Inter Partes Review
`United States 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
`
`Patent No. 8,293,742
`Filing Date: July 27, 2009
`Issue Date: October 23, 2012
`
`Title
`PREFERENTIAL VASOCONSTRICTION COMPOSITIONS
`AND METHODS OF USE
`
`
`Case No. IPR2022-00142
`
`
`
`PETITION FOR INTER PARTES REVIEW
`Filed November 4, 2021
`
`
`
`1
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`Inter Partes Review
`United States Patent No. 8,293,742
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`
`TABLE OF CONTENTS
`
`Page
`
`TABLE OF AUTHORITIES ..................................................................................... 7 
`LISTING OF EXHIBITS ........................................................................................... 9
`I.
`INTRODUCTION ......................................................................................... 12
`
`
`
`
`
`
`
`
`
`Summary of Grounds .......................................................................... 14
`
`Chain of Priority -- Earliest Effective Filing Date .............................. 14
`
`Person of Ordinary Skill in the Art (POSA) ....................................... 15
`
`Background Facts ................................................................................ 15
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`Vasoconstrictor Eye Drops to Reduce Eye Redness Were
`Known ....................................................................................... 15
`
`2-Imidazoline Derivatives Were Known as Vasoconstrictors
`to Reduce Eye Redness ............................................................. 16
`
`Brimonidine Was Known as Potent Vasoconstrictor With
`Favorable Properties for Reducing Eye Redness ...................... 17
`
`Brimonidine Was Approved in 1996 for Eye Drops ................ 19
`
`Prior Art Disclosed Brimonidine Drops to Reduce Eye
`Redness from LASIK Surgery .................................................. 21
`
`Prior Art Discloses “Low Concentrations” of Brimonidine,
`The Alleged Basis of the Claimed Invention ............................ 22
`
`Prior Art Disclosed Brimonidine Eye Drops With pH 6.3
`to 6.5 .......................................................................................... 23
`
`II. U.S. PATENT 8,293,742 ............................................................................... 24
`
`
`
`Summary of the “Present Invention” .................................................. 24
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`Inter Partes Review
`United States Patent No. 8,293,742
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`Background of the Invention ............................................................... 24
`
`“Brimonidine” Is Defined Broadly ..................................................... 25
`
`“Ocular Conditions” Are Listed Broadly ............................................ 25
`
`The 0.02% and 0.03% Brimonidine of the Prior Art Fall Within
`Preferred Ranges of the ‘742 Patent .................................................... 26
`
`
`
`
`
`
`
`
`
`III. CLAIM CONSTRUCTION .......................................................................... 26
`
`
`
`
`
`
`
`Claim Construction Is Needed for “about 0.025%” ............................ 26
`
`“about 0.025%” Includes “0.03%” ...................................................... 27
`
`“Ocular condition” .............................................................................. 31
`
`IV. CLAIMS 1-6 ARE UNPATENTABLE ........................................................ 32
`
` Ground 1: Claims 1-2 Anticipated by ‘553 Patent ............................. 32
`
`1.
`
`2.
`
`U.S. Patent 6,294,553 ............................................................... 32
`
`Claim 1: Anticipated by ‘553 Patent Example 1 ...................... 33
`
`a.
`
`b.
`
`c.
`
`d.
`
`[1.P] “[a] method for reducing eye redness” .................. 33
`
`[1.1] “consisting essentially of administering
`brimonidine” ................................................................... 34
`
`[1.2] “to a patient having an ocular condition” .............. 35
`
`[1.3] “wherein brimonidine is present at a
`concentration between about 0.001% weight by
`volume and about 0.05% weight by volume” ................ 35
`
`3.
`
`Claim 2: Anticipated by the ‘553 Patent ................................... 36
`
`a.
`
`[2.1] “wherein brimonidine is present at a
`concentration between about 0.001% to about
`0.025% weight by volume” ............................................ 36
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`United States Patent No. 8,293,742
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` Ground 2: Claims 1-2 Anticipated by Walters 1991 .......................... 37
`
`1. Walters 1991 ............................................................................. 37
`
`2.
`
`Claim 1: Anticipated by Walters 1991 ..................................... 40
`
`a.
`
`b.
`
`c.
`
`d.
