Paper No. __
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`INNOPHARMA LICENSING, INC., INNOPHARMA LICENSING LLC,
`INNOPHARMA INC., INNOPHARMA LLC,
`MYLAN PHARMACEUTICALS INC., MYLAN INC., LUPIN LTD., and LUPIN
`PHARMACEUTICALS, INC.
`Petitioner,
`
`v .
`
`SENJU PHARMACEUTICAL CO., LTD., BAUSCH & LOMB, INC., and
`BAUSCH & LOMB PHARMA HOLDINGS CORP.
`Patent Owner.
`__________________
`
`Case IPR2015-009031
`Patent 8,129,431
`__________________
`
`Filed: March 18, 2016
`__________________
`
`Petitioner’s Reply to Patent Owner’s Response to Petition
`
`1 IPR2015-01871 has been joined with IPR2015-00903.
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`INNOPHARMA LICENSING, INC., INNOPHARMA LICENSING LLC,
`INNOPHARMA INC., INNOPHARMA LLC,
`MYLAN PHARMACEUTICALS INC., MYLAN INC., LUPIN LTD., and LUPIN
`PHARMACEUTICALS, INC.
`Petitioner,
`
`v .
`
`SENJU PHARMACEUTICAL CO., LTD., BAUSCH & LOMB, INC., and
`BAUSCH & LOMB PHARMA HOLDINGS CORP.
`Patent Owner.
`__________________
`
`Case IPR2015-009031
`Patent 8,129,431
`__________________
`
`Filed: March 18, 2016
`__________________
`
`Petitioner’s Reply to Patent Owner’s Response to Petition
`
`1 IPR2015-01871 has been joined with IPR2015-00903.
`
`
`
`I.
`II.
`
`TABLE OF CONTENTS
`INTRODUCTION ...........................................................................................1
`ARGUMENT...................................................................................................1
`A.
`Patent Owner Fails to Consider the Full Scope of the Prior Art...........1
`1.
`Complexation of Acidic NSAIDs and BAC Was Known..........1
`
`2.
`
`Ethoxylated Octylphenols Were Known to Solve the
`
`Complexation Problem ...............................................................5
`
`3.
`
`BAC Was Commonly Used for Ophthalmic Products ...............9
`
`B.
`
`The Claims are Obvious under Patent Owner’s Theory that a
`POSA Would Have Used Antioxidants to Stabilize Bromfenac ........11
`1.
`Tyloxapol is in the Class of Alkylphenols Disclosed in
`
`Doi.............................................................................................12
`
`2.
`
`Tyloxapol’s General Antioxidant Properties Were
`
`Known.......................................................................................12
`
`C.
`
`D.
`
`A POSA Would Have Expected Tyloxapol to Improve Stability
`and Preservative Efficacy....................................................................14
`A POSA Would Have Considered Ogawa Example 6 and
`Sallmann Example 2............................................................................16
`1.
`Bromfenac Was an NSAID with Superior Efficacy and a
`
`POSA Would Have Considered Ogawa Example 6.................17
`
`2.
`
`A POSA Would Have Considered Sallmann Example 2 .........18
`
`E.
`
`A POSA Would Have Arrived at the Appropriate Concentration
`of Tyloxapol through Routine Optimization.......................................18
`
`ii
`
`
`
`Paper No. __
`
`F.
`
`Patent Owner’s Evidence of Alleged Objective Indicia is Not
`Probative of Patentability....................................................................20
`1.
`Patent Owner Did Not Compare to the Closest Prior Art.........20
`
`2.
`
`Patent Owner’s Evidence of Secondary Considerations
`
`are Not Commensurate with the Scope of the Claims..............20
`
`3.
`
`Evidence of Commercial Success Lacks Factual Support
`
`and Nexus with the Claims .......................................................23
`
`4.
`
`Patent Owner’s Arguments Regarding Licensing and
`
`Copying are Misplaced .............................................................25
`
`III. CONCLUSION..............................................................................................25
`CERTIFICATION OF SERVICE..............................................................................1
`
`iii
`
`
`
`Paper No. __
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`CASES
`Apple Inc. v. Samsung Elecs. Co., Ltd.,
`No. 2015-1171, 2016 WL 761884 (Fed. Cir. Feb. 26, 2016).........................7, 10
`Bayer Healthcare Pharm., Inc. v. Watson Pharm., Inc.,
`713 F.3d 1369 (Fed. Cir. 2013) ..........................................................................25
`Bristol-Myers Squibb v. Teva Pharm. USA,
`752 F.3d 967 (Fed. Cir. 2014) ............................................................................20
`In re Harris,
`409 F.3d 1339 (Fed. Cir. 2005) ..........................................................................21
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) ..........................................................................21
`Iron Grip Barbell Co. v. USA Sports, Inc.,
`392 F.3d 1317 (Fed. Cir. 2004) ..........................................................................25
`ISTA Pharms., Inc. v. FDA,
`898 F. Supp. 2d 227 (D.D.C. 2012)....................................................................24
`Wyers v. Master Lock Co.,
`616 F.3d 1231 (Fed. Cir. 2010) ..........................................................................23
`STATUTES
`35 U.S.C. § 103..........................................................................................................1
`OTHER AUTHORITIES
`37 C.F.R. 42.65(a)....................................................................................................16
`
`iv
`
`
`
`I.
