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

`

`I.
`II.
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`III.
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`Case IPR2022-00142
`Patent Owner’s Sur-Reply
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`
`Table of Contents
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`
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`
`
`Introduction ...................................................................................................... 1
`Claim Construction .......................................................................................... 1
`“ocular condition” ................................................................................. 1
`“about 0.025%” ..................................................................................... 3
`1.
`“about 0.025%” does not embrace 0.03% .................................. 3
`2.
`Petitioner’s other arguments are unavailing ............................... 6
`Petitioner has failed to establish that any claim is unpatentable ..................... 8
` Ground 1: Example 1 of the ’553 patent does not inherently
`anticipate claims 1-2 .............................................................................. 8
`Ground 2: Walters does not anticipate claims 1-2 ..............................10
`Ground 3: Petitioner has failed to establish that claims 1-6 are
`obvious ................................................................................................10
`1.
`Petitioner has failed to establish that claim 3 of the ’742
`patent is obvious........................................................................10
`A POSA would not have been motivated to use
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`brimonidine at all, let alone with any reasonable expectation of
`success .......................................................................................10
` Neither the ’553 patent nor Norden suggests using
`brimonidine to reduce ocular redness .............................11
` A POSA would not have looked to the highly
`selective α-2 agonist brimonidine nor reasonably
`expected it to reduce eye redness ...................................13
`If anything, the art pointed towards needing high
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`concentrations of brimonidine to obtain any whitening effect .16
`Petitioner’s remaining criticisms are unavailing ............19
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`The art teaches away from the claimed pH ....................21
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`Case IPR2022-00142
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`2.
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`Petitioner has failed to establish that claims 4-6 are
`obvious ......................................................................................23
`Objective, real-world evidence of nonobviousness ..................23
`3.
`IV. Conclusion .....................................................................................................27
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`ii
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`Case IPR2022-00142
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`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Allergan, Inc. v. Sandoz Inc.,
`796 F.3d 1293 (Fed. Cir. 2015) ............................................................................ 5
`Forest Lab’ys, Inc. v. Ivax Pharms., Inc.,
`438 F. Supp. 2d 479 (D. Del. 2006).................................................................... 27
`Jansen v. Rexall Sundown, Inc.,
`342 F.3d 1329 (Fed. Cir. 2003) ........................................................................ 2-3
`Millennium Pharms., Inv. v. Sandoz Inc.,
`862 F.3d 1356 (Fed. Cir. 2017) .......................................................................... 25
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) ........................................................................ 3, 6
`In re Soni,
`54 F.3d 746 (Fed. Cir. 1995) .............................................................................. 26
`In re Spormann,
`363 F.2d 444 (C.C.P.A. 1966) ...................................................................... 11, 24
`Trivascular, Inc. v. Samuels,
`812 F.3d 1056 (Fed. Cir. 2016) .......................................................................... 11
`WBIP v. Kohler Co.,
`829 F.3d 1317 (Fed. Cir. 2016) .......................................................................... 24
`In re Wesslau,
`353 F.2d 238 (C.C.P.A 1965) ............................................................................. 18
`Regulations
`37 C.F.R. § 42.23(b) .................................................................................................. 8
`37 C.F.R. § 42.65(a) ................................................................................................. 22
`
`
`iii
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`

`

`Introduction
`Petitioner continues to assert an overly simplistic view of the art and relies on
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`Case IPR2022-00142
`Patent Owner’s Sur-Reply
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`I.
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`cherry-picked statements to the exclusion of the most pertinent prior art, all to
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`advance meritless, litigation-driven positions. But as set forth herein and in Patent
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`Owner’s prior responses, when viewed correctly from the perspective of a person of
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`ordinary skill in the art (“POSA”), the prior art neither inherently anticipated nor
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`rendered obvious the claims of the ’742 patent.