`
`[1.P] “A method for reducing eye redness”.................... 40
`
`[1.1] “consisting essentially of administering
`brimonidine” ................................................................... 41
`
`[1.2] “to a patient having an ocular condition” .............. 42
`
`[1.3] “wherein brimonidine is present at a
`concentration between about 0.001% weight by
`volume and about 0.05% weight by volume” ................ 42
`
`3.
`
`Claim 2: Anticipated by Walters 1991 ..................................... 43
`
`a.
`
`[2.1] “wherein brimonidine is present at a
`concentration between about 0.001% to about 0.025%
`weight by volume” .......................................................... 43
`
` Ground 3: Claims 1-6 Are Obvious ................................................... 44
`
`1.
`
`Patents and Printed Publications Listed in Ground 3 ............... 44
`
`a.
`
`b.
`
`c.
`
`d.
`
`e.
`
`‘553 Patent ...................................................................... 44
`
`Norden 2002 ................................................................... 46
`
`‘442 Patent ...................................................................... 48
`
`Alphagan® Label 1998 ................................................... 48
`
`Federal Register 1988 ..................................................... 49
`
`2.
`
`Claims 1-6 Are Obvious Claim By Claim Analysis ................. 50
`
`a.
`
`Claim 3 is Obvious ......................................................... 50
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`Inter Partes Review
`United States Patent No. 8,293,742
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`
`[3.P] “A method for reducing eye redness
`consisting essentially of” [3.1] “topically
`administering to a patient having an ocular
`condition a composition” ..................................... 50
`
`[3.2] “to a patient having an ocular condition” .... 51
`
`[3.3] “a composition consisting essentially of
`brimonidine” ......................................................... 52
`
`[3.4] “into ocular tissue” ...................................... 54
`
`[3.5] wherein pH of said composition is
`between about 5.5 and about 6.5 .......................... 55
`
`[3.6] “wherein said brimonidine concentration
`is between about 0.001% and about 0.025%
`weight by volume” ............................................... 56
`
`i.
`
`ii.
`
`iii.
`
`iv.
`
`v.
`
`vi.
`
`b.
`
`c.
`
`d.
`
`e.
`
`Claim 1 Is Obvious ......................................................... 60
`
`Claim 2 Is Obvious ......................................................... 60
`
`Claim 4 Is Obvious ......................................................... 61
`
`Claims 5 and 6 Are Obvious........................................... 62
`
` A Proper Comparison to the Prior Art Would Be to the 0.02%
`Brimonidine in Walters 1991 or the 0.03% Brimonidine in
`Example 1 of the ‘553 Patent .............................................................. 63
`
`
`
`The ‘553 Patent, Norden 2002 and Walters 1991 Were Not
`Before the Examiner During Prosecution ........................................... 64
`
`V. MANDATORY NOTICES ........................................................................... 65
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`Real Parties-In-Interest ........................................................................ 65
`
`Related Matters .................................................................................... 65
`
`Identification of Counsel and Service Information ............................. 66
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`United States Patent No. 8,293,742
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`VI. CERTIFICATION UNDER 37 C.F.R. § 42.24(d) ........................................ 67
`
`VII. GROUNDS FOR STANDING ...................................................................... 67
`
`VIII. STATEMENT OF PRECISE RELIEF REQUESTED FOR EACH
`CLAIM CHALLENGED .............................................................................. 67
`
`IX. CONCLUSION .............................................................................................. 68
`
`CERTIFICATE OF SERVICE ................................................................................ 69
`
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`United States Patent No. 8,293,742
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`TABLE OF AUTHORITIES
`
`Page
`
`Cases
`Alcon Research, Ltd. v. Apotex Inc.,
`687 F.3d 1352 (Fed. Cir. 2012) .................................................................... 33, 40
`Cohesive Techs. v. Water Corp.,
`543 F.3d 1351 (Fed. Cir. 2008) .............................................................. 27, 28, 30
`E.I. Dupont De Nemours & Co. v. SYNVINA C.V.,
`904 F.3d 996 (Fed. Cir. 2019) ...................................................................... 57, 58
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398, 127 S. Ct. 1727 (2007) ................................................................. 58
`Monsanto Tech. LLC v. E.I. DuPont de Nemours & Co.,
`878 F.3d 1336 (Fed. Cir. 2018) .......................................................................... 27
`Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co. Ltd.,
`868 F.3d 1013 (Fed. Cir. 2017) .......................................................................... 26
`
`
`Statutes
`35 U.S.C. §102(b) .............................................................................................passim
`35 U.S.C. § 103(a) ............................................................................................. 12, 67
