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`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`
`SLAYBACK PHARMA LLC,
`
`Petitioner,
`
`v.
`
`EYE THERAPIES, LLC,
`
`Patent Owner.
`
`__________________
`
`Case IPR2022-00142
`U.S. Patent No. 8,293,742
`__________________
`
`PATENT OWNER’S RESPONSE
`
`
`

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`Case IPR2022-00142
`Patent Owner Response
`
`
`Table of Contents
`
`
`I.
`
`
`
`
`
`
`
`Preliminary Statement ..................................................................................... 2
`The ’742 patented invention: a clinically acclaimed, instant
`marketplace success .............................................................................. 2
`The ’742 patented invention: prima facie non-obvious ........................ 3
`Strong objective evidence of non-obviousness ..................................... 6
`The POSA ........................................................................................................ 7
`II.
`III. The ’742 Patent ................................................................................................ 8
`IV. Technical Background ..................................................................................... 9
` Anatomy of the eye and drug delivery .................................................. 9
`Ocular Conditions ................................................................................ 12
`1.
`Glaucoma .................................................................................. 12
` Overview ............................................................................... 12
` Treatments ............................................................................. 13
`Eye Redness .............................................................................. 13
`2.
`State of the art of adrenergic receptor agonists ................................... 15
`1.
`Adrenergic receptors mediate different effects ......................... 15
`2.
`Not all α-adrenergic receptor agonists characterized as
`“vasoconstrictors” work similarly............................................. 15
` Vasoconstriction(an α-1 effect) ............................................. 16
` Vasodilation (an α2 effect) .................................................... 18
`Brimonidine ......................................................................................... 19
`1.
`Background ............................................................................... 19
` Prior art brimonidine products were associated with
`significant adverse events, including hyperemia (redness) ...... 21
`
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`i
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`

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`2.
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`3.
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`4.
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`
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`V.
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`Prior art brimonidine products established that brimonidine’s
`redness reduction effects were concentration dependent .......... 22
`Chemistry of brimonidine ......................................................... 22
`2.
`Ophthalmic product formulation is complex and unpredictable ......... 24
`Claim Construction ........................................................................................ 25
`“ocular condition” ............................................................................... 25
`“about 0.025%” ................................................................................... 27
`1.
`A concentration of “about 0.025%” brimonidine does not
`encompass 0.03% brimonidine ................................................. 28
`The specification clearly conveys the clinical distinction
`between 0.025% and 0.03% brimonidine ................................. 31
`“about 0.025%” means “0.025% plus or minus 10%,”
`equating to an upper limit of 0.0275% ..................................... 35
`Petitioner’s reasons for asserting that “about 0.025%”
`includes 0.03% are unavailing .................................................. 36
`VI. Petitioner has failed to establish that any of the claims of the ’742 patent are
`unpatentable ................................................................................................... 39
` Ground 1: Example 1 of the ’553 patent (EX-1004) does not
`inherently anticipate claims 1-2 .......................................................... 40
`Ground 2: Walters (EX-1005) does not inherently anticipate
`claims 1-2 ............................................................................................ 43
`Ground 3: Petitioner has failed to establish that claims 1-6 are
`obvious ................................................................................................ 44
`1.
`Petitioner has failed to establish that claim 3 of the ’742
`patent is obvious ........................................................................ 45
`A POSA would not have been motivated to use brimonidine,
`let alone with any reasonable expectation of success, and the
`prior art taught away from doing so .......................................... 45
`
`Case IPR2022-00142
`Patent Owner Response
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`ii
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`

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`Case IPR2022-00142
`Patent Owner Response
`
`
`2.
