Slayback Pharma
`
`SLAYBACK PHARMA LLC
`v.
`EYE THERAPIES, LLC
`
`IPR2022-00142
`
`U.S. Patent No. 8,293,742
`
`Oral Hearing
`February 27, 2023
`
`Demonstrative Exhibit - Not Evidence
`
`1
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.001
`
`

`

`Introduction
`
`Demonstrative Exhibit - Not Evidence
`
`2
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.002
`
`

`

`The Board Should Find All Challenged Claims Unpatentable
`
`• Ground 1: Gil (the ’553 patent) anticipates claims 1–2
`
`‒ Example 1 discloses a clinical study in which radial keratotomy patients were to be
`treated with brimonidine to reduce neurogenic inflammation
`
`– Administration of brimonidine (a vasoconstrictor) reduces redness
`
`– “about 0.025%” includes 0.03% brimonidine—the concentration administered in Example 1
`
`– “ocular condition” includes radial keratotomy, but even if it does not, the radial keratotomy
`procedure necessarily causes redness via neurogenic inflammation
`
`• Ground 2: Walters anticipates claims 1–2
`
`Demonstrative Exhibit - Not Evidence
`
`3
`
`Petition (Paper 2) at 32–44; Reply (Paper 43) at 7–9; Gil (EX-1004); Walters (EX-1005).
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.003
`
`

`

`The Board Should Find All Challenged Claims Unpatentable
`
`• Ground 3: Claims 1-6 are invalid because it would have been obvious
`to combine:
`
`‒ Low dose brimonidine (e.g., Gil)
`
`‒ For the reduction of eye redness (e.g., Gil, Norden 2002)
`
`‒ Formulated at the known, commercially available pH levels (e.g., Alphagan®)
`
`‒ In patients with various causes of eye redness (e.g., Gil, Norden 2002)
`
`• Secondary considerations do not support a finding of non-obviousness
`
`Demonstrative Exhibit - Not Evidence
`
`4
`
`Petition (Paper 2) at 50–64; Reply (Paper 43) at 9–26, Gil (EX-1004); Norden (EX-1002).
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.004
`
`

`

`11■1111111111111
`
`US0062~,74lB2
`
`cuJ United Slates Parent
`
`(IOJ P1ttn1No.:
`(U) OattorPaltrll:
`
`US S.293,742 IJ2
`(x1.2J.ZO l2
`
`(7') .....,,_ r-.w ll_l_ll(l.l!ll
`
`(~) ~~:~~~~~~:~~?::~:;:..c;~~?.:',.,: .=.~ .. "':"..:..~~~
`,..,_._ol.__ _ _ _ , __
`(7ll ...._, .,i,i.,~·•~ -•.._..., , .. ~
`._."' -..s.11,..__-~ ... 11.
`(') -r :;...~~:::_,dw..,,.of._ ==--"':,~::..;:::~.:2:-:~~-
`::: ::.,.~:;~:;~.:::: E:~~~~
`
`,..... • ..-.-"'ad.,......,_1J
`(ll) Appl t1o ~~~tl,y)tHi,-.
`
`:,;.,<.s.i,.o..-. ,.. ..,..._,)
`~..:;~~1'f=,';';'.
`
`22
`21
`,-. _ _ , _ . , , a J n .~ \ tlo.i.-_,. _ _ of .... .-001r,,_,....,._.i,..,
`
`C_,,.. ... _ . . ,.. __ _,.-""'_do! I ---of--••-(cid:173)
`::::::-:--""'"----...- ____ ..... ,_,
`
`USS,293,742B2
`
`Page 20 of20
`
`SLAYBACK EXHIBIT 1001
`
`Demonstrative Exhibit - Not Evidence
`
`Claims of the ’742 Patent
`
`The invention claimed is:
`1. A method for reducing eye redness consisting essentially
`of administering brimonidine to a patient having an ocular
`condition, wherein brimonidine is present at a concentration
`between about 0.001 % weight by volume and about 0.05%
`weight by volume.
`2. The method of claim 1, wherein brimonidine is present
`at a concentration between about 0.001 % to about 0.025%
`weight by volume.
`3. A method for reducing eye redness consisting essentially
`of topically administering to a patient having an ocular con(cid:173)
`dition a composition consisting essentially of brimonidine
`into ocular tissue, wherein pH of said composition is between
`about 5.5 and about 6.5, wherein said brimonidine concen(cid:173)
`tration is between about 0.001 % and about 0.025% weight by
`volume and wherein said composition is formulated as an
`ocular drop.
`4. The method of claim 3, wherein said composition is
`topically administered within about 24 hours after a Lasik
`surgery on said patient.
`5. The method according to claim 1, wherein said ocular
`condition is chronic red eye.
`6. The method according to claim 3, wherein said ocular
`condition is chronic red eye.
`
`Reducing redness
`with low
`concentrations
`of brimonidine
`
`pH between about
`5.5 and about 6.5
`
`Chronic red eye &
`after LASIK surgery
`
`’742 Patent (EX-1001).
`
`5
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.005
`
`