`35 U.S.C. § 311(a) ................................................................................................... 64
`35 U.S.C. § 314(a) ................................................................................................... 64
`35 U.S.C. § 315(d) ................................................................................................... 65
`37 C.F.R. § 42.24(d) ................................................................................................ 67
`37 C.F.R. § 42.122(a) ............................................................................................... 65
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`United States Patent No. 8,293,742
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`Other Authorities
`83 Fed. Reg. 51,340, 51,353 (Oct. 11, 2018) ........................................................... 26
`
`Patents
`U.S. Patent No. 6,242,442 .................................................................................passim
`U.S. Patent No. 6,294,553 .................................................................................passim
`U.S. Patent No. 6,562,873 ........................................................................................ 55
`U.S. Patent No. 8,293,742 .................................................................................passim
`U.S. Patent No. 9,259,425 .................................................................................. 65, 66
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`Inter Partes Review
`United States Patent No. 8,293,742
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`
`LISTING OF EXHIBITS
`
`Exhibit
`1001
`
`1002
`1003
`1004
`
`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)
`1005 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)
`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
`
`1006
`
`1007
`
`1008
`
`1009
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`
`1015
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`{80276397:1}
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`United States Patent No. 8,293,742
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`1016
`
`1018
`
`1019
`
`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)
`1017 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
`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)
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
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`United States Patent No. 8,293,742
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`
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`1026 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 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
`
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`Inter Partes Review
`United States Patent No. 8,293,742
`
`Petitioner Slayback Pharma LLC requests inter partes review (IPR) of claims
`
`1-6 of U.S. Patent 8,293,742 (EX-1001, ‘742 patent), assigned to Eye Therapies,
`
`LLC (Patent Owner). This Petition relies on prior art patents and printed
`
`publications and is supported by the Declaration of Neal A. Sher, M.D., an expert in
`
`ophthalmology and LASIK surgery (EX-1002) and the Declaration of Paul A.
`
`Laskar, Ph.D., an expert in ophthalmic formulations (EX-1003).
`
`This Petition shows claims 1 and 2 anticipated under pre-AIA 35 U.S.C.
`
`§102(b) by two references: U.S. Patent 6,294,553 (EX-1004, ‘553 patent)
`
`(Ground 1) and Walters 1991 (EX-1005) (Ground 2). This petition also shows that
`
`claims 1-6 are obvious under pre-AIA 35 U.S.C. § 103(a) (Ground 3).
`
`I.
`
`INTRODUCTION
`The ‘742 patent relates to vasoconstrictor ocular drops (eye drops) to reduce
`
`eye redness. Claims 1-6 are directed to using brimonidine as the vasoconstrictor
`
`compound.
`
`Brimonidine was a prior art compound known to be a potent vasoconstrictor
`
`and was approved by U.S. FDA in eye drops for lowering intraocular pressure in
`
`patients with open angle glaucoma or ocular hypertension. A person of ordinary
`
`skill in the art (POSA) had a reasonable expectation that brimonidine would be
`
`useful to reduce eye redness. Indeed, prior art reported refractive surgeons used
`
`brimonidine drops to reduce eye redness from LASIK surgery.
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`United States Patent No. 8,293,742
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`LASIK is a refractive surgery on the cornea to improve vision. Many patients
`
`consider eye redness from LASIK and other refractive surgery to be annoying,
`
`unappealing and unwanted. Norden 2002 (EX-1006) reported refractive surgeons
`
`were administering brimonidine to “improve the postoperative appearance.” Norden
`
`2002 presented results from a clinical study where 0.2% brimonidine eye drops
`
`significantly reduced subconjunctival bleeding and hyperemia (eye redness) in
`
`LASIK patients.
`
`Simply put, there was nothing new about using brimonidine to reduce eye
`
`redness. Undaunted, the ‘742 patent asserts the alleged invention resides in using
`
`brimonidine at “low concentrations,” i.e., below “about 0.05%.” This Petition
`
`establishes that use of these so-called “low concentrations” to reduce eye redness is
`
`anticipated by and obvious over the prior art.
`
`Ground 1 demonstrates the ‘553 patent (EX-1004) anticipates claims 1 and 2.
`
`The ‘553 patent discloses administering 0.03% brimonidine drops in conjunction
`
`with radial keratotomy. Radial keratotomy is refractive surgery that preceded
`
`LASIK. As with LASIK, radial keratotomy also makes the eye look red. The
`
`Examiner did not consider the ‘553 patent.
