN 190342, and Clonidine in Rabbit Eyes.” Current
`Eye Research, vol. 9, no. 11, 1990, pp. 1051–1059 (Chien 1990)
`Burke, James, and Michal Schwartz. “Preclinical Evaluation of
`Brimonidine.” Survey of Ophthalmology, vol. 41, no. 1, Nov. 1996, pp.
`S9–S18 (Burke 1996)
`Petitioner’s Limitation By Limitation Listing for U.S. Patent No.
`8,293,742
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`1037-
`1042
`
`Not used
`
`
`
`
`
`1043
`
`1044
`
`1045
`
`1046
`
`1047
`
`1048
`
`1049
`
`1050
`
`Case IPR2022-00142
`U.S. Patent No. 8,293,742
`Slayback Defendants’ Stipulation to Limit Invalidity Contentions [D.I. 18]
`in Bausch & Lomb, Inc. et al. v. Slayback Pharma LLC et al., Civil Action
`No. 21-16766 (D.N.J.) (Stipulation)
`Declaration of Robert Frederickson III in Support of Motion for Pro Hac
`Vice Admission
`Bausch Health Companies, 2018 Q3 Earnings Call Transcript, dated
`November 6, 2018
`Side-by-Side Comparison of Figures 2 and 6 of U.S. Patent No. 9,259,425
`(filed October 3, 2013) (issued February 16, 2016) (Noecker)
`Declaration of Ivan T. Hofmann in Support of Petitioner’s Reply
`(Hofmann Reply)
`Declaration of Paul Laskar, Ph.D In Support of Petitioner’s Reply
`Declaration of Neal A. Sher, M.D. in Support of Petitioner’s Reply (Sher
`Reply)
`Deposition Transcript of Stephen G. Davies, DPhil, dated October 28,
`2022
`Deposition Transcript of John Ferris, dated November 2, 2022
`Deposition Transcript of John Jarosz, dated November 11, 2022
`Deposition Transcript of Robert Noecker, M.D., dated November 13, 2022
`Deposition Transcript of Robert O. Williams, III, Ph.D., dated November
`15, 2022
`U.S. Pharmacopeia 28-National Formulary 23, 2005
`Conrad, J.M., Reay, W.A., Polcyn, R.E., and Robinson, J.R., Influence of
`Tonicity and pH on Lacrimation and Ocular Drug Availability, Journal of
`the Parenteral Drug Association, vol. 32, no. 4, pp. 149-161, July-August
`1978 (Conrad 1978)
`
`1051
`1052
`1053
`
`1054
`
`1055
`
`1056
`
`
`
`
`
`1057
`
`1058
`
`1059
`
`1060
`
`Case IPR2022-00142
`U.S. Patent No. 8,293,742
`Gonnering, R., Edelhauser, H.F., Van Horn, D.L., and Durant, W., The pH
`Tolerance of Rabbit and Human Corneal Endothelium, Investigative
`Ophthalmology & Visual Science, vol. 18, no. 4, pp. 373-390, April 1979
`(Gonnering 1979)
`Naphcon A, Alcon Laboratories, Inc.
`Srinivasan, S. and Venkiteshwar, M., A Decade of Effective Dry Eye
`Disease Management with Systane Ultra (Polyethylene Glycol/Propylene
`Glycol with Hydroxypropyl Guar) Lubricant Eye Drops, Clinical
`Ophthalmology, vol. 15, pp. 2421-2435, June 9, 2021 (Srinivasan 2021)
`Brimonidine Tartrate, Drugs@FDA: FDA-Approved Drugs,
`https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overvie
`w.process&ApplNo=020613 (last accessed December 8, 2022)
`Aieta, E.M. & Roberts, P.V. (1985) The chemistry of oxo-chlorine
`compounds relevant to chlorine dioxide generation. In: Jolley, R.L., Bull,
`R.J., Davis, W.P., Katz, S., Roberts, M.H., Jr & Jacobs, V.A., eds, Water
`Chlorination: Chemistry, Environmental Impact and Health Effects, Vol.