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`II. Claim Construction
`“ocular condition”
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`Petitioner argues that Patent Owner’s construction of “ocular condition,”
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`improperly narrows the definition set forth in the specification. Reply § II.A.
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`Petitioner further argues that “LASIK is an ocular condition of the claims,” so radial
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`keratotomy must also be. Id. Petitioner misinterprets the passage in column 12
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`because LASIK is not an “ocular condition.” Instead, consistent with Patent Owner’s
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`construction, the specification indicates LASIK is a procedure giving rise to an
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`ocular condition (i.e., hyperemia). See, EX-1001 at 12:14-16 (“ocular conditions
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`include…ocular vascular congestion after Lasik surgery”) (emphasis added).
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`A POSA, moreover, would construe “ocular condition” in light of the claim
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`as a whole, including specifically, the limiting preamble, which sets forth the
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`objective of the invention: reducing eye redness, defined as hyperemia. EX-1001 at
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`1
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`1:9. Resolving any doubt that reducing hyperemia was the objective of the claimed
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`invention,
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`the specification repeatedly mentions vasoconstriction, reducing
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`hyperemia, and whitening of the sclera. See generally EX-1001. It identifies several
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`causes of hyperemia (EX-1001 at 2:15-21) and discusses the need to develop a
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`redness reducer that would effectively vasoconstrict—which a POSA would
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`understand would reduce hyperemia (EX-2020, ¶¶99-105)—without causing
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`rebound hyperemia (E.g., EX-1001 at 2:21-33, 2:38-41 (describing the use of a
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`highly selective α-2 agonist to achieve vasoconstriction without rebound hyperemia
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`as a key discovery of the present invention). Petitioner’s attempt to broaden the
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`scope of “ocular condition,” by pointing to conditions that do not give rise to
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`hyperemia is unavailing.
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`Logically, a POSA would have understood “ocular condition” in a claim
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`requiring reducing redness to mean the ocular condition must result in redness that
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`can actually be reduced—i.e., not something like hemorrhage that only dissipates
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`with time.1 EX-2020, ¶168; EX-2162 at 112:18-23. This understanding is supported
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`1 Later in its Reply, Petitioner effectively argues the preamble is non-limiting,
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`suggesting the claims require only an “intent” to reduce eye redness. Reply at 7-8.
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`This is wrong as a matter of common sense and law, for the claims are not directed
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`to compositions but to specific methods of reducing redness. See Jansen v. Rexall
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`2
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`by the specification, which a POSA would understand teaches only preventing or
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`reducing the occurrence of subconjunctival hemorrhages. EX-1001 at 12:14-19.
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`
`
` “about 0.025%”
`“about 0.025%” does not embrace 0.03%
`1.
`The issue here is whether a POSA would have understood from the intrinsic
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`record that “about 0.025%” includes 0.03%. The answer is no. Petitioner’s
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`arguments to the contrary fail to acknowledge that the patent itself refers to 0.025%
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`and 0.03% as separate embodiments and to take into account the plain and ordinary
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`meaning of the term “about.” Worse still, Petitioner fails to account for the clinical
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`distinction the specification creates between compositions containing 0.03% and
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`compositions containing less than 0.03%, such as about 0.025%. See Response,
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`§§ V.B.1-V.B.2.
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`Importantly, claims are construed based on what the specification conveys to
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`a POSA that the inventor discovered or invented. See Phillips v. AWH Corp., 415
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`F.3d 1303, 1316 (Fed. Cir. 2005). A key discovery here, which is touted repeatedly,
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`was the ability to induce vasoconstriction thereby reducing eye redness (benefit)
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`Sundown, Inc., 342 F.3d 1329, 1333 (Fed. Cir. 2003) (finding the preamble was a
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`purposeful statement for which the method must be performed, not merely a
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`statement of desired effect).
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`while minimizing rebound hyperemia (risk). See, e.g., EX-1001 at 2:38-41, 4:25-30,
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`4:47-56, and 6:37-39.