`
`Ground 2 demonstrates Walters 1991 (EX-1005) anticipates claims 1 and 2.
`
`Walters 1991 discloses administering 0.02% brimonidine drops to patients with
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`United States Patent No. 8,293,742
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`open-angle glaucoma or ocular hypertension. The Examiner did not consider
`
`Walters 1991.
`
`Ground 3 demonstrates claims 1-6 of the ‘742 patent are obvious over the ‘553
`
`patent in combination with Norden 2002 and other prior art patents and printed
`
`publications.
`
` Summary of Grounds
`
`Ground 1
`
`Claims 1-2 anticipated by ‘553 patent (EX-1004)
`
`Ground 2
`
`Claims 1-2 anticipated by Walters 1991 (EX-1005)
`
`Ground 3
`
`Claims 1-6 obvious over ‘553 patent (EX-1004) in combination
`
`with Norden 2002 (EX-1006), U.S. Patent 6,242,442 (EX-1007,
`
`‘442 patent), Alphagan® Label 1998 (EX-1008) and Federal
`
`Register 1988 (EX-1009)
`
`
`
` Chain of Priority -- Earliest Effective Filing Date
`The ‘742 patent’s earliest effective filing date is August 1, 2008.
`
`The ‘742 patent issued October 23, 2012 from U.S. Application 12/460,941
`
`(EX-1010, ‘941 Application), filed July 27, 2009. It claims priority to U.S.
`
`Provisional Application 61/207,481 (EX-1011, ‘927 Provisional) filed February 12,
`
`2009; U.S. Provisional Application 61/203,120 (EX-1012, ‘120 Provisional) filed
`
`December 18, 2008; U.S. Provisional Application 61/192,777 (EX-1013, ‘777
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`Inter Partes Review
`United States Patent No. 8,293,742
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`Provisional) filed September 22, 2008; and U.S. Provisional Application 61/137,714
`
`(EX-1014, ‘714 Provisional) filed August 1, 2008. Petitioner does not concede the
`
`foregoing applications support any of the challenged claims.
`
`Based on the August 1, 2008 filing date of the ‘714 Provisional (EX-1014),
`
`patents and printed publication publically available before August 1, 2007 are prior
`
`art to the ‘742 patent under pre-AIA 35 U.S.C §102(b).
`
`
`Person of Ordinary Skill in the Art (POSA)
`A POSA was a composite person (or team) that included a medical doctor and
`
`a pharmaceutical formulator. EX-1002, Sher, ¶26; EX-1003, Laskar, ¶29. The
`
`medical doctor was an ophthalmologist with at least three to four years of experience
`
`in LASIK surgery, clinical trials and U.S. FDA regulation of eye products, and had
`
`experience in the use of topical brimonidine and apraclonidine and topical
`
`vasoconstrictors such as naphazoline and tetrahydrozoline. EX-1002, Sher, ¶26. The
`
`pharmaceutical formulator had a doctorate in pharmaceutics or a related degree and
`
`at least three to five years of experience developing eye drop formulations for
`
`clinical trial and regulatory approval. EX-1003, Laskar, ¶29.
`
` Background Facts
`1.
`Vasoconstrictor Eye Drops to
`Reduce Eye Redness Were Known
`The use of vasoconstrictor-based eye drops to reduce eye redness was well-
`
`established. In the late 1980s U.S. FDA required labels for over-the-counter (OTC)
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`vasoconstrictor eye drops to identify the product as a “redness reliever.” Federal
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`Register 1988 (EX-1009, p.7092); EX-1003, Laskar, ¶31.
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`2.
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`2-Imidazoline Derivatives Were Known as
`Vasoconstrictors to Reduce Eye Redness
`“2-imadazoline derivatives” take their name from an imidazoline moiety (red)
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`substituted at the 2- position:
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`
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`2-Imidazoline
`
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`EX-1003, Laskar, ¶32.
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`Going back to at least the 1980’s, naphazoline and tetrahydrozoline were
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`2-imidazoline derivatives used as vasoconstrictor compounds in OTC redness
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`reducing drops. Federal Register 1988 (EX-1009, p. 7089); EX-1003, Laskar, ¶33.
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`Like naphazoline and tetrahydrozoline, brimonidine is a 2-imidazoline
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`derivative:
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`
`
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` Naphazoline Brimonidine Tetrahydrozoline
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`EX-1003, Laskar, ¶33.