`5, Ann Arbor, MI, Lewis Publishers, pp. 783–794 (Aieta 1985)
`Not Used
`Center For Drug Evaluation and Research, Application Number: 21-770
`Medical Review
`Remington: The Science and Practice of Pharmacy, pp. 1380-1416, 1563-
`1576; 1995 (Remington 1995)
`Not Used
`Not Used
`
`1065
`1066
`
`1061
`
`1062
`
`1063
`
`1064
`
`
`
`
`
`1067
`
`Case IPR2022-00142
`U.S. Patent No. 8,293,742
`Patent Assignment Search,
`https://assignment.uspto.gov/patent/index.html#/patent/search/resultFilter?
`searchInput=8293742 (last accessed Dec. 2, 2022)
`Ivan T. Hofmann CV and Testimony
`Bausch SEC Form 10-Q, for the period ended June 30, 2022, available at
`https://otp.tools.investis.com/clients/us/bausch_health_companies/SEC/sec
`
`1068
`
`- s
`
`how.aspx?FilingId=16064281&Cik=0000885590&Type=PDF&hasPdf=1
`(last accessed Nov. 17, 2022)
`Bausch Fourth Quarter 2018 Earnings Call Transcript, dated February 20,
`2019, available at https://seekingalpha.com/article/4242568-bausch-health-
`companies-inc-bhc-ceo-joseph-papa-on-q4-2018-results-earnings-call-
`transcript (last accessed Nov. 17, 2022)
`Bausch Second Quarter 2019 Earnings Call Transcript, dated August 6,
`2019, available at https://seekingalpha.com/article/4282236-bausch-health-
`companies-inc-bhc-ceo-joseph-papa-on-q2-2019-results-earnings-call-
`transcript (last accessed Nov. 17, 2022)
`Bausch Fourth Quarter 2020 Earnings Call Transcript, dated February 24,
`2021, available at https://seekingalpha.com/article/4408646-bausch-health-
`companies-inc-bhc-ceo-joe-papa-on-q4-2020-results-earnings-call-
`transcript (last accessed Nov. 17, 2022)
`Bausch Fourth Quarter 2021 Earnings Call Transcript, dated February 23,
`2022, available at https://seekingalpha.com/article/4489552-bausch-health-
`companies-inc-bhc-ceo-joseph-papa-on-q4-2021-results-earnings-call-
`transcript (last accessed Nov. 17, 2022)
`
`1069
`
`1070
`
`1071
`
`1072
`
`1073
`
`
`
`
`
`1075
`
`1076
`
`1077
`
`1078
`
`1079
`
`1080
`
`1074
`
`Case IPR2022-00142
`U.S. Patent No. 8,293,742
`MUSE Creative Awards, dated Apr. 11, 2019,
`https://www.hg.agency/news/muse-awards (last accessed Nov. 17, 2022).
`MUSE Creative Awards, https://museaward.com/ (last accessed Nov. 17,
`2022)
`Helen & Gertrude, https://www.hg.agency/ (last accessed Nov. 17, 2022)
`2019 Silver Winner, Lumify® Redness Reliever Drops,
`https://museaward.com/winner-info.php?id=2187 (last accessed Nov. 17,
`2022)
`2019 Rose Gold Winner, Lumify® Redness Reliever Drops,
`https://museaward.com/winner-info.php?id=2186 (last accessed Nov. 17,
`2022)
`Wavemaker US wins two Gold Effie Awards, dated June 3, 2019,
`https://wavemakerglobal.com/usa/news-wavemaker-us-wins-two-gold-
`effie-awards (last accessed Nov. 17, 2022)
`Our Work, Wavemaker, https://wavemakerglobal.com/our-work (last
`accessed Nov. 17, 2022)
`Ben Adams, Bausch + Lomb kicks off TikTok challenge for Lumify,
`asking consumers to ‘dance with their eyes,’ FiercePharma (July 29,
`2022), https://www.fiercepharma.com/marketing/bausch-lomb-kickstarts-
`tiktok-campaign-lumify-it-asks-consumers-dance-their-eyes (last accessed
`Nov. 17, 2022)
`Bausch + Lomb Launches the #LUMIFYEyeDance Challenge on TikTok,
`PRNewsWire (July 28, 2022), https://www.prnewswire.com/news-
`releases/bausch--lomb-launches-the-lumifyeyedance-challenge-on-tiktok-
`301594922.html (last accessed Nov. 17, 2022)
`
`1081
`
`1082
`
`
`
`
`
`1083
`
`1084
`
`1085
`
`Case IPR2022-00142
`U.S. Patent No. 8,293,742
`#lumifyeyedance, TikTok,
`https://www.tiktok.com/tag/lumifyeyedance?lang=en (last accessed Nov.