`
` It would not have been obvious to use brimonidine at a
`concentration between about 0.001% and about 0.025%, and
`the prior art taught away from doing so .................................... 49
` The art teaches away from the claimed pH ........................... 51
` Petitioner’s combination of asserted references does not
`render claim 3 obvious .............................................................. 53
`The ’553 patent does not suggest a method of reducing
`redness ............................................................................ 53
`A POSA would not have combined Norden 2002 with
`’553 patent ...................................................................... 55
` None of Petitioner’s other cited references cure the
`deficiencies of the ’553 patent and Norden 2002 ........... 56
`Petitioner has failed to establish that claims 1-2, 4-6 are
`obvious ...................................................................................... 58
` Objective, real-world evidence of non-obviousness ........................... 59
`1.
`Unexpected superiority of the ’742 patent’s invention
`over prior art .............................................................................. 59
`The claimed low-concentration brimonidine was unexpectedly
`better than tetrahydrozoline ...................................................... 61
` The claimed low-concentration brimonidine was
`unexpectedly better than naphazoline ....................................... 62
`The claimed low-concentration brimonidine was unexpectedly
`better than oxymetazoline ......................................................... 63
` The cascade of real-world benefits attributable to the claimed
`invention .................................................................................... 66
`Lumify’s rapid, significant industry praise ............................... 67
`Commercial Success, Licensing, and Copying Further
`Demonstrate Nonobviousness ................................................... 69
`VII. Conclusion ..................................................................................................... 70
`
`
`
`2.
`3.
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`
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`iii
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`

`
`TABLE OF AUTHORITIES
`
`Case IPR2022-00142
`Patent Owner Response
`
`
` Page(s)
`
`Cases
`Allergan, Inc. v. Sandoz Inc.,
`796 F.3d 1293 (Fed. Cir. 2015) .......................................................................... 67
`Biogen, Inc. v. Berlex Lab’ys, Inc.,
`318 F.3d 1132 (Fed. Cir. 2003) .......................................................................... 28
`Boehringer Ingelheim Vetmedica, Inc. v. Schering-Plough Corp.,
`320 F.3d 1339 (Fed. Cir. 2003) .......................................................................... 26
`Cohesive Techs. v. Water Corp.,
`483 F.3d 1531 (Fed. Cir. 2008) .............................................................. 30, 34, 38
`Crocs, Inc. v. Int’l Trade Comm’n,
`598 F.3d 1294 (Fed. Cir. 2010) .......................................................................... 67
`In re Glatt Air Techniques, Inc.,
`630 F.3d 1026 (Fed. Cir. 2011) .................................................................... 67, 70
`Glaxo Inc. v. Novopharm Ltd.,
`52 F.3d 1043 (Fed.Cir.1995) ........................................................................ 41, 43
`Hybritech Inc. v. Monoclonal Antibodies, Inc.,
`802 F.2d 1367 (Fed. Cir. 1986) .......................................................................... 59
`Institut Pasteur & Universite Pierre Et Marie Curie v. Focarino,
`738 F.3d 1337 (Fed. Cir. 2013) .................................................................... 67, 70
`Jansen v. Rexall Sundown, Inc.,
`342 F.3d 1329 (Fed. Cir. 2003) .......................................................................... 26
`Kingston Tech. Co. v. SPEX Techs., Inc.,
`798 F. App’x 629 (Fed. Cir. 2020) .................................................................... 44
`Merck & Co. v. Teva Pharms. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005) .......................................................................... 28
`
`iv
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`

`Case IPR2022-00142
`Patent Owner Response
`
`
`Mintz v. Dietz & Watson, Inc.,
`679 F.3d 1372 (Fed. Cir. 2012) .......................................................................... 59
`PPC Broadband, Inc. v. Iancu,
`739 F. App’x 615 (Fed. Cir. 2018) (unpublished) .............................................. 69
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) (en banc) .......................................................... 29
`Polaris Indus. v. Arctic Cat, Inc.,
`882 F.3d 1056 (Fed. Cir. 2018) .................................................................... 49, 50
`Procter & Gamble Co. v. Teva Pharms. USA, Inc.,
`566 F.3d 989 (Fed. Cir. 2009) ............................................................................ 59
`Sandoz Inc. v. EKR Therapeutics, LLC,
`IPR2015-00008, Paper No. 20 ...................................................................... 43, 44
`Federal Statutes
`35 U.S.C. § 316(e) ................................................................................................... 40
`
`
`
`
`v
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`

`

`Case IPR2022-00142
`Patent Owner Response
`
`Patent Owner Eye Therapies, LLC (“Eye Therapies” or “Patent Owner”)
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`submits this Response to the Petition for Inter Partes Review of U.S. Patent No.