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`Timmermans 1980 (EX-1015, p. 30, Fig. 34) shows structures for naphazoline
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`and tetrahydrozoline (“tetryzoline”). EX-1003, Laskar, ¶34. Timmermans 1980
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`(EX-1015, p. 28, Fig 31) shows the structure of brimonidine (“UK-14,304-18”). EX-
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`1003, Laskar, ¶34. Timmermans 1980 (EX-1015, p. 1) discusses the use of
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`imidazoline derivatives “in practical pharmacotherapy” as vasoconstrictors that “can
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`temporarily relieve the unpleasant symptoms of rhinitis or conjunctivitis, as a result
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`of vasoconstriction within the congested tissues.” EX-1003, Laskar, ¶34. The
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`classic symptom of conjunctivitis is a red eye. EX-1002, Sher, ¶28.
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`Griffith 2003 (EX-1016, p. 13) describes naphazoline and tetrahydrozoline as
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`imidazoline α1-agonists “widely employed as vasoconstrictors for treating []
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`bloodshot eyes,” and brimonidine as “[c]losely related to the imidazoline
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`α1-agonists” (Id. p. 30). EX-1003, Laskar, ¶35.
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`3.
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`Brimonidine Was Known as Potent Vasoconstrictor
`With Favorable Properties for Reducing Eye Redness
`Because brimonidine was a 2-imidazoline derivative with a bicyclic
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`substituent similar to naphazoline and tetrahydrozoline, a POSA had a reasonable
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`expectation that brimonidine was a vasoconstrictor that could be used to reduce eye
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`redness. EX-1003, Laskar, ¶36. But Petitioner does not rest on the expectation of
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`brimonidine’s vasoconstrictor activity. Rather, prior art described brimonidine as a
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`“potent” vasoconstrictor compound. Wikberg 2001 (EX-1017, p. 2049) (“The α2-
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`adrenoceptor agonists brimonidine, apraclonidine, and oxymetazoline are potent
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`vasoconstrictors in the porcine ciliary artery.”); Norden 2002 (EX-1006, p. 468)
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`(“the alpha-2 adrenergic agonist drugs as a class are also considered to be strong
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`vasoconstrictors). EX-1002, Sher, ¶31. The ‘742 patent admits brimonidine was a
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`known vasoconstrictor. EX-1001, 1:61-63 (“It is a known property of all
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`a adrenergic receptor agonists, including brimonidine, to cause vasoconstriction.”);
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`EX-1002, Sher, ¶31; EX-1003, Laskar, ¶55.
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`In addition to teaching brimonidine was a vasoconstrictor, prior art taught
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`brimonidine caused vasoconstriction primarily in the front (anterior) part of the eye
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`but not the posterior part (where vasoconstriction was not needed and not desirable).
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`Robin 1998 (EX-1018, p. 32) (“Locally in the eye, both brimonidine and
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`apraclonidine produce anterior segment (i.e., conjunctiva, iris, ciliary body)
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`vasoconstriction.”); Lachkar 1998 (EX-1019, p. 1593) (“Topically applied 0.2%
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`brimonidine tartrate . . . does not appear to alter the hemodynamics of the posterior
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`segment of the eye.”); ‘442 Patent (EX-1007, 2:35-38) (“Upon topical ocular
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`administration brimonidine causes vasoconstriction in scieral [scleral] vessels.
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`However, brimonidine does not appear to be a vasoconstrictor in vessels in the back
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`of the eye.”); Carlsson 2000 (EX-1020, p. 301) (“topical brimonidine reduces
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`intraocular pressure without altering retinal blood flow.”); Norden 2002 (EX-1006,
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`p. 468) (“two independent clinical studies have shown that brimonidine does not
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`significantly alter posterior segment hemodynamics”); EX-1002, Sher, ¶32. A
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`POSA considered brimonidine’s site specific vasoconstrictor activity an important
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`property in reducing eye redness because vasoconstriction is only needed in the front
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`part of the eye. EX-1002, Sher, ¶33.
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`Brimonidine’s potent vasoconstrictor activity, selective for the front of the
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`eye, made brimonidine an excellent choice for a redness reducing eye drop. Id.
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`4.
`Brimonidine Was Approved in 1996 for Eye Drops
`Because the eye is delicate and sensitive, and eyesight so important to quality
`
`of life, not all chemical compounds are suitable for the eye. EX-1003, Laskar, ¶40.
