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