`17, 2022)
`Disclosures 101 for Social Media Influencers, Federal Trade Commission
`(Nov. 2019), https://www.ftc.gov/system/files/documents/plain-
`language/1001a-influencer-guide-508_1.pdf (last accessed Nov. 17, 2022)
`@Allenface, Tik Tok,
`https://www.tiktok.com/@allanface/video/7129967072628657454?is_cop
`y_url=1&is_from_webapp=v1&lang=en (last accessed Nov. 17, 2022)
`@orionsisters, TikTok,
`https://www.tiktok.com/@orionsisters/video/7124396970558459179?is_c
`opy_url=1&is_from_webapp=v1&lang=en (last accessed Nov. 17, 2022)
`Bausch + Lomb #LUMIFYEyeDance Challenge Wins 2022 Public
`Relations and Marketing Excellence Award for External Campaign of the
`Year from Business Intelligence Group, PRNewsWire (Nov. 1, 2022),
`https://www.prnewswire.com/news-releases/bausch--lomb-
`lumifyeyedance-challenge-wins-2022-public-relations-and-marketing-
`excellence-award-for-external-campaign-of-the-year-from-business-
`intelligence-group-301664009.html (last accessed Nov. 17, 2022)
`Wilson, et al., The Corneal Wound Healing Response: Cytokine-mediated
`Interaction of the Epithelium, Stroma, and Inflammatory Cells, Progress in
`Retinal and Eye Research, Volume 20, Issue 5, 2001, Pages 625-637,9462
`https://doi.org/10.1016/S1350-9462(01)00008-8. (Wilson 2001)
`Solomon, et al., Pro- and anti-inflammatory forms of interleukin-1 in the
`tear fluid and conjunctiva of patients with dry-eye disease. Invest
`
`1089
`
`1086
`
`1087
`
`1088
`
`
`
`
`
`1091
`
`1092
`
`1093
`
`1090
`
`Case IPR2022-00142
`U.S. Patent No. 8,293,742
`Ophthalmol Vis Sci. 2001 Sep;42(10):2283-92. PMID: 11527941
`(Solomon 2001)
`Langer S.Z. & Hicks, P.E., Alpha-Adrenorecepter Subtypes in Blood
`Vessels: Physiology and Pharmacology, Journal of Cardiovascular
`Pharmacology, vol. 6, supplement 4, pp. S547-558, 1984 (Langer 1984)
`Duka, et al., Catecholamines induce direct vasoconstriction mediated by
`postsynaptic α-adrenergic receptors (α-ARs) of both the α1 and α2 type.
`General Pharmacology: The Vascular System Volume 34, Issue
`2, February 2000, Pages 101-106 (Duka 2001)
`Philipp M., Brede M., and Hein L., Physiological significance of α2-
`adrenergic receptor subtype diversity: one receptor is not enough,
`American Journal of Physiology: Regulatory, Integrative and Comparative
`Physiology, vol. 2, pp. R287–295, 2002 (Philipp 2002)
`Angus J.A., Cocks T.M., Wright C.E., Satoh K., and Campbell G.R.