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`Petitioner argues there is no meaningful difference between the two
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`concentrations. Reply, 4-5. In support, Petitioner focuses on the patent’s description
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`of brimonidine’s maximum “Net Vasoconstriction Benefit,” arguing that the peak of
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`0.03% is “optimal.” Id. (citing EX-1001 at 19:52-55; EX-1053 at 86:7-17).
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`Petitioner is wrong, and its citations do not support its position. To the contrary, the
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`patent explicitly states that “increased rebound hyperemia begins at around 0.03%”
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`and “net effectiveness” “is greatest between about 0.01% and about 0.03%.” EX-
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`1001 at 19:52-57. Suggesting that 0.03%—the specific concentration called out by
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`the patent as increasing rebound hyperemia—is clinically equivalent to about
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`0.025% runs afoul of the purpose of the invention. Viewing Figure 6, a POSA would
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`have understood the blue dot, which lands at about 0.025%, represents the optimal
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`brimonidine concentration. EX-1001 at Fig. 6, 19:52-54; 11:32-41; EX-2020, ¶¶95,
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`111-113. This is no coincidence, for a POSA would have considered Figure 6 in the
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`context of the complete specification, in which the inventor identified “about
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`0.025%” as preferred 22 times. See, e.g., EX-2020, ¶115. On the other hand, 0.03%
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`is mentioned just three times and is associated with rebound hyperemia.2 EX-1001
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`at 19:52-54, 21:8-9. A POSA would thus understand that concentrations below
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`0.03%, such as about 0.025%, critically differ from about 0.03% because they still
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`have high vasoconstrictive activity but also have reduced propensity to cause
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`rebound hyperemia. EX-2020, ¶¶94-95, 116.
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`Petitioner criticizes Figure 6 as purportedly not backed by clinical data. Reply,
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`5-6. Whether it was is of no moment, because examples are not required, much less
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`examples based on clinical data. See Allergan, Inc. v. Sandoz Inc., 796 F.3d 1293,
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`1309-10 (Fed. Cir. 2015). Moreover, even without Figure 6, the specification
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`distinguishes “around 0.03%” based on the drawbacks associated with the
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`2 Petitioner argues that a provisional application teaches that the net vasoconstrictive
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`effect peaks at “about 0.025% +/- 0.01% (intersecting dashed lines).” Reply at 5
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`(citing EX-1011 at 68). The reference in Figure 4 to 0.025% is clearly incorrect
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`because the dashed lines intersect exactly at 0.03% (EX-1011 at 111), which is
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`consistent with Figure 6 of the ’742 patent conveying that rebound hyperemia begins
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`at 0.03% (EX-2020, ¶¶94-95, 111). Moreover, Figure 13 of the provisional
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`application teaches that despite the increased vasoconstrictive effect at and above
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`0.03%, below 0.03% is preferred due to the lower incidence of rebound hyperemia.
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`EX-1011 at 121.
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`appearance of rebound hyperemia. See Response, § V.B.2. What matters for claim
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`construction is what the inventor conveys was found or discovered. Phillips, 415
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`F.3d at 1316. Here, the specification clearly conveys the inventor’s finding that
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`brimonidine concentrations around 0.03% causes rebound hyperemia, whereas
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`“about 0.025%” aligns with the key and surprising discovery of the claimed
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`invention—achieving high vasoconstriction while minimizing rebound redness. EX-
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`1001 at 19:52-54; EX-2020, ¶¶110-113. Thus, even if a POSA would have been
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`skeptical about Figure 6, as Petitioner suggests, the POSA would have relied upon
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`the remainder of the specification, which conveys that they are distinct
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`embodiments.3 Response, § V.B.1.
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`Petitioner’s other arguments are unavailing
`2.