`

`Anticipation
`
`Demonstrative Exhibit - Not Evidence
`
`6
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.006
`
`

`

`Gil Anticipates Claims 1 and 2 of the ’742 Patent
`
`The ’742 Patent
`
`Gil (’553 Patent)
`
`[1.preamble] A method for reducing eye redness
`
`[1.1] consisting essentially of administering brimonidine
`
`[1.2] to a patient having an ocular condition
`
`[1.3] wherein brimonidine is present at a concentration
`between about 0.001% weight by volume and about
`0.05% weight by volume
`
`[2.1] wherein brimonidine is present at a concentration
`between about 0.001% to about 0.025% weight by volume
`
`Demonstrative Exhibit - Not Evidence
`
`Reply (Paper 43) at 7; Gil (EX-1004).
`
`7
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.007
`
`

`

`Gil Discloses a Method
`for Reducing Eye Redness
`
`• Gil discloses the administration of low concentrations of brimonidine to treat
`pain and ocular inflammation
`
`EXAMPLE 1
`
`A clinical study is performed to compare the analgesic
`effect of topically administered brimonidine and placebo
`following radial keratotomy surgery. One hundred and
`twenty-four male and female subjects, 21 to 45 years of age,
`undergo routine, elective, unilateral radial keratotomy for
`the correction of myopia and brimonidine is administered as
`a 0.03% ophthalmic solution.
`Each subject receives one drop of the assigned study
`medication every four hours while awake one day prior to
`surgery and again every 20 minutes for the two hours just
`before surgery. Each subject then undergoes unilateral radial
`keratotomy. Following surgery, each subject receives one
`drop of the study medication in the operated eye every four
`hours while awake for 14 consecutive days. Postoperative
`examinations occur at davs 1, 3 7 and 14.
`Efficacy is assessed by evaluation of pain intensity, pain
`relief, subjective global analgesic efficacy. Symptoms of
`ocular inflammation (burning/stinging, tearing, etc.) are also
`recorded.
`The results of this study show greater pain relief at hours
`2, 3 and 4 in the brimonidine- group over the group treated
`with placebo. This appears to suggest that brimonidine,
`administered preoperatively, blocks the perception of pain.
`
`'"
`
`Gil (EX-1004) at 4:45–5:2.
`
`FIELD OF THE INVENTION
`
`This invention relates to the topical application of bri(cid:173)
`monidine for treating ocular pain and neurogenic inflamma(cid:173)
`tion and compositions useful for such application.
`
`BACKGROUND OF THE ART
`
`Pain is a well known phenomenon as an indicator of
`injury or tissue damage due to inflammation, ischemia,
`mechanical or other irritation.
`
`Gil (EX-1004) at 1:10–19.
`
`Efficacy is assessed by evaluation of pain intensity, pain
`relief, subjective global analgesic efficacy. Symptoms of
`ocular inflammation (burning/stinging, tearing, etc.) are also
`recorded.
`
`Gil (EX-1004) at 4:62–65.
`
`Petition (Paper 2) at 32; Reply (Paper 43) at 8; Sher Reply Decl. (EX-1049) ¶ 55.
`
`Demonstrative Exhibit - Not Evidence
`
`8
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.008
`
`

`

`Gil Discloses a Method
`for Reducing Eye Redness
`
`• Gil’s Example 1 discloses a clinical study of 0.03% brimonidine before and
`after radial keratotomy
`
`(•ii United States Patent
`Gil d 111.
`
`11■1111111111111
`US006~55J III
`US 6,294,553 HI
`!kp. 25, 2001
`
`(ID) l'a1co1 No.:
`1u1 D• tc or 1•11m11 :
`
`::: = '.:::1:'.·::·::.::~;\J~' ::: ~!'!--. -. ~~-==:::::
`~~==·:...~~t.fu"~
`(7:J) ,..__, ,....,...s..,..1 .. ~ 1rv•.CA(US)
`("J -
`..... ,
`
`(56)
`
`Jl4=.I
`lo.'lOOI ~.04.
`6.Z.OZ.+U
`oJ4,?<I I +'»ll-lc,.o& _ _ j Wlf!I
`
`r,;_,1.:----a..yaam 1i.:a.,. 111
`(74),1,,..._,1,-,ir l~n l Ror.M-A.
`-,c.,io.11. . • -......
`(J7)
`n......- .. u ... ..,..,._or~a ..... ,...
`
`ocolo,...,..
`
`s.i.,...10-,dilo:L>ima.lllc"rmor11...
`P""••c-.il0<..t;,,>1«1...Ju»
`U.'l.C. 15-1(1,JbrOd.,...
`
`,\j>pl. J,lo o,/l'lll.l~
`(2 1)
`(22) mN,
`t'...,1-',MI
`
`RtlilNIUS. Appllca1loaDa11
`(60) ~~J,lo...:\l&l,oO!l,-ooF•u.
`
`Includes 124
`patients undergoing
`unilateral radial
`keratotomy
`
`A clinical study is performed to compare the analgesic
`effect of topically administered brimonidine and
`lacebo
`following radial keratotomy surgery. One hundred and
`twenty-four male and female subjects, 21 to 45 years of age,
`undergo routine, elective, unilateral radial keratotomy for
`the correction of myopia and brimonidine is administered as
`a 0.03% ophthalmic solution.
`
`(Jl)
`
`l oLC..'L' - - -
`
`uc..-..-. 1 11 .... 1 .. s-,
`
`Page1of5
`
`SLAYBACK EXHIBIT 1004
`
`Demonstrative Exhibit - Not Evidence
`
`Gil (EX-1004) at 4:46–53.
`
`Petition (Paper 2) at 33–34; Reply (Paper 43) at 8–9.
`
`9
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.009
`
`