`(1988) Endothelium-Dependent Responses in Large Arteries and in the
`Microcirculation, in Vanhoutte P.M., ed., Relaxing and Contracting
`Factors, Humana Press Inc, pp. 361–386 (Angus 1988)
`Bockman C.S., Jeffries W.B., Abel P.W., Binding and Functional
`Characterization of Alpha-2 Adrenergic Receptor Subtypes on Pig
`Vascular Endothelium, Journal of Pharmacology and Experimental
`Therapeutics, vol. 267, no. 3, pp. 1126–1133, 1993 (Bockman 1992)
`Spector S.L. & Raizman M.B., Conjunctivitis Medicamentosa, Journal of
`Allergy and Clinical Immunology, vol. 94, no. 1, pp. 134–136, July 1994
`(Spector 1994)
`Soparkar, C.N.S., et al., Acute and Chronic Conjunctivitis Due
`
`1094
`
`1095
`
`1096
`
`
`
`
`
`1097
`
`1098
`
`1099
`
`1100
`
`1101
`
`1102
`
`Case IPR2022-00142
`U.S. Patent No. 8,293,742
`to Over-the-counter Ophthalmic Decongestants. Arch Ophthalmol 1997;
`115:34-38 (Soparkar 1997)
`Stedman’s Medical Dictionary, 28th Ed, pp. 688-689
`Morrow G.L. & Abbott R.L., Conjunctivitis, American Family Physician,
`vol. 57, no. 4, pp. 735–746, Feb. 15 1998 (Morrow 1998)
`Pink Eye (Conjunctivitis), Mayo Clinic,
`https://www.mayoclinic.org/diseases-conditions/pink-eye/symptoms-
`causes/syc-
`20376355#:~:text=Pink%20eye%20(conjunctivitis)%20is%20an,to%20ap
`pear%20reddish%20or%20pink (last accessed Dec. 14, 2022) (Mayo
`Clinic 2022)
`Subconjunctival hemorrhage - American Academy of Ophthalmology,
`https://www.aao.org/image/subconjunctival-hemorrhage-7 (last accessed
`December 14, 2022)
`Chapter 43: Ophthalmic Solutions of Remington: The Science and Practice
`of Pharmacy (2000)
`Aslanides I.M., et al., Letter to the Editor. Ophthalmology Volume 112,
`Number 12, December 2005. 2238.e8-2238.e9 (Aslanides 2005)
`Aslanides I.M., et al., The Effect of Topical Apraclonidine on
`Subconjunctival Hemorrhage and Flap Adherence in LASIK Patients.
`Journal of Refractive Surgery, Volume 22, June 2006. 585-588
`Hong, S., et al., Effect of Prophylactic Brimonidine Instillation on
`Bleeding During Strabismus Surgery in Adults. American Journal of
`Ophthalmology. Volume 144, Issue 3, pp. 469-470, September 2007
`(Hong 2007)
`
`1103
`
`1104
`
`
`
`
`
`I. INTRODUCTION
`As set forth in the Petition, the challenged claims are either anticipated or
`
`rendered obvious in light of the prior art. Patent Owner’s Response seeks to
`
`obscure the relevant issues and ignores key aspects of the prior art. In all, Patent
`
`Owner’s arguments are insufficient to overcome a finding that the challenged
`
`claims are invalid.
`
`II. CLAIM CONSTRUCTION
`Patent Owner disputes the construction of two terms in the challenged
`
`claims. In both instances, Patent Owner’s arguments unduly narrow the claims and
`
`should be rejected.