`
`8,293,742 (“the ’742 patent”) filed by Slayback Pharma LLC (“Slayback” or
`
`“Petitioner”). The Board instituted trial on the following grounds:
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`• Ground No. 1 – claims 1-2 are allegedly anticipated by U.S. Patent No.
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`6,294,553 (EX-1004 (“the ’553 patent”)
`
`• Ground No. 2 – claims 1-2 are allegedly anticipated by Walters 1991 (EX-
`
`1005)
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`• Ground No. 3 – claims 1-6 are allegedly rendered obvious by the ’553
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`patent (EX-1004) in combination with Norden 2002 (EX-1006), U.S.
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`Patent No. 6,242,442 (EX-1007 (“the ’442 patent”)), Alphagan® Label
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`1998 (EX-1008) and Federal Register 1998 (EX-1009)
`
`Institution Decision at 3-4, 55.
`
`As discussed below, however, Slayback has failed to meet its burden to
`
`establish unpatentability by a preponderance of the evidence. Indeed, neither the
`
`’553 patent nor Walters inherently anticipate claims 1 and 2. Nor do the asserted
`
`combination of references render obvious the methods of claims 1-6 directed to
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`using low-concentration brimonidine to reduce eye redness. Because Petitioner has
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`failed to carry its burden, the Board should confirm the patentability of claims 1-6
`
`of the ’742 patent.
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`1
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`

`

`I.
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`Case IPR2022-00142
`Patent Owner Response
`
`
`Preliminary Statement
` The ’742 patented invention: a clinically acclaimed, instant
`marketplace success
`The ’742 patent claims methods of using low-concentration brimonidine—a
`
`highly selective α-2 agonist—for reducing eye redness (ocular hyperemia). It covers
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`a commercially successful over-the-counter (OTC) redness reducer, Lumify. Indeed,
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`only three months after its launch in 2018, Lumify became the #1 eye doctor
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`recommended redness relieving drop.
`
`Lumify has been acclaimed by eye doctors for its safety and efficacy, and
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`these attributes have made Lumify an instant marketplace success. Lumify is
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`unexpectedly superior in reducing redness compared to prior art OTC redness
`
`relievers. But it also surprisingly and beneficially works within one minute and
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`reduces redness for up to eight hours, 30% longer than the closest Visine® products.
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`Doctors have particularly praised Lumify because, unlike the other commercial
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`redness reducers, it has little or no rebound hyperemia (i.e., eyes becoming redder
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`than before after the drug wears off) or tachyphylaxis (rapid decrease in drug
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`effectiveness after repeated uses over time).
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`The lack of these adverse side-effects is especially important for OTC
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`products, which typically treat self-diagnosed conditions, are administered without
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`doctor supervision, and are susceptible to misuse. Consumers, dissatisfied with their
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`Case IPR2022-00142
`Patent Owner Response
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`previous OTC redness-relieving products, would often instill more of the eyedrops,
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`leading to shorter duration of action and, unknowingly, the development of
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`tachyphylaxis. The continued overuse of these OTC products can cause ocular
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`toxicity, and potentially lead to medicamentosa—a severe and lasting swelling of
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`the eye. Lumify avoids these problems, as shown in its clinical trials and
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`acknowledged by FDA.