`

`Gil Discloses a Method
`for Reducing Eye Redness
`
`• Ocular inflammation is a proximal cause of pain and eye redness
`
`(1J)~cAlltrpn S.i.... 1•~ 1,viot,CA(US)
`
`(")Noi .. ,.,
`
`-,....., .. y....,i.im.u .......... oru ...
`po1<m;,.,_-d.,.....,.Mo«1...iu.H
`U.SC:.ls-(1,)byO<Up.
`
`(!I) Ai,,! No. otnill,IMI
`
`Ill) Filed
`
`t·m 1t.JNI
`
`~..-l
`
`&..!.,,.,
`
`i,.'lO}I ~ " al
`
`.'10),,._., ... _
`
`.,_
`JWUUI
`
`/'n.-yt~~ll<nl<y,111
`
`~ -A= /~ " ' / : i - r t J. l!-w.-;M ... i,ol\,
`
`""
`
`( U) United States Patent
`Gild 111.
`
`11■ 1 11 1111111111
`US0062'),ljjJIJI
`US 6,294,553 HI
`Sep.25.2001
`
`110) l'11l ~nt No.:
`1•S> lllltcor Pah.-n t:
`
`::; = ',::1:.:;•~•::_~;:;\IN !~ ~~~----- _- _-_(cid:173)
`~~=~.=-~-=~t= (56)
`
`Tloo"""'•-,.i.i.,.00111,-"'brimo,oidi"°r..,..,.. ...
`RollltdUS.Appllati..l"""
`(OOl ~~No.~lll,oO!l,fiWoof•1s, oaill•-
`
`Page 1 ofS
`
`SLAVBACK EXHIBIT 1004
`
`1. Activation of
`primary afferents
`(neurons)
`
`2. Release of
`neuropeptides →
`neurogenic
`inflammation
`
`The first step leading to the sensation of pain is the
`activation of nociceptive primary afferents by intense
`thermal, mechanical or chemical stimuli.
`
`* * *
`The stimulation of primary afferents leads to action poten(cid:173)
`tials in their axons which propagate to the spinal cord. In
`addition, excited primary afferents release neuropeptides
`(substance P, calcitonin gene-related peptide, neurokinin A)
`at their peripheral terminals. Neuropeptides enhance inflam(cid:173)
`matory reactions in the injured tissue, contributing to
`vasodilation, edema, and increased vascular permeability,
`this phenomenon is called ' neurogenic inflammation' .
`
`Gil (EX-1004) at 1:2–43.
`
`Ocular responses characteristic of neurogenic
`inflammation, including redness and pupillary constriction,
`are also observed in rabbits following external stimuli.
`Gil (EX-1004) at 5:39–41.
`
`Demonstrative Exhibit - Not Evidence
`
`Reply (Paper 43) at 8–9; Sher Reply Decl. (EX-1049) ¶¶ 48–55.
`
`10
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.010
`
`

`

`Radial Keratotomy Necessarily
`Causes Eye Redness
`
`• Lid speculum mechanically forces the eyelids
`to remain open
`
`Incision sites
`
`• Surgeon makes numerous incisions to the cornea
`
`• Corneal incisions result in tissue damage
`
`• Tissue damage triggers inflammatory cascade
`(release of inflammatory mediators)
`
`• Inflammatory cascade results in redness and pain
`(vasodilation of the nearby blood vessels)
`
`a:
`w
`
`I->-0
`
`m
`I
`(/)
`w
`_j
`a:
`<(
`I u
`
`T"""
`0
`0
`N
`®
`
`Demonstrative Exhibit - Not Evidence
`
`Noecker Decl. (EX-2020) ¶ 104.
`
`Reply (Paper 43) at 8–9; Sher Reply Decl. (EX-1049) ¶¶ 45–50.
`
`11
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.011
`
`