`Petitioner suggests that Patent Owner’s construction is based on a
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`lexicography argument. Reply at 2. To be clear, Patent Owner maintains that a POSA
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`would understand the term “about” means no more than ±10%, consistent with its
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`plain and ordinary meaning in the pharmaceutical arts. EX-2021, ¶¶39-45; see also
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`Response, § V.B.3.
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`3 Dr. Laskar opines that “about 0.025%” would round to 0.03%, but he admits that
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`applying general chemistry rounding principles, 0.025% would round down to
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`0.02%, not up to 0.03%. EX-2212 at 134:11-18.
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`Petitioner criticizes Patent Owner’s reliance on FDA acceptance criteria and
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`USP guidance, alleging nothing in the patent would lead a POSA to consider them.
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`Reply at 4. But the claimed invention is directed to the use of a pharmaceutical.
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`Common sense dictates that such well-known pharmaceutical guides would have
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`informed a POSA’s understanding of “about,” where no one disputes the POSA has
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`experience in pharmaceuticals, including regulatory knowledge, EX-2021, ¶¶41-45.
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`Also, Patent Owner never suggested FDA acceptance criteria and USP serve
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`the same purpose. Instead, Patent Owner and its expert, Dr. Williams, correctly
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`noted that formulators rely on these relevant materials (which Petitioner’s expert
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`admitted (EX-2212 at 129:14-130:3)), which are consistent with a POSA’s
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`understanding of “about” to mean no more than ±10%. EX-2021, ¶¶39-45. Though
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`the acceptance criteria may vary from product to product, even Dr. Laskar admits
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`the typical acceptance criteria is ±10%.4 EX-1048, ¶9; EX-2198 at 51:1-12.
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`4 While Dr. Laskar originally testified a POSA would not consider the USP to
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`interpret “about,” he later testified a POSA would look to USP in connection with
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`the patent claims. EX-2212 at 128:24-130:3.
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`III. Petitioner has failed to establish that any claim is unpatentable
` Ground 1: Example 1 of the ’553 patent does not inherently
`anticipate claims 1-2
`In response to Patent Owner’s argument that Example 1 of the ’553 patent
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`(directed to the use of brimonidine to treat ocular pain) does not inherently
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`anticipate the claimed redness reducing methods, Petitioner makes three points,
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`improperly attempting to use its expert to supply disclosure where none is present.
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`The first is new and contrary to law. The second is inconsistent with admissions
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`previously made by Petitioner’s expert. And the third improperly shifts the burden
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`to patentee. All are unavailing.
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`First, Petitioner newly argues that the claimed methods are directed to an
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`“intent to reduce redness” and Example 1 of the ’553 somehow inherently discloses
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`such an intent. Reply at 7-8. While Petitioner’s improper new argument should be
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`stricken (37 C.F.R. § 42.23(b)), it also makes no sense. Example 1 describes use of
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`brimonidine to treat pain. EX-2020, ¶145. It cannot disclose an intent to reduce
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`redness, which Petitioner argues is inherent and thus undisclosed. Because one
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`cannot intend an unknown outcome, Petitioner’s argument must fail.
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`Second, Petitioner argues that the radial keratotomy patients of Example 1
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`would have inflammation and ocular redness, and thus 0.03% brimonidine must
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`have reduced such hypothetical redness. Reply at 8. But Dr. Sher admitted that, if
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`done properly, redness does not necessarily result from radial keratotomy. EX-2162
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`at 113:6-114:4; EX-2020, ¶¶148-149. He also conceded that a patient can have
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`inflammation with pain but without redness. EX-2162 at 104:23-106:14, 107:2-11,
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`109:3-11. He testified that radial keratotomy patients preoperatively receive anti-
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`inflammatories (steroids and NSAIDs), tear drops (for lubrication), and antibiotics
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`(for infection), which could prevent a patient from developing hyperemia. EX-2213
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`at 15:8-16:18, 17:19-21:8, 23:5-13. Indeed, Dr. Sher acknowledged repeatedly that
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`hyperemia is merely a possible outcome, thus failing to establish its inevitability.