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`Lumify’s unexpectedly superior redness-relieving efficacy, rapid onset,
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`extended duration of action, and lack adverse side-effects—which make it a
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`particularly safe and commercially successful OTC product—all tie back to the use
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`of low-concentration brimonidine (0.025%) claimed in the ’742 patent. Lumify’s
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`marketplace success has spurred two companies, including Petitioner, to seek FDA
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`approval for generic copies of Lumify, and led to this patent challenge. But a person
`
`of ordinary skill in the art (“POSA”) objectively considering what was known
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`concerning brimonidine at the time of invention would not have considered it
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`obvious to use brimonidine at any concentration to reduce eye redness, let alone
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`using the low concentrations claimed herein, particularly in a composition with the
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`claimed pH.
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`The ’742 patented invention: prima facie non-obvious
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`Petitioner argues that all compounds broadly labelled as “vasoconstrictors”
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`would have reduced redness, and thus it would have been obvious to use brimonidine
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`Case IPR2022-00142
`Patent Owner Response
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`for this purpose. This is the linchpin of Petitioner’s position, and it is wrong. Not
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`only does it overly simplify the art, but it is scientifically inaccurate, for not all
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`compounds in the general “vasoconstrictor” category function similarly. While all
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`commercial redness relievers contain α-adrenergic receptor agonists, not all α-
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`adrenergic receptor agonists function in the same way. Different agonists can
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`stimulate different receptors that may even work in opposition to each other.
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`Importantly, a POSA would have known that certain α-agonists cause ocular
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`vasoconstriction and redness reduction, whereas others cause vasodilation and eye
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`redness. Notably, redness was a common side effect when brimonidine was
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`administered to treat glaucoma.
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`There are two types of α-agonists: α-1 and α-2 agonists. Alpha-1 agonists were
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`known to work by constricting blood vessels on the ocular surface, decongesting
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`them, and making the eyes appear white—the so-called “α-1 effect.” Unsurprisingly,
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`many prior commercial redness relievers contained α-1 agonists. By contrast, α-2
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`agonists (including brimonidine) were known to work by mediating vasodilation,
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`congesting and engorging blood vessels, and making the eyes appear red or
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`hyperemic—an “α-2 effect.” Brimonidine, a highly selective α-2 agonist, had an
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`affinity for α-2 receptors at least 1000 times greater than its affinity for α-1 receptors,
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`and thus was known to have an overwhelming propensity for the α-2 effect. A skilled
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`artisan would thus have avoided its use if seeking to develop a redness reliever.
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`4
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`Case IPR2022-00142
`Patent Owner Response
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`Initially approved as a glaucoma medication, brimonidine was plagued by
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`high incidences of ocular allergic reactions. Indeed, Petitioner’s own art
`
`demonstrates that brimonidine clinically exhibited a high rate of hyperemia
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`(upwards of 30%). EX-1031 at 109, 129. While this may have been a tolerable side
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`effect for glaucoma patients, who risk blindness if untreated, it would have
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`discouraged skilled artisans from considering brimonidine for eye redness.
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`Although at high concentrations, brimonidine had reported side effects of
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`blanching (redness reduction) due to its minimal α-1 effect, the prior art established
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`that the effect was concentration dependent, further teaching away from the use of
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`low-dose brimonidine to reduce redness. See EX-2020, ¶¶76-79. As its concentration
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`decreased, so too did brimonidine’s propensity to reduce redness, dropping
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`precipitously from 50% for the Alphagan® (0.5%) product to 3.5% for the
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`Alphagan® (0.2%) product and essentially disappearing for the Alphagan® P
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`products (0.15% and 0.1%). See EX-2012 at 14, 16; EX-1031 at 109; EX-2014 at 3,
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`6.
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`With all of this knowledge, skilled artisans would not have had any reason to
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`use low-dose brimonidine nor any reasonable expectation of reducing redness—in
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`short, this invention was entirely unexpected and ran directly counter to the art’s
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`teachings. Even if a POSA would have considered using brimonidine to reduce
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`redness, which they would not have, if anything, they would have increased its
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`Case IPR2022-00142
`Patent Owner Response
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`concentration in the direction of brimonidine’s redness reducing effect—i.e., to 0.2%
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`and above. Moreover, they would have targeted a pH at or around the physiological
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`pH to facilitate maximum penetration, to avoid eye irritation that can lead to tearing
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`and drug washout, and to avoid discomfort that can lead to redness.