`

`Radial Keratotomy Necessarily
`Causes Eye Redness
`
`D R . S H E R :
`
`on "ocular con<lit10n Additionally, and as discussed in more detail below, in my
`
`experience, all radial keratotomy patients have some degree of eye redness after the
`
`THE WITNESS: As -- as I detailed in
`
`my declaration and based on my experience
`
`in RK surgery or -- AK surgery is no
`
`procedure. Therefore, even under Dr. Noecker's construction of this term, radial
`
`different, I have never seen a patient who
`
`keratotomy would still be an "ocular condition" of the claims.
`
`I've cut the cornea on or for that matter
`
`done cataract surgery on or any of these
`
`Sher Reply Decl. (EX-1049) ¶ 40.
`
`procedures who have not had some eye
`
`Demonstrative Exhibit - Not Evidence
`
`redness, some tearing, some irritation
`
`symptoms after the surgical procedure.
`
`That's my experience.
`
`Sher Dep. Tr. (EX-2213) at 35:1–10.
`
`Petition (Paper 2) at 34; Reply (Paper 43) at 8–9.
`
`12
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.012
`
`

`

`The Natural Result of Administering Low Concentrations of
`Brimonidine to Radial Keratotomy Patients Is Reduced Redness
`
`“In general, a limitation or the entire invention is inherent and in the
`
`public domain if it is the ‘natural result flowing from’ the explicit
`
`disclosure of the prior art.”
`
`Schering Corp. v. Geneva Pharms., 339 F.3d 1373, 1379 (Fed. Cir. 2003)
`(citing Eli Lilly & Co. v. Barr Laby’s, Inc., 251 F.3d 955, 970 (Fed. Cir. 2001)).
`
`Demonstrative Exhibit - Not Evidence
`
`Reply (Paper 43) at 8.
`
`13
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.013
`
`

`

`Administering Brimonidine 0.03% to Patients Undergoing Radial
`Keratotomy Necessarily Reduces Eye Redness
`
`FlG.6
`
`r, FE;asabilitv C % Oetern1ination
`·
`:..-:-,o·>··i-·
`·),·l•► '-:
`·
`.
`... · .. ·. · .... · .... : .. ~«~❖:❖:❖:-»»:«->:««.-,.;
`
`1.·
`
`+,+'+ '~'
`
`.
`
`.
`
`·:
`
`FIG. 6 depicts a graphical representation of a finding of the
`present invention that an increased rebound hyperemia begins
`at around 0.03% for brimonidine. It thus demonstrates that
`the net effectiveness of brimonidine as a decongestant is
`greatest between about 0.01 % andlabout 0.03%,;lpreferably,
`between about 0.012% and about 0.02%
`
`FIG. 4E shows the effect ofbrimonidine at 0.033% on the left
`eye only, 4 hrs after the effect shown in FIG. 4D (showing
`the third application to be without rebound hyperemia).
`
`’742 Patent (EX-1001) at 19:52–57, 20:17–19.
`
`,. '•·--- - - - - - - - -
`
`,:o,wx , '& .
`
`.
`
`. . .. .. :..r:i ... _ ... . ___ _
`
`~.c ........ -.•-·········-·-·-·-
`
`Demonstrative Exhibit - Not Evidence
`
`Petition (Paper 2) at 30; Reply (Paper 43) at 9.
`
`14
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.014
`
`

`

`Gil Discloses a Method
`for Reducing Eye Redness
`
`• The challenged claims contain no efficacy limitation.
`
`Based on the foregoing and our review of the record as a whole, we find no persuasive support
`
`for construing the preamble recitation of a “method for treating a patient with an angiogenic eye
`
`disorder” as requiring such “treating” to achieve any particular level of effectiveness, much less
`
`a “high level of efficacy.” Rather, as discussed above, we find that the evidence of record and the
`
`Specification support construing the phrase as meaning administering a compound, i.e., the
`
`recited VEGF antagonist, to such patient for the purpose of improving or providing a beneficial
`
`effect in their angiogenic eye disorder.
`
`Demonstrative Exhibit - Not Evidence
`
`Reply (Paper 43) at 7–8.
`
`15
`
`Mylan Pharms. Inc. v. Regeneron Pharms., Inc.,
`No. IPR2021-00881, 2022 WL 16842073, at *11 (P.T.A.B. Nov. 9, 2022).
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.015
`
`

`

`Gil Anticipates Claims 1 and 2 of the ’742 Patent
`
`The ’742 Patent
`
`Gil (’553 Patent)
`
`[1.preamble] A method for reducing eye redness
`
`[1.1] consisting essentially of administering brimonidine
`
`[1.2] to a patient having an ocular condition
`
`[1.3] wherein brimonidine is present at a concentration
`between about 0.001% weight by volume and about
`0.05% weight by volume
`
`[2.1] wherein brimonidine is present at a concentration
`between about 0.001% to about 0.025% weight by volume
`
`Demonstrative Exhibit - Not Evidence
`
`Petition (Paper 2) at 33–34; Reply (Paper 43) at 8–9; Gil (EX-1004).
`
`16
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.016
`
`