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`EX-1049, ¶¶47, 50.
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`Third, having failed to provide substantiating data to carry the heavy burden
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`of inherency, Petitioner improperly attempts to shift its burden to Patent Owner. The
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`’742 patent itself teaches that rebound redness begins at around 0.03%. EX-1001 at
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`19:52-54, Figure 6; EX-2020, ¶¶150, 188-194.5 Ironically, Petitioner takes issue
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`with Patent Owner’s reliance on this teaching, arguing that it is not supported by
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`data (Reply at 9), but Petitioner itself has provided no data to substantiate its
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`inherency position. Nevertheless, the specifically articulated “finding of the present
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`5 Accusing Dr. Noecker of having inconsistent standards for the references,
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`Petitioner ignores that claim construction and inherency have different legal
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`standards.
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`invention” that 0.03% brimonidine can cause hyperemia, undermines Petitioner’s
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`argument that administration of 0.03% brimonidine in the prophetic Example 1
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`would have inevitably reduced redness. EX-2020, ¶150.
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` Ground 2: Walters does not anticipate claims 1-2
`Because Petitioner did not reply to Patent Owner’s position on Walters, Patent
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`Owner rests on its prior responses.
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` Ground 3: Petitioner has failed to establish that claims 1-6
`are obvious
`Petitioner has failed to establish that claim 3 of the
`1.
`’742 patent is obvious
`A POSA would not have been motivated to use
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`brimonidine at all, let alone with any reasonable
`expectation of success
`Petitioner contends a POSA would have selected brimonidine for three main
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`(incorrect) reasons. Reply at 10. Petitioner’s hindsight-based arguments—ignoring
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`the most pertinent prior art in favor of cherry-picked references—fail.
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`10
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` Neither the ’553 patent nor Norden suggests using
`brimonidine to reduce ocular redness
`Petitioner first argues the ’553 patent and Norden expressly taught that
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`brimonidine could be used to reduce ocular redness, and thus would have motivated
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`a POSA to use brimonidine. See Reply, 10-11. That is incorrect.6
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`Having advanced an inherent anticipation argument, Petitioner cannot
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`credibly contend that in the obviousness context, Example 1 expressly teaches using
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`brimonidine to reduce redness. As is well-established, that which is inherent is
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`unknown, and obviousness cannot be predicated on what is unknown. In re
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`Spormann, 363 F.2d 444, 448 (C.C.P.A. 1966). In fact, all that Example 1 suggests
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`is that brimonidine can block the perception of pain. EX-2020, ¶¶144-153; see also
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`EX-1006 at 471. That is how an anesthetic works, as both the ’553 patent and Dr.
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`Sher acknowledge. EX-1004 at 1:54-55; EX-2213 at 23:14-22, 24:21-25:12.
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`Importantly, Dr. Sher has admitted that an anesthetic cannot reduce ocular
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`hyperemia (EX-2213 at 25:13-26:15), confirming that a POSA would not understand
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`Example 1’s conclusion that brimonidine blocks the perception of pain to suggest
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`6 Petitioner’s argument largely presumes the Institution Decision has made
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`Petitioner’s position a fait accompli. See Reply at 10. That is wrong. See, e.g.,
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`Trivascular, Inc. v. Samuels, 812 F.3d 1056, 1068 (Fed. Cir. 2016).
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`brimonidine would reduce redness. EX-2020, ¶¶150-151.7 Indeed, the conclusion
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`does not mention anything about reducing eye redness. EX-1004 at 6:24-27.
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`Petitioner attempts to rehabilitate Norden by arguing that Uretmen—an article
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`criticizing Norden’s conclusions—merely suggests testing for allergies before using
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`brimonidine. Reply at 11. Actually, Uretman reported that 0.2% brimonidine (the
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`same concentration used in Norden) caused an allergic reaction accompanied by
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`hyperemia that was “so severe that [they] had to postpone surgery” in 30% of
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`patients. EX-2186 at 1. This is consistent with the level of hyperemia clinically
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`observed with the Alphagan® products (EX-2012 at 9; EX-1031 at 129; EX-2014 at
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`4) and would hardly have suggested using brimonidine as a redness reliever.