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`Strong objective evidence of non-obviousness
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`Low-concentration brimonidine would not have been expected to have any
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`appreciable redness reducing ability compared to the prior commercial redness
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`relievers, whose “α-1 effect” was from 200 times (oxymetazoline) to 500 times
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`(naphazoline) and even higher (tetrahydrozoline) than brimonidine. Yet quite
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`unexpectedly, as represented by Lumify (0.025% brimonidine) and other
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`embodiments within the scope of the ’742 patent claims, low-concentration
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`brimonidine reduced redness more effectively than the selective α-1 agonists, like
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`tetrahydrozoline and naphazoline, and mixed α-1/α-2 agonists, like oxymetazoline.
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`The discovery that low-concentration brimonidine could so effectively reduce
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`redness led to a cascade of real-world benefits. Lumify, which works in one minute
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`and lasts for up to eight hours (outperforming the label claim for Visine® L.R.
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`(oxymetazoline) by more than 30%) while also exhibiting no rebound hyperemia or
`
`tachyphylaxis, drew effusive praise from all angles: from consumers to practicing
`
`doctors to the FDA itself! Indeed, the FDA praised Lumify’s clinical trial results,
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`Case IPR2022-00142
`Patent Owner Response
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`recognizing the “absence of tachyphylaxis or rebound congestion” as a significant
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`advantage for the OTC consumer.
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`Lumify’s superiority naturally segued into its rapid commercial success and
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`made it the #1 eye doctor recommended redness reliever within three months of
`
`launch. Put simply, if brimonidine’s benefits, as seen with Lumify, had been even
`
`slightly appreciated, it would not have taken almost 40 years to discover and
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`subsequently commercialize a redness reliever with low-concentration brimonidine.
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`Lumify’s unparalleled rise to market pre-eminence defies Petitioner’s overly
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`simplistic, scientifically inaccurate, revisionist, litigation-driven obviousness
`
`positions.
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`In short, no motivation nor any reasonable expectation of success existed to
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`use low-concentration brimonidine to reduce eye redness, let alone at the claimed
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`concentrations and pH, which the objective evidence of non-obviousness in this
`
`record independently substantiates.
`
`II. The POSA
`The field to which the ’742 patent pertains is interdisciplinary. EX-2020, ¶29.
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`The POSA in the relevant art may be represented by a team of individuals with
`
`experience and various skills relating to eye care, including, inter alia, the medical
`
`and pharmaceutical formulation arts. EX-2020, ¶29; EX-2021, ¶33; EX-2022, ¶19.
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`The POSA would also have had access to team members with experience in
`
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`Case IPR2022-00142
`Patent Owner Response
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`chemistry, in designing and evaluating ophthalmic formulations, and/or in
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`administering ophthalmic formulations to treat ocular conditions obtained by some
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`combination of education and work experience. EX-2020, ¶29; EX-2021, ¶33; EX-
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`2022, ¶19.
`
`Petitioner contends that “[a] POSA was a composite person (or team) that
`
`included a medical doctor and a pharmaceutical formulator.” Petition at 11. But the
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`qualifications Petitioner attributes to the formulator POSA go beyond those of a
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`person of “ordinary skill.” EX-2020, ¶28; EX-2021, ¶34. Patent Owner’s POSA, a
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`pharmaceutical formulator with a Bachelor’s degree in pharmaceutics or a related
`
`discipline with about three to five years of work experience in this area, or a
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`comparable level of education and training, such as a Ph.D. with one to two years of
`
`experience in this area, more accurately reflects the level of skill in the relevant field.
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`EX-2020, ¶28; EX-2021, ¶32.