`

`Claim Construction – “ocular condition”
`
`Petitioner’s Construction
`
`Patent Owner’s Construction
`
`“ocular condition” includes, without limitation:
`
`eye redness; glaucoma (including open-angle
`glaucoma); elevated intraocular pressure,
`also known as ocular hypertension;
`postoperative reduction of subconjunctival
`hemorrhage and hyperemia after refractive
`surgery such as LASIK and radial keratotomy;
`subconjunctival hemorrhage and hyperemia
`prophylaxis prior to refractive surgery such as
`LASIK and radial keratotomy; and redness in
`the eye following LASIK or radial keratotomy.
`
`a condition of the eye causing ocular
`hyperemia that can be reduced
`
`• Not subconjunctival hemorrhage
`
`• Not effects of radial keratotomy
`
`Demonstrative Exhibit - Not Evidence
`
`17
`
`Petition (Paper 2) at 31; Reply (Paper 43) at 1–2; PO Resp. (Paper 30) at 25–27.
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.017
`
`

`

`Radial Keratotomy Results in Ocular Conditions
`
`b) Ocular Conditions
`Ocular conditions include but are not limited to red e e
`including chronic red eye; ocular vascular congestion after
`Lasik surgery ; prophylacti c intraoperative and postoperative
`reduction of hemorrhage and hyperemia after Lasik surgery ;
`preoperative hemorrhage and hyperemia prophylaxis prior to
`Lasik su ery; prophylactic diabetic retina athy; macular
`1a etes; con 1t1ons o
`e ema sue 1 as t mt associate wit
`retinal degeneration such as glaucoma, macular degeneration
`such as age-related macular degeneration (ARMD) and retin(cid:173)
`itis.pigmentosa; retinal dystrophies; elevated baseline hype(cid:173)
`remia in glaucoma patients; inflammatory di sorders of the
`retina; vascular occlusive conditions of the retina such as
`retinal vein occlusions or branch or central retinal artery
`occlu sions; retinopathy of prematurity ; retinopathy associ(cid:173)
`ated with blood disorders such as sickle cell anemia; elevated
`.
`.
`.
`.
`
`detaclm1ent; damage or insult due to vitrectomy, retinal or
`other surgery; and other retinal damage including therapeutic
`a resu mg ro m aser rea men o
`1e
`amage sue 1 as
`retina, for example, pan-retinal photocoagulation for diabetic
`retinopathy or photodynamic therapy of the retina. Ocular
`conditions that can be prevented or alleviated by administer(cid:173)
`ing the topical fonnulations of the present invention further
`include, without limitation, generic and acquired optic neu(cid:173)
`ropathies such as optic neuropathies characteri zed primarily
`by loss of centra l vision, fo r example, Leber's hered itary
`optic neuropathy (LEON), autosomal dominant optic atrophy
`(Kj er disease) and other optic neuropathies such as those
`involving mitochondrial defects aberrant dynamin-related
`proteins or inappropriate apoptosis; and optic neuritis such as
`that associated with multiple sclerosis, retinal vein occlusions
`or photodynamic or laser therapy. See, fo r example, Carelli et
`
`.-l r,
`ocular vascular congestion after
`o
`Lasik surgery; prophylactic intraoperative and postoperative
`reduction of hemorrhage and hyperemia after Lasik surgery;
`preoperative hemorrhage and hyperemia prophylaxis prior to
`Lasik surgery; prophylactic diabetic retinopathy;
`
`u
`
`u
`
`* * *
`damage or insult due to vitrectomy, retinal or
`other surgery;
`a
`""
`{,,;
`
`'"'
`
`c:
`
`* * *
`
`'?7 .77
`The term "ocular condi(cid:173)
`tion" also encompasses aesthetic conditions, for example,
`excessive redness of an eye.
`
`’742 Patent (EX-1001) at 12:13–49.
`
`Demonstrative Exhibit - Not Evidence
`
`18
`
`Petition (Paper 2) at 25, 31; Reply (Paper 43) at 1–2; Sher Reply Decl. (EX-1049) ¶¶ 38–40.
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.018
`
`