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`For this reason, at all relevant times U.S. FDA was especially careful about
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`chemicals it would approve for eye drops. Id. Therefore, it was significant to a
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`POSA that U.S. FDA approved brimonidine for eye drops in 1996, more than ten
`
`years before the ‘742 patent’s earliest effective filing date. David 2001 (EX-1021,
`
`p. S72); EX-1003, Laskar, ¶40. In fact, medical literature reported “30 million units
`
`dispensed” the first four years after launch. Id.; EX-1003, Laskar, ¶40.
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`In addition, brimonidine was considered to be safe, well-tolerated, and with a
`
`low rate of allergic response. Schuman 1997 (EX-1022, p. 847) (“Brimonidine is
`
`safe . . . well tolerated, and has a low rate of allergic response.”); David 2001 (EX-
`
`1021, p. s76) (“all known side effects of brimonidine are generally minor and
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`transient”); EX-1002, Sher, ¶35.
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`Although prior approval of brimonidine eye drops (i.e. Alphagan®) was to
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`lower intraocular pressure and not reduce eye redness, prior U.S. FDA approval, and
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`over decade of use, gave a POSA confidence that brimonidine could be used safely
`
`in topical eye drops. EX-1002, Sher, ¶36; EX-1003, Laskar, ¶42.
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`Also, it had been reported that brimonidine drops dripping from the eye
`
`caused “blanching,” i.e. whitening, of the skin on the cheeks, further suggesting that
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`brimonidine could be used to reduce eye redness. Scruggs 2000 (EX-1023, p. 671);
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`EX-1002, Sher, ¶99; EX-1003, Laskar, ¶93.
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`Thus, there were excellent reasons why a POSA had a reasonable expectation
`
`that brimonidine could be used as a vasoconstrictor in topical eye drops to reduce
`
`redness:
`
`a) 2-imidazoline derivatives had been in commercial use for decades
`
`as vasoconstrictor compounds in redness reducing topical eye drops;
`
`b) brimonidine was a 2-imidazoline derivative and was known to be a
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`potent vasoconstrictor;
`
`c) brimonidine was known to exert its vasoconstrictor activity on the
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`front but not the back portion of the eye;
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`d) brimonidine was approved by the U.S. FDA for use in a topical eye
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`drop for over ten years;
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`e) brimonidine was considered to be safe, well tolerated and with a low
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`Inter Partes Review
`United States Patent No. 8,293,742
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`rate of allergic response; and
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`f) it had been reported that brimonidine drops dripping from the eye
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`caused “blanching,” i.e. whitening, of the skin on the cheeks.
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`EX-1002, Sher, ¶37; EX-1003, Laskar, ¶43
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`Tellingly, use of brimonidine to reduce eye redness was more than a
`
`reasonable expectation. Indeed, prior art reported refractive surgeons used
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`brimonidine drops to reduce eye redness associated with LASIK surgery. Norden
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`2002 (EX-1006, p. 468); EX-1002, Sher, ¶38.
`
`5.
`
`Prior Art Disclosed Brimonidine Drops to
`Reduce Eye Redness from LASIK Surgery
`Brimonidine eye drops to reduce eye redness was more than a reasonable
`
`expectation. Much more. Norden 2002 (EX-1006) discloses the actual use of 0.2%
`
`brimonidine drops to reduce eye redness caused by LASIK surgery. LASIK is a
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`refractive surgery involving the cornea that uses a lamellar incision to modify its
`
`curvature and improve vision. EX-1002, Sher, ¶38. Petitioner’s ophthalmology
`
`expert, Dr. Sher, is an expert in LASIK who has performed 1000s of LASIK
`
`surgeries and related procedures. Id., ¶3. Norden 2002 (p. 468) reported refractive
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`surgeons were administering brimonidine
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`to “improve
`
`the postoperative
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`appearance” (eye redness) of their patients. EX-1002, Sher, ¶38. Norden 2002 (p.
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`468) presented a clinical study “in patients who underwent LASIK with or without
`
`prophylactic brimonidine.” Norden 2002 (p. 470) reported the “amount of
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`hyperemia” (eye redness) “was notably lower in the eyes treated prophylactically
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`with brimonidine.” EX-1002, Sher, ¶38.
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`6.
`
`Prior Art Discloses “Low Concentrations” of Brimonidine,
`The Alleged