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`Response, § VI.C.1.a.
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`Petitioner bewilderingly ignores the only clinical in vivo data in the record:
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`the Alphagan® and Alphagan® P labels, both of which taught that brimonidine
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`caused hyperemia. EX-1031 at 109, 129; EX-2014 at 4. Instead, it argues that a
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`7 Even though Dr. Sher considers Example 1 of the ’553 patent to be the closest prior
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`art (EX-1049, ¶115), Patent Owner also addresses Example 4. It too just assesses the
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`anesthetic effects of brimonidine to block nerve traffic and relieve the sensation of
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`ocular pain. EX-2020, ¶¶154-160. As such, a POSA would not have understood
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`Example 4 to suggest that brimonidine reduces redness. Id.
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`POSA would have looked to references like the ’553 patent, which Dr. Sher admitted
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`he was unaware of until his work on this matter (EX-2162 at 114:8-16, 116:4-8), and
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`Norden, which at most only suggests that high-concentrations of brimonidine (0.2%)
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`may reduce hyperemia. EX-2020, ¶¶173, 244-245. But the Alphagan® clinical
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`studies taught that while high concentrations of brimonidine might cause
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`conjunctival blanching, no blanching was observed with the lower concentration
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`Alphagan® P products, and brimonidine caused redness at all concentrations. See,
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`infra § III.C.1.b; Response, § VI.C.1.b.
`
` A POSA would not have looked to the highly
`selective α-2 agonist brimonidine nor reasonably
`expected it to reduce eye redness
`Petitioner’s second argument is premised on its mistaken belief that
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`brimonidine was recognized as a “viable option” for an ocular redness reliever and
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`a misunderstanding of the art’s teaching regarding α-1 and α-2 agonists.
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`Petitioner asserts that Patent Owner has created a “false dichotomy” between
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`α-1 and α-2 agonists, arguing that (1) the prior art taught the vasoconstrictive
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`properties of α-2 agonists and (2) even though α-2 agonists may vasodilate in one
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`tissue type (endothelial), a POSA would not assume they would have a vasodilative
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`effect in the eye. Reply, 12-13. First, as previously discussed, an α-2 agonist could
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`induce vasoconstriction, but only when the concentration is high enough to trigger
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`its α-1 effect. Response, § VI.C.1.b. Second, Petitioner’s newly cited references do
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`not teach that stimulating α-2 receptors in ocular tissue would have caused
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`vasoconstriction and reduce redness.
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`Notably, Dr. Sher argues that only references concerning the eye are relevant.
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`EX-1049, ¶67. Yet the prior art Dr. Sher relies on does not concern the eye or ocular
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`tissue.8 And Dr. Sher ignores the record evidence related to the mechanism of action
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`of adrenergic drugs in the eye. Specifically, Derick 1995 describes the mechanism
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`of action of adrenergic agonists and teaches that the ocular effect of adrenergic drugs
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`can “be anticipated by knowing the location and type of adrenoceptors.” EX-2169
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`at S4; EX-2020, ¶65. Table 3 indicates that α-1 receptors are located in the
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`conjunctiva and will cause constriction, while α-2 receptors are located on the ciliary
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`body (not visible) and will cause decreased aqueous production, consistent with the
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`relaxation associated with vasodilation. EX-2169 at Tables 2-3; EX-2020, ¶¶63-64.
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`8 See, e.g., EX-1090 at S549 (evaluates constriction in the vasculature of kidneys);
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`EX-1091 (evaluated α-2-AR peripheral vasoconstriction, which does not include the
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`eye); and EX-1092 (experimenting on genetically engineered mice with no
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`evaluation on vasoconstriction in the eye).