`

`Ocular Condition Is Not Limited to Conditions that Cause
`Ocular Hyperemia
`
`b) Ocular Conditions
`Ocular conditions include, but are not limited to, red eye,
`including chronic red eye; ocular vascular congestion after
`Lasik surgery ; prophylactic intraoperative and postoperative
`reduction of hemorrhage and hyperemia after Lasik surgery ;
`preoperative hemorrhage and hyperemia prophylaxis prior to
`Lasik surgery; prophylactic diabetic retinopathy; macular
`edema such as that associated with diabetes; conditions of
`retinal degeneration such as glaucoma, macular degeneration
`such as age-related macular degeneration (ARMD) and retin(cid:173)
`itis.pigmentosa; retinal dystrophies ; elevated baseline hype(cid:173)
`remia in glaucoma patients; inflanuuatory disorders of the
`retina; vascular occlusive conditions of the retina such as
`retinal vein occlusions or branch or central retinal artery
`occlusions; retinopathy of prematurity; retinopathy associ(cid:173)
`ated with blood disorders such as sickle cell anemia ; elevated
`intraocular pressure; ocular itch; damage following retinal
`detaclunent; damage or insult due to vitrectomy, retinal or
`other surgery; and other retinal damage including therapeutic
`damage such as that resulting from laser treatment of the
`retina, for example, pan-retinal photocoagulation for diabetic
`retinopathy or photodynamic therapy of the retina. Ocular
`conditions that can be prevented or alleviated by administer(cid:173)
`ing the topical fonnu lations of the present invention further
`include, without limitation, generic and acquired optic neu(cid:173)
`ropathies such as optic neuropathies characterized primarily
`by loss of central vision, fo r examp le, Leber's hereditary
`optic neuropathy (LEON), autosomal dominant optic atrophy
`(Kjer disease) and other optic neuropathies such as those
`involving mitochondrial defects aberrant dynamin-related
`proteins or inappropriate apoptosis; and optic neuritis such as
`that assoc iated with multiple sclerosis , retinal vein occlusions
`or photodynamic or laser therapy. See, for example, Carelli et
`al., Neurochem. Intl. 40:573-584 (2002); and Olichon et al., J.
`Biol. Chem. 278:7743-7746 (2003). The term "ocular condi(cid:173)
`tion" also encompasses aesthetic conditions, for example,
`excessive redness of an eye.
`
`Demonstrative Exhibit - Not Evidence
`
`“Ocular Condition” includes:
`
`Eye conditions that do not cause redness
`
`‒ Diabetic retinopathy
`
`‒ Macular degeneration
`
`‒ Glaucoma
`
`‒ Retinal artery occlusion
`
`‒ Retinal detachment
`
`Hemorrhages
`
`‒ Prophylactic intraoperative and postoperative
`reduction of hemorrhage after Lasik surgery
`
`‒ Preoperative hemorrhage prophylaxis
`prior to Lasik surgery
`
`Reply (Paper 43) 1–2; Sher Reply Decl. (EX-1049) ¶¶ 36, 38.
`
`19
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.019
`
`

`

`Gil Anticipates Claims 1 and 2 of the ’742 Patent
`
`The ’742 Patent
`
`Gil (’553 Patent)
`
`[1.preamble] A method for reducing eye redness
`
`[1.1] consisting essentially of administering brimonidine
`
`[1.2] to a patient having an ocular condition
`
`[1.3] wherein brimonidine is present at a concentration
`between about 0.001% weight by volume and about
`0.05% weight by volume
`
`[2.1] wherein brimonidine is present at a concentration
`between about 0.001% to about 0.025% weight by volume
`
`Demonstrative Exhibit - Not Evidence
`
`Petition (Paper 2) at 33–36; Reply (Paper 43) at 8–9; Gil (EX-1004).
`
`20
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.020
`
`

`

`Claim Construction – “about 0.025%”
`
`Petitioner’s Construction
`
`“about 0.025%” includes 0.03%
`
`Results of
`Patent Owner’s Construction
`
`“about 0.025%” excludes 0.03%
`
`Demonstrative Exhibit - Not Evidence
`
`21
`
`Petition (Paper 2) at 27–31; Reply (Paper 43) at 2–7; PO Resp. (Paper 30) at 27–36.
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.021
`
`

`

`The Use of the Word “About” Avoids
`a Strict Numerical Boundary
`
`“When ‘about’ is used as part of a numeric range, ‘the use of the word ‘about’ avoids a strict
`
`numerical boundary to the specified parameter.’”
`
`Cohesive Techs. v. Waters Corp., 543 F.3d 1351, 1368 (Fed. Cir. 2008).
`
`“Under Cohesive, claim construction of ‘about 0.025%’ in this IPR ‘must focus . . . on the
`
`criticality of the [numerical limitation] to the invention.’”
`
`Petition (Paper 2) at 28 (quoting Ortho-McNeil Pharm., Inc. v. Caraco Pharm. Lab’ys, Ltd., 476 F.3d 1321,1327 (Fed. Cir. 2007)
`(ellipses and bracketed language by the Federal Circuit in Cohesive)).
`
`“The relevant inquiry ‘is the purpose of the limitation in the claimed invention.’”
`
`Demonstrative Exhibit - Not Evidence
`
`Petition (Paper 2) at 28 (quoting Ortho-McNeil, 476 F.3d at 1327 (italics in original)).
`
`Petition (Paper 2) at 27–28.
`
`22
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.022
`
`