`
`A. Ocular Condition
`Patent Owner contends that “ocular condition” should be limited to “a
`
`condition of the eye causing ocular hyperemia,” but does not point to anything in
`
`the specification to support that interpretation. Paper-30, p.25. The ’742 patent
`
`provides a broad, non-limiting list of ocular conditions for which the claimed
`
`invention can be used. EX-1001, 12:13-13:10. This list includes examples of both
`
`redness and hemorrhage that occur after ocular surgeries, and conditions that are
`
`not known to cause hyperemia. EX-1001, 12:15-19; EX-1049, ¶36. Patent
`
`Owner’s claim construction would improperly create a definition for “ocular
`
`condition” in the claims that is narrower than the explicit definition in the
`
`specification. Patent Owner’s argument is specifically aimed at establishing that
`
`
`
`Case IPR2022-00142
`U.S. Patent No. 8,293,742
`radial keratotomy is not an “ocular condition,” but as Dr. Sher explains, there is no
`
`basis for this exclusion, particularly since Patent Owner does not dispute that
`
`LASIK is an ocular condition of the claims. EX-1049, ¶¶45-48. Therefore, Patent
`
`Owner’s arguments attempting to carve out problematic aspects of the prior art
`
`should be rejected.
`
`B.
`“About 0.025%”
`The Board should reject Patent Owner’s attempt to construe “about 0.025%”
`
`to exclude 0.03%. As Patent Owner acknowledges, “the term ‘about’ should be
`
`given its ordinary and accepted meaning of ‘approximately,’ absent patentee acting
`
`as his own lexicographer.” Paper-30, pp.27-28 (citing Merck & Co. v. Teva
`
`Pharms. USA, Inc., 395 F.3d 1364, 1370-72 (Fed. Cir. 2005)). Patent Owner is
`
`wrong, however, that the patentee here was its own lexicographer. Id., p.30. The
`
`standing for lexicography is “exacting.” Hill-Rom Servs., Inc. v. Stryker Corp.,
`
`755 F.3d 1367, 1371 (Fed. Cir. 2014). “To act as its own lexicographer, a patentee
`
`must clearly set forth a definition of the disputed claim term” and must “clearly
`
`express an intent to redefine the term.” Id. Although express definitions for other
`
`terms appear under the heading “Definitions,” there is no definition of “about” or
`
`“about 0.025%.” See EX-1001, 3:55-4:24.
`
`The crux of Patent Owner’s argument is that the ’742 patent separately
`
`refers to “about 0.025%” and “about 0.03%” in “two successive paragraphs.”
`
`
`
`2
`
`
`
`Case IPR2022-00142
`U.S. Patent No. 8,293,742
`Paper-30, p.29. At the outset, the mere use of these terms in the specification is
`
`not lexicography. See Micron Tech., Inc. v. Lone Star Silicon Innovations LLC,
`
`IPR2017-01562, 2018 WL 6602102, *4-*5 (P.T.A.B. Dec. 13, 2018) (finding
`
`individual embodiments do not amount to lexicography). Notably, the “two
`
`successive paragraphs” referred to in the specification have nothing to do with
`
`reducing eye redness, and Patent Owner offers no explanation for why the cited
`
`embodiments change the commonly used meaning of “about.”1 EX-1001, 8:46-55;
`
`8:56-63.
`
`Patent Owner’s claim that the patentee acted as a lexicographer is
`
`particularly untenable in view of its separate argument—based entirely on extrinsic
`
`evidence—that “about” should mean ±10%. Paper-30, pp.35-36. Patent Owner
`
`relies on “typical” FDA acceptance criteria and a notation in the U.S.P. for this
`
`definition (id.), but cannot point to anything in the ’742 patent that adopts the
`
`numerical limitations of this extrinsic evidence. See Microsoft Corp. v. Mira
`
`
`1 Patent Owner’s logic is also flawed. Even if the patentee intended “about
`
`0.025%” and “about 0.03%” to have separate meanings, the two ranges could still
`
`overlap and “about 0.025%” could still capture a brimonidine concentration of
`
`0.03%. EX-1048, ¶¶14-15 (illustrating that Patent Owner’s alternative
`
`construction of “about” also results in overlapping ranges).