`
`INTRODUCTION
`Petitioner requests cancellation of claims 1-22 (“challenged claims”) of U.S.
`
`Patent No. 8,129,431 (“the ’431 patent”) (EX1001). The Board instituted IPR of
`
`Claims 1-5, 7-14, and 18-19 as obvious over Ogawa and Sallmann under 35 U.S.C.
`
`§ 103, and Claims 6, 15-17, and 20-22 as obvious over Ogawa, Sallmann, and Fu
`
`under 35 U.S.C. § 103.
`
`(“Decision,” Paper 15). Nothing in Patent Owner’s
`
`Response (“Response,” Paper 34) should change the Board’s conclusion.
`
`II.
`
`ARGUMENT
`A.
`Patent Owner Fails to Consider the Full Scope of the Prior Art
`Patent Owner does not dispute that the prior art disclosed the combination of
`
`bromfenac with tyloxapol, (see EX1005, 3:23-39), but asserts that only hindsight
`
`would provide a reason for that combination. Those arguments, however, are based
`
`on inaccurate recitations of the state of the prior art and clear mischaracterization of
`
`(EX2114, 260:15-22).
`
`Complexation of Acidic NSAIDs and BAC Was Known
`1.
`Patent Owner suggests that there is no teaching in the prior art that bromfenac
`
`and BAC will form complexes. (Resp. at 5; EX2105, ¶37, 76; EX2082, ¶63). Not
`
`true: the complexation problem between acidic NSAIDs (e.g., bromfenac) and BAC
`
`was well known. Fu described the prior art as teaching “an insoluble complex was
`
`1
`
`
`
`found to form between the NSAID and the BAC” and that “BAC has typically been
`
`considered to be incompatible with anionic drugs . . . forming insoluble complexes
`
`which cause the solution to become cloudy or turbid.” (EX1011, 2:1-2, 3:1-4).
`
`There is no dispute that Bromfenac would be an anionic compound at the relevant
`
`pH. (EX1061, 80:19-81:3).
`
`This same caution about the incompatibility of NSAIDs and quaternary
`
`ammonium compounds (“QACs”) was expressed multiple times in the art.
`
`(EX1019, 2:18-30; EX1005, 1:27-37, 3:20-25; EX1006, 1:15-21; EX1020, 2:2-3:2;
`
`EX1063, 1:29-38; EX1064, 1:31-61; EX1065, 2:34-39; EX1078, 4:39-44). Indeed,
`
`the incompatibility issue involving BAC was so ubiquitous that it even appeared in
`
`Remington, which states BAC “is not compatible with anionic compounds”
`
`(EX1059, 831:1:3), and as Dr. Williams testified, a POSA would have looked to
`
`Remington “quite frequently.” (EX1079, 24:8-15; 16:7-14 (agreeing that all of his
`
`answers are from the perspective of a POSA)). Moreover, Dr. Williams, Patent
`
`Owner’s expert, testified that a POSA would have taken such statements at “face
`
`value.” (EX1067, 81:4). Significantly, the ’431 patent expressly discusses this same
`
`incompatibility issue, citing to the corresponding Japanese patent application of
`
`prior art Desai ’929 (EX1005). (EX1001, 1:62-2:3).
`
`a)
`
`Patent Owner Does Not Provide a Credible Explanation
`for Why a POSA Would Ignore this Prior Art Teaching
`
`2
`
`
`
`Dr. Davies, Patent Owner’s other expert, contends only that the statements in
`
`the prior art do not include experimental evidence confirming the identity of the
`
`BAC-NSAID complex. (EX1061, 86:16-87:3, 89:25-90:11).2 Fu, however, states
`
`that the precipitate is “between the Ketorolac moiety and [BAC].” (EX1011, 19:19-
`
`22). As Dr. Laskar explains, there are only four components in Example 5 of Fu:
`
`water; ketorolac; BAC; and one of three surfactants, meaning the BAC-NSAID
`
`complex is the only conclusion. (EX1011, 6:15-22, 8:8-26, 18:9-30; EX