`

`The Specification Does Not Show “About 0.025%” Is Critical
`
`For purposes of the present invention, the terms below are
`defined as follows.
`111e term "low concentrations" refers to concentrations
`from between about 0.0001 % to about 0.05%; more prefer(cid:173)
`ably, from about 0.001 % to about 0.025%; even more pref(cid:173)
`erably, from about 0.01 % to about 0.025%; and even more
`preferably, from about 0.01 % to about 0.02% weight by vol(cid:173)
`ume.
`
`When the methods and compositions of the resent inven(cid:173)
`tion are used in conjunction with Lasik surgery the preferred
`a-2 agonist is brimonidine at a concentration of from about
`0.015% to about ~
`
`For the methods of scleral whitening, the preferred a-2
`agonist is brimonidine at a concentration of from about 0.01 %
`to about 0.05%1
`
`’742 Patent (EX-1001) at 12:60–63.
`
`’742 Patent (EX-1001) at 14:14–16.
`
`’742 Patent (EX-1001) at 3:58–65.
`
`Fig 4e: Brimonidine {l.03.3% OS only; 4 hours after 4d
`
`Vs. Baseline l l hours earlier:
`
`FIC.4E
`
`FIG. 6 depicts a graphical representation of a finding of the
`present invention that an increased rebound hyperemia begins
`at around 0.03% for brimonidine. It thus demonstrates 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%
`
`’742 Patent (EX-1001) at 19:52–57.
`
`Demonstrative Exhibit - Not Evidence
`
`23
`
`Petition (Paper 2) at 27–31; ’742 Patent (EX-1001) at Abstract, 3:30–33, 5:52–54, 9:11–14:6; Laskar Decl. (EX-1003) ¶¶ 65, 67–73.
`
`’742 Patent (EX-1001) at Fig. 4E.
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.023
`
`

`

`The Prosecution History Confirms that the
`Applicants Did Not Intend to Exclude 0.03%
`
`FIG. 4
`
`Table 3
`
`>> Sel Alpha 2 Agonists
`
`reachings.Qf The Present Invention
`
`Ettect
`
`-+-
`-
`·······►
`
`Lc-cend
`Vasoc~ ~ - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - ~
`
`IOPR
`El\do
`Rebou
`NetVa
`
`Fig. 4 is a graphical depiction (Table 3) of the variation of clinical effectiveness
`
`against concentration for compositions comprising the alpha 2 agonist brimonidine which may
`
`be used in the present invention providing at lower concentrations than shown in Fig. 3
`
`The net
`is shown by the
`rebound)
`vasoconstrictive effect curve (vasoconstriction
`thicker light gray curve, and peaks at~ 0.025% +/- 0.01 % (intersecting dashed
`lines) .
`
`’481 Provisional (EX-1011) at 68, 111.
`
`. 001
`
`.005
`
`0 .01
`
`0 .0•3
`
`0 .0!;,
`
`0 .08
`
`0.10
`
`0 .3
`
`0.5
`
`% Brimonldine
`
`Demonstrative Exhibit - Not Evidence
`
`24
`
`Reply (Paper 43) at 4–5; Laskar Reply Decl. (EX-1048) ¶ 16; Sher Reply Decl. (EX-1049) ¶ 22.
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.024
`
`

`

`Patent Owners Arguments All Fail
`
`The patentee did not act as lexicographers to define
`“about 0.025%” as excluding 0.03%
`
`The specification does not “clinically distinguish”
`0.025% from 0.03%”
`
`There is no basis to use extrinsic evidence to import
`a ± 10% limitation into the meaning of “about”
`
`Demonstrative Exhibit - Not Evidence
`
`Reply (Paper 43) at 2–7.
`
`25
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.025
`
`

`

`The Patentee Was Not Its Own Lexicographer
`
`PAT E N T O W N E R C L A I M S :
`
`0.025°/o. (Petition at 27. First, doing so ignores that Patentee was his own
`
`lexicographer and defined 0.025% as separate from 0.03%, which is improper.
`
`PO Resp. (Paper 30) at 30.
`
`“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.”
`
`Hill-Rom Servs., Inc. v. Stryker Corp., 755 F.3d 1367, 1371 (Fed. Cir. 2014).
`
`Demonstrative Exhibit - Not Evidence
`
`26
`
`Reply (Paper 43) at 2–4; PO Resp. (Paper 30) at 27–29; ʼ742 Patent (EX-1001) at 3:55–4:24, 8:46–55, 8:56–63;
`Laskar Reply Decl. (EX-1048) ¶¶ 7–13; Williams Dep. Tr. (EX-1054) at 26:2–14.
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.026
`
`