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`Thus, the art relevant to the eye taught that α-1 receptors are the predominant drivers
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`of vasoconstriction, leading a POSA to focus, if anything, on α-1 agonists. Response,
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`§§ IV.C.1; VI.C.1.a; EX-2020, ¶¶58-67.
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`Moreover, Petitioner’s own references repeatedly taught that brimonidine
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`caused vasodilation in endothelial cells, which the blood vessels in the front of the
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`eye mainly consist of. EX-2176 at Abstract, 725 (“both conjunctival and episcleral
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`blood vessels possess a continuous endothelium”); EX-1019 at 3 (“brimonidine
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`tartrate may also produce vasodilation via the α2-adrenergic receptors on endothelial
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`cells”); EX-1035 at 5 (“brimonidine can produce vasodilation via α2-adrenoceptors
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`on endothelial cells”); EX-2020, ¶63.9
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`Thus, the prior art taught that, α-1 receptors predominantly mediated
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`vasoconstriction and α-2 receptors would have caused, if anything, vasodilation.
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`Response, §§ IV.C.2.b, VI.C.1.a. On this basis alone, there would have been no
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`reason, absent hindsight, for a POSA to look to the highly selective α-2 agonist
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`brimonidine and reasonably expect that it would reduce eye redness.
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`
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`If anything, the art pointed towards needing high
`concentrations of brimonidine to obtain any
`whitening effect
`The prior art Alphagan® products demonstrated a concentration dependent
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`relationship between brimonidine and whitening, with only higher concentrations
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`showing any potential for blanching. Response, §§ IV.D.1.b, VI.C.1.b. Even
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`Petitioner’s own reference explicitly acknowledges that conjunctival blanching is
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`concentration dependent. EX-1027 at 135 (“Not only was a dose response relation
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`shown for the ocular hypotensive effects of brimonidine, but also for the effects
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`on…conjunctival blanching”) (emphasis added). A POSA would have thus
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`9 Regarding Petitioner’s sub-type position (Reply, 13, n.7), human ocular tissue
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`contains “only the α2A-adrenoreceptor” (EX-1017, 2053), which, when stimulated,
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`causes vasodilation (EX-1092, Fig.3; EX1001, 1:45-47.).
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`recognized this trend in the art and understood that with the declining concentration,
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`brimonidine’s limited α-1 effect would disappear and brimonidine would lose its
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`blanching capability but still retain its tendency to regularly cause redness at lower
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`concentrations. EX-2020, ¶¶69-79.
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`Petitioner does not, and cannot, refute the Alphagan® and Alphagan® P
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`adverse event data. Instead, Petitioner argues a POSA could not “draw a conclusion
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`as to concentration dependence” and provides purely speculative alternative
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`explanations for the lack of blanching data in the Alphagan® P label. See Reply at
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`15-17. Indeed, Dr. Sher admitted he has no personal knowledge of what was
`
`observed in those trials, and that when clinical investigators initially observe a side-
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`effect for a drug, it would be looked for in subsequent clinical trials. EX-2213 at
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`50:12-51:6, 51:21-52:13. He also confirmed that there was commonality in the
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`investigators across the studies, further supporting the idea that blanching would
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`have been considered in all studies. Id. at 61:5-64:5. Even if Petitioner is correct,
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`Petitioner has failed to address the clear concentration dependent relationship
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`demonstrated by the data for the Alphagan® 0.5% and 0.2% products. See EX-2020,
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`¶135.
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`Petitioner next argues that a conclusion cannot be drawn from the different
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`data sets. Reply at 15. But it has failed to explain why, particularly when the two
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`clinical trials reported on the Alphagan® labels studied the same active ingredient,
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`in the same patient population, for the same indication. Response, § IV.D.1. And
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`contemporaneous references acknowledge that clinicians did compare the adverse
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`event profiles of these two products and preferred the lower-dose products. EX-2007
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`at 344; EX-2018.