`
`III. The ’742 Patent
`The ’742 patent has six claims, each directed to, inter alia, methods for
`
`reducing eye redness consisting essentially of administering brimonidine to a patient
`
`having an ocular condition, wherein the brimonidine is present at a concentration
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`between about 0.001% w/v and about 0.05% w/v. EX-1001, Claims 1-6. The ’742
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`patent contains two independent claims (claims 1 and 3) and four dependent claims
`
`(EX-1001 at 22:16-39), each of which are separately patentable. The claims of the
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`Case IPR2022-00142
`Patent Owner Response
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`’742 patent are entitled to at least an August 1, 2008 priority date, which is not
`
`challenged. See EX-1001 at 1; Petition at 15.
`
`As discussed, the ’742 patent protects Lumify, the #1 eye doctor
`
`recommended redness relieving eye drop, and the first and only FDA-approved OTC
`
`product containing brimonidine. EX-2020, ¶313; EX-2023, ¶¶6-7. The ’742 patent
`
`is listed in the FDA Orange Book in conjunction with NDA No. 208144 for Lumify
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`(brimonidine tartrate) ophthalmic solution, 0.025%.
`
`IV. Technical Background
`Patent Owner disagrees with Petitioner’s characterization of the “background
`
`facts.” See Petition at § I.D. Those alleged “facts” and subsequent arguments are
`
`premised on an overly simplistic view of the relevant art and fail to acknowledge
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`critical information possessed by a POSA as of the priority date for the ’742 patent.
`
` Anatomy of the eye and drug delivery
`The eye is a complex and multi-layer organ and, even today, certain parts of
`
`the eye are not completely understood. EX-2020, ¶32.
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`9
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`Case IPR2022-00142
`Patent Owner Response
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`
`
`
`Ophthalmic products intended to reduce redness target the conjunctiva, the
`
`episclera, and the sclera. EX-2020, ¶34; EX-1001 at 14:7-14; EX-1002, ¶71. The
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`conjunctiva is a clear, thin tissue that covers the sclera and lubricates and lines the
`
`inside of the eyelids. EX-2020, ¶36; EX-2172 at 4. The sclera is an external
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`connective tissue that provides a protective covering of the eyeball. EX-2020, ¶36;
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`10
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`Case IPR2022-00142
`Patent Owner Response
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`EX-2178 at 2. The sclera consists of four layers, including the episclera, which is a
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`thin tissue resting on top of the eyeball. EX-2020, ¶37; EX-2178 at 3.
`
`
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`Each of the conjunctiva, episclera, and sclera has blood vessels. Dilation of these
`
`blood vessels can trigger redness. EX-2020, ¶38; EX-2179 at 1.
`
`
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`Depending on the disease state and desired therapeutic effect, different parts
`
`of the eye may be targeted. But to reach its target, the drug must overcome the eye’s
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`natural defenses, including blinking and reflex tearing, which have long been
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`recognized as significant challenges for ophthalmic products. EX-2020, ¶40.
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`11
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`Case IPR2022-00142
`Patent Owner Response
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`Like the eye itself, the mechanism of action for many drugs is not completely
`
`understood. EX-2020, ¶32. As a result, treating eye conditions is complex and
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`unpredictable. EX-2020, ¶205. The delivery requirements and the drug product
`
`characteristics necessary to achieve therapeutic effects vary depending on the type
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`of treatment and which part of the eye needs treatment. EX-2020, ¶¶83, 206, 258.
`
`As a result, the characteristics of a formulation intended to treat one ophthalmic
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`condition may not be suitable (and may in fact be disadvantageous) for a product
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`intended to treat another. EX-2020, ¶¶83, 206, 258.
`
` Ocular Conditions
`There are a variety of ocular conditions. Each has different signs and
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`symptoms and different methods of treatment. EX-2020, ¶46. Glaucoma and eye
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`redness (ocular hyperemia) are relevant here and are discussed in further detail
`
`below.