`

`The Patentee Was Not Its Own Lexicographer
`
`• Listing preferred embodiments is not lexicography
`Micron Tech., Inc. v. Lone Start Silicon Innovations LLC, No. IPR2017-01562, 2018 WL 6602102, at *4–*5 (P.T.A.B. Dec. 13, 2018).
`
`In a preferred embodiment, the invention generally relates
`to a method of reducing capillary permeability in a pulmo(cid:173)
`nary condition associated with swollen nasal turbinates com(cid:173)
`prising administering to a patient in need thereof a composi(cid:173)
`tion consisting essentially of brimonidine, wherein pH of said
`composition is between about 5 .0 and about 6.5 wherein said
`brimonidine concentration is from between about 0.001 % to
`about 0.025% wei ht by volume and wherein said composi(cid:173)
`tion is formulated as an aerosolized composition and admin(cid:173)
`istered into a nasal airway of the patient.
`In another embodiment, the invention generally relates to a
`method of treating respiratory syncytial virus (RSV) bronchi(cid:173)
`tis comprising administering to a patient in need thereof a
`composition consisting essentially of brimonidine, wherein
`pH of said composition is between about 5.0 and about 6.5,
`wherein said brimonidine concentration is from between
`about 0.001 % to about 0.07%, more preferably, from between
`about 0.001 % to about 0.03% weight by volume.
`
`Method of reducing capillary
`permeability in pulmonary
`condition associated with
`swollen nasal turbinates
`
`Method of treating
`respiratory syncytial virus
`(RSV) bronchitis
`
`Demonstrative Exhibit - Not Evidence
`
`’742 Patent (EX-1001) at 8:46–63.
`
`Reply (Paper 43) at 3.
`
`27
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.027
`
`

`

`The Specification Does Not “Clinically Distinguish”
`0.025% from 0.03%
`
`Figure 2
`
`Figure 6
`
`Effect
`
`♦
`
`♦
`
`0
`
`001 0 5 001
`
`0
`
`0 05
`
`0 08
`
`010
`
`0 . .3
`
`0
`
`% Brimonidine
`
`Demonstrative Exhibit - Not Evidence
`
`Reply (Paper 43) at 5–6.
`
`28
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.028
`
`

`

`The Specification Does Not Convey
`The “Criticality” Of 0.025%
`
`IH, . 11
`
`~et\s<1b1l1t\ C 0 o Dete, m1 nat1 on
`
`’481 Provisional
`(EX-1011)
`
`Figure 6
`(annotated by Noecker, EX-2020)
`
`Reply (Paper 43)
`at 5; Sher Reply
`Decl. (EX-1049)
`¶¶ 22, 28.
`
`Demonstrative Exhibit - Not Evidence
`
`0.025% in
`’481 Provisional…
`
`…is at same
`position as…
`
`…0.03% in
`Noecker’s Decl.
`
`29
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.029
`
`

`

`It Would Be Improper To Import a ± 10% Limitation
`From Extrinsic Evidence
`
`• Nothing in the specification adopts numerical limitations of
`extrinsic evidence, such as FDA acceptance criteria or the U.S.P.
`
`•
`
`If the inventors intended to define “about” with a strict ± 10%
`limitation, they would have done so.
`
`• FDA acceptance criteria and U.S.P. definitions account for
`variability and experimental error, not a range of concentrations.
`
`Demonstrative Exhibit - Not Evidence
`
`Reply (Paper 43) at 3–4; Laskar Reply Decl. (EX-1048) ¶¶ 7–13.
`
`30
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.030
`
`

`

`Gil Anticipates Claims 1 and 2 of the ’742 Patent
`
`The ’742 Patent
`
`Gil (’553 Patent)
`
`[1.preamble] A method for reducing eye redness
`
`[1.1] consisting essentially of administering brimonidine
`
`[1.2] to a patient having an ocular condition
`
`[1.3] wherein brimonidine is present at a concentration
`between about 0.001% weight by volume and about
`0.05% weight by volume
`
`[2.1] wherein brimonidine is present at a concentration
`between about 0.001% to about 0.025% weight by volume
`
`Demonstrative Exhibit - Not Evidence
`
`Petition (Paper 2) at 33–37; Reply (Paper 43) at 8–9; Gil (EX-1004).
`
`31
`
`Slayback Pharma LLC
`Petitioner's Demonstratives.031
`
`

`

`Ground 1: Anticipated by Gil (the ’553 Patent)
`
`Claim 1 of the ’742 Patent
`
`Gil (the ’553 Patent)
`
`1. A method for reducing eye redness
`
`Express references in Gil to reducing ocular inflammation, i.e., eye redness:
`• Example 1 intended to reduce inflammation
`•
`“Symptoms of ocular inflammation (burning/stinging, tearing, etc.) are also recorded).”
`
`Inherent disclosure that administering 0.03% brimonidine would necessarily reduce redness
`• Radial keratotomy necessarily results in redness
`• Corneal incision → tissue damage → inflammatory cascade → eye redness (vasodilation of
`surrounding blood vessels)
`
`consisting essentially of administering
`brimonidine
`
`“brimonidine is administered”
`
`“A clinical study is performed to compare the analgesic effect of topically administered
`brimonidine and placebo following radial keratotomy surgery.”
`
`to a patient having an ocular condition,
`
`Claim construction:
`