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`Petitioner’s harsh criticism of these human clinical results (which report
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`actual results related to redness), starkly contrasts with Petitioner’s unquestioned
`
`reliance on preclinical data and prophetic examples with no reported results on
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`redness. Indeed, while Petitioner criticizes Dr. Noecker’s conclusions regarding the
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`Alphagan® labels, the ’553 patent, and Norden, the reality is these documents contain
`
`vastly different disclosures, and a POSA would understand their hierarchical
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`importance in assessing the state of the art. The ’553 patent examples were neither
`
`designed to assess redness nor provided any data showing redness reduction. EX-
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`2020, ¶¶144-153, 166-175. By contrast, the Alphagan® studies included data for
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`commercial products, which showed redness, allergy, and blanching, side effects
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`familiar to Dr. Noecker and a POSA. EX-2020, ¶¶68-75.
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`In short, Petitioner “pick[s] and choose[s] from any one reference only so
`
`much of it as will support a given position, to the exclusion of other parts necessary
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`to the full appreciation of what such reference fairly suggests” to a POSA. In re
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`Wesslau, 353 F.2d 238, 241 (C.C.P.A 1965). That is impermissible within the
`
`framework of § 103. Id. Petitioner’s own references clearly indicate that low-dose
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`brimonidine, if anything, caused redness and certainly did not reduce it. See, e.g.,
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`EX-2020, ¶¶69, 215-222; EX-1031 at 109, 129.
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`Petitioner’s remaining criticisms are unavailing
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`Petitioner contends that knowledge of brimonidine’s safety and stability
`
`profile would have motivated a POSA to use brimonidine. Reply at 14. But
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`brimonidine’s safety and stability profile would have taught away from using
`
`brimonidine as a redness reliever. Brimonidine products were known to cause
`
`redness and had high incidences of serious adverse events, leading to non-
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`compliance, discontinuation, and limitations on use. EX-2020, ¶74; EX-2011 at 1-
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`2; EX-2211. Petitioner curiously suggests that there was “promising data regarding
`
`brimonidine’s redness-reducing properties.” Reply at 14. Yet the clear evidence
`
`demonstrating that brimonidine causes redness undermines this. See, e.g., EX-2020,
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`¶¶69, 216; EX-1031 at 109; EX-2012 at 11. Thus, a POSA’s knowledge regarding
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`brimonidine’s side effects (like redness) would have in fact discouraged the pursuit
`
`of brimonidine for redness reduction.
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`Ignoring this evidence, Petitioner argues that lowering the concentration of
`
`brimonidine would reduce these adverse effects. Reply at 14. But Petitioner fails to
`
`acknowledge that the prior art taught that lowering the concentration would require
`
`increasing the pH to achieve the same efficacy. EX-2021, ¶¶98-101, 111. Even if a
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`POSA were motivated to use low-dose brimonidine to reduce the incidence of
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`adverse events, which Petitioner has not established, a POSA would have targeted,
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`if anything, a pH above 7 (outside of the claimed range). Response, § VI.C.1.b. That
`
`is exactly what Allergan did when it formulated Alphagan® P. EX-2007 at 339-340.
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`Notably, Allergan did not formulate down to 0.025% and did not discover that low-
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`dose brimonidine reduced ocular redness.
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`It also defies logic that one would even consider using a compound that causes
`
`hyperemia to reduce redness. Response, § VI.C.1.a. Invention is about improving
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`upon or providing a better product than what existed previously. To suggest that one
`
`would develop another redness reliever and simply accept its problematic adverse
`
`side-effect profile because it was “in line with” all other redness relievers, as
`
`Petitioner argues, is not credible.
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`Misconstruing the record, Petitioner suggests Patent Owner argued a POSA
`
`would start from scratch and make an entirely new compound, rather than look first
`
`to known compounds that had