`
`
`
`3
`
`
`
`Case IPR2022-00142
`U.S. Patent No. 8,293,742
`Advanced Tech., Inc., IPR2017-01411, 2018 WL 6204170, *12 (P.T.A.B. Nov. 27,
`
`2018) (“Upon weighing the competing extrinsic evidence …, we find Patent
`
`Owner’s extrinsic evidence is not sufficient to overcome the plain meaning….”).
`
`Even taking this extrinsic evidence into account, FDA acceptance criteria are not
`
`an appropriate guidepost for these claims. As Dr. Laskar explains, and Dr.
`
`Williams agrees, there is no requirement from the FDA that all acceptance criteria
`
`be set at ±10%. EX-1048, ¶¶9-13; EX-1054, 26:2-14. Additionally, a POSA
`
`would have recognized that the FDA acceptance criteria and U.S.P. definitions
`
`serve a different purpose than the language of the challenged claims. EX-1048,
`
`¶¶7-10. Therefore, a POSA would not have understood “about” to mean ±10% in
`
`the context of the ’742 patent. Id., ¶¶9-13.
`
`Having failed to establish lexicography, the inquiry turns to the “criticality
`
`of the [numeric limitation] to the invention.” Ortho-McNeil Pharm., Inc. v.
`
`Caraco Pharm. Lab’ys, Ltd., 476 F.3d 1321, 1327 (Fed. Cir. 2007); Par Pharm.,
`
`Inc. v. Hospira, Inc., 835 F. App’x 578, 584 (Fed. Cir. 2020) (construing the
`
`claims based on “the purpose of the upper limit” of a range). Importantly, the ’742
`
`patent represents that the maximum “Net Vasoconstriction Benefit” peaks at
`
`around 0.03% brimonidine. EX-1001, 19:52-55. Patent Owner does not dispute
`
`that this curve represents the benefit of the invention after accounting for any
`
`adverse effects, such as rebound hyperemia, indicating that “around 0.03%” would
`
`
`
`4
`
`
`
`Case IPR2022-00142
`U.S. Patent No. 8,293,742
`be the optimal concentration for maximum benefit, not some arbitrary number
`
`below the peak. EX-1053, 86:7-17.
`
`The prosecution history further confirms that the patentee saw no
`
`meaningful difference between brimonidine concentrations of 0.025% and 0.03%.
`
`Figure 4 of the ’481 provisional is another, similar “graphical depiction … of the
`
`variation of clinical effectiveness against concentration for compositions
`
`comprising … brimonidine….” EX-1011, p.68. Applicant explained that “[t]he
`
`net vasoconstrictive effect curve (vasoconstriction - rebound) is shown by the
`
`thicker light gray curve, and peaks at ~ 0.025% +/- 0.01% (intersecting dashed
`
`lines).” Id., p.111. Thus, the applicant represented that the maximum clinical
`
`benefit occurs in the range of 0.015% to 0.035%,2 confirming that 0.025% is not
`
`critical. EX-1049, ¶22.
`
`Patent Owner places particular emphasis on the unlabeled curve in Figure 6
`
`that Patent Owner refers to as representing “Rebound Hyperemia,” but its reliance
`
`on this Figure is misplaced for several reasons. Paper-30, pp.33-35. First, Figure 6
`
`contains no information about how any observations reported were made; there is
`
`
`2 Unlike Patent Owner’s construction here, it appears that the applicant used
`
`± 0.01% to refer to a literal range around 0.025%, rather than referring to a range
`
`that was 0.01% of 0.025% (± 0.00025%). EX-1048, ¶16.
`
`
`
`5
`
`
`
`Case IPR2022-00142
`U.S. Patent No. 8,293,742
`no scale on the y-axis; there are no error bars or any accounting for variability.