`
`1. Glaucoma
` Overview
`Glaucoma is a serious eye condition and if left untreated can gradually damage
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`the optic nerve and ultimately lead to blindness. EX-2020, ¶55. While the exact
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`cause is not known, an increase in intraocular pressure (IOP) caused by a buildup of
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`fluid in the area between the cornea and the lens is thought to be a major contributor.
`
`EX-2020, ¶55.
`
`12
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`

`

`Treatments
`
`Ophthalmic products intended to treat glaucoma target the ciliary body. EX-
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`Case IPR2022-00142
`Patent Owner Response
`
`
`2020, ¶68. The ciliary body is a part of the middle layer of the eye including a
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`circular band of muscle surrounding the lens. EX-2020, ¶39. It produces clear fluid
`
`(aqueous humor) that fills the space located between the cornea and the iris, known
`
`as anterior chamber, providing nutrients to these parts of the eye. EX-2020, ¶39. An
`
`increased amount of the aqueous humor increases the intraocular pressure, which
`
`can cause glaucoma. EX-2020, ¶39.
`
`Alpha-2 agonists, such as brimonidine and apraclonidine, have traditionally
`
`been used to treat glaucoma. EX-2020, ¶57. Studies indicate these α-2 agonists work
`
`to decrease IOP by: (1) reducing the production of aqueous humor and (2) increasing
`
`the fluid drainage. EX-2020, ¶57. A POSA would understand that lowering IOP
`
`would not be expected to reduce redness. EX-2020, ¶¶83, 206, 258.
`
`Eye Redness
`2.
`Eye redness or hyperemia refers to a common condition caused by
`
`vasodilation—an increase in the diameter of the blood vessels due to the influx of
`
`blood. EX-2020, ¶47; EX-2162 at 113:3-11. Ocular hyperemia can result from
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`vasodilation of intact blood vessels in any of the visible layers in the eye. EX-2020,
`
`¶101.
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`13
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`Case IPR2022-00142
`Patent Owner Response
`
`Because of the social stigma associated with eye redness, individuals with red
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`eye are eager to effectively manage the redness. EX-2020, ¶48. But to determine
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`how to treat the red eye, the physician must first determine the underlying cause.
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`EX-2020, ¶49. Common causes of red eye include conjunctivitis (infectious and
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`non-infectious), foreign body, and dry eye. The treatment of red eye will differ
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`depending on the underlying cause. EX-2020, ¶49.
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`Eye redness caused by vasodilation of intact blood vessels is distinct from eye
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`redness resulting from a hemorrhage, as can be seen in the images below. EX-2020,
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`¶102.
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`
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`Subconjunctival hemorrhage
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`
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`Eye Redness (Vasodilation)
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` A
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` hemorrhage in the eye is typically the result of trauma that breaks the ocular
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`blood vessels, resulting in blood pouring out and settling beneath the conjunctiva.
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`EX-2020, ¶102; EX-2162 at 111:14-113:5. Redness arising from vasodilation of
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`intact blood vessels can be treated, but a subconjunctival hemorrhage cannot—only
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`with the passage of time will the hemorrhage disappear. EX-2020, ¶168; EX-2162
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`at 112:18-23.
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`
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`State of the art of adrenergic receptor agonists
`Adrenergic receptors mediate different effects
`1.
`Adrenergic receptors are receptors on the surface of cells in the sympathetic
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`nervous system. EX-2020, ¶41. There are two types of adrenergic receptors: alpha
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`and beta. EX-2020, ¶41. The alpha-adrenergic receptors are further categorized into
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`two subtypes: α-1 and α-2. EX-2020, ¶41. The eye contains both α-1 and α-2
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`receptors.
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`When activated, α-1 receptors elicit an excitatory response (i.e., fight or
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`flight), which results in vasoconstriction of blood vessels and smooth-muscle
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`contractions. EX-2020, ¶43; EX-2162 at 74:9-24, 75:11-17; EX-2169 at 2, 4. This
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`is known as an α-1 mediated effect. EX-2020, ¶43; EX-1016 at 12-13; EX-1035 at
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`S10. On the other hand, when α-2 receptors are activated, they elicit a relaxation
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`response, which results in dilation of blood vessels and redness. EX-2020, ¶44; EX-
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`2169 at S2-S4.
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`2.
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`Not all α-adrenergic receptor agonists characterized
`as “vasoconstrictors” work similarly
`Whether a particular agonist interacts with an α-1 or α-2 receptor is
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`determined, at least in part, by its selectivity. EX-2020, ¶66. Selectivity refers to the
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`propensity of a drug to interact with a specific receptor subtype. EX-2020, ¶66.
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`Whenpresent in low concentrations, a selective adrenergic receptor agonist would
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`be expected to interact only with the specific receptor for which it is selective. EX-
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`2020, 66. However,at higher concentrations, it may interact with the other receptor.
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`EX-2020, §66. Adrenergic receptor agonists fall
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`into one of three categories:
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`selective a-1, selective a-2, and mixed a-1/a-2. EX-2020, 966.
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`Numerousadrenergic receptor agonists were known, as wastheir selectivity
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`for a particular receptor, as identified in the followinglist.
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`Agonist—|selectivity
`Tetrahydrozoline
`a-l
`Xylometazoline
`a-1
`Naphazoline
`mixed a-1/a-2
`Oxymetazoline
`mixed a-1/a-2
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`
`
`
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`Ephedrine
`Phenylephrine
`Clonidine
`Apraclonidine
`Brimonidine
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`mixed a-1/a-2
`mixed a-1/a-2
`a-2
`a-2
`a-2
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`See, e.g., EX-2020, 4959-60, 80.
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`a.
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`Vasoconstriction (an a-1 effect)
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`Asofthe priority date for the ’742 patent, reduction in redness (whitening or
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`blanching) was recognized bythose skilled in the art to be an a-1 mediated effect.
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`EX-2020, §63: EX-1016 at 12, 13; EX-2169 at S4, Table 2. Consistent with this
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`recognition, a// FDA-approved redness relievers contained either selective a-1
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`receptor agonists or mixed a-1/a-2 receptor agonists. EX-2020, 459; EX-1009 at 16;
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`EX-1016 at 13; EX-1001 at 2:8-13. Not surprisingly, none of these existing products
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`containeda selective a-2 receptor agonist (muchless a highly selective a-2 receptor
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`agonist) because these would have been expected to cause dilation (and thus
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`redness). EX-2020, 63; EX-2169 at S4-S5; EX-1019 at 3.
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`There are a variety of FDA-approved redness reducing eye drops on the
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`market, many of which had been andstill were on the market for years prior to the
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`priority date of the ’742 patent. EX-2020, §60. Below is a list ofjust some of those
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`products:
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`naphazoline 0.025%
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`a-Agonist API
`naphazoline 0.012%
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`EX-2020, 960.
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`These OTC rednessrelievers had short durations of action typically lasting
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`about an hour and were frequently associated with adverse side effects, including
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`rebound hyperemia and tachyphylaxis. EX-2020, 961.
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`Rebound hyperemia occurs whena patient stops using a redness reliever. EX-
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`2020, §53. The initial vasoconstriction reduces the flow of blood and oxygen to
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`ocular blood vessels. EX-2020, 53; EX-1001 at 4:40-46. Whenthe drug wearsoff,
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`compensatory vasodilation occurs, engorging those vessels with blood and oxygen.
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`EX-2020, ¶53. The consumer’s eyes “rebound” with more redness than before using
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`the redness reliever. EX-2020, ¶53. As often occurs with OTC products, which are
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`used to treat a self-diagnosed condition and are administered without supervision by
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`a medication professional, the consumer instills more eyedrops not knowing that the
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`body compensates for that by downregulating the α-1 receptors. EX-2020, ¶54. This
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`leads to a rapid decrease in the drug’s efficacy,