`
`EX-1001, Fig. 6; EX-1049, ¶¶13-17. Patent Owner has not made any
`
`representation, nor can it, that Figure 6 contains data from a clinical study. EX-
`
`1053, 89:2-90:3. Second, as the Board acknowledged, the patentee explained that
`
`Figure 6 represents “finding[s] of the present invention” and that “the net
`
`effectiveness of brimonidine as a decongestant is greatest between about 0.01%
`
`and about 0.03%; preferably, between about 0.012% and about 0.02%.” Paper-13,
`
`pp.10-11; EX-1001, 19:52-57. Nothing in the text of the specification identifies
`
`0.025% as having any criticality to the claimed redness reducing invention.3 See
`
`Vitronics Corp. v. Conceptronic, Inc., 90 F.3d 1576, 1583 (Fed. Cir. 1996).
`
`Finally, Patent Owner’s argument also ignores Figure 2. Assuming the
`
`figures have the same key, Dr. Noecker admitted that the rebound hyperemia
`
`curves appear at different places in the two figures. See EX-1046; EX-1053, 91:2-
`
`93:9. These differences highlight the illustrative nature of these figures, and as a
`
`result, a POSA would not have drawn exacting conclusions regarding any specific
`
`data points. The specification does not distinguish between the clinical results at
`
`
`3 In fact, Patent’s Owner’s representations regarding where 0.025% appears on the
`
`x-axis conflict with the applicants’ representations to the Patent Office. EX-1049,
`
`¶¶27-29.
`
`
`
`6
`
`
`
`Case IPR2022-00142
`U.S. Patent No. 8,293,742
`0.025% and 0.03% brimonidine, and a POSA would not have imported such
`
`meaning to these figures. EX-1049, ¶¶28-29.
`
`III. THE ’553 PATENT ANTICIPATES CLAIMS 1 AND 2
`Patent Owner does not dispute that the ’553 patent discloses administration
`
`of 0.03% brimonidine to patients that underwent radial keratotomy. Paper-30,
`
`p.41. Instead, Patent Owner advances the two claim construction arguments
`
`discussed above—(1) whether the 0.03% brimonidine meets the “about 0.025%”
`
`limitation of the claims and (2) whether the radial keratotomy patients in the ’553
`
`patent suffer from an “ocular condition.” As discussed above, under the proper
`
`claim constructions, 0.03% falls within the scope of the challenged claims, and
`
`radial keratotomy is an “ocular condition.”
`
`Aside from claim construction, Patent Owner only disputes whether the
`
`radial keratotomy patients would have had redness that was actually reduced.
`
`Paper-30, pp.41-43. Here, Patent Owner incorrectly presumes that claims 1 and 2
`
`require efficacy—i.e., redness to actually be reduced. See Paper-30, pp.40-42. But
`
`the challenged claims contain no efficacy requirement, and there is no basis for
`
`reading one into the claims. Mylan Pharms. Inc. v. Regeneron Pharms., Inc., No.
`
`IPR2021-00881, 2022 WL 16842073, at *10 (P.T.A.B. Nov. 9, 2022) (“We reject
`
`Patent Owner’s proposed construction because it requires importing limitations
`
`into the claims.”). At most, the claims require that the composition be
`
`
`
`7
`
`
`
`Case IPR2022-00142
`U.S. Patent No. 8,293,742
`administered with the intent to reduce redness. Id., *8. Example 1 of the ’553
`
`patent discloses such a method.
`
`The ’553 patent discloses administering 0.03% brimonidine with the intent
`
`of monitoring for a reduction in signs of ocular inflammation. EX-1004, 4:45-5:2.
`
`It is undisputed that redness is a sign of ocular inflammation. EX-1004, 5:38-40;
`
`EX-2020, ¶146. Therefore, Example 1 of the ’553 patent discloses a method that
`
`sought to reduce redness by administering low dose brimonidine, as claimed in the
`
`challenged claims, and the inquiry should end there.
`
`Assuming, however, that the claims require an actual reduction of redness,
`
`the ’553 patent also inherently discloses this feature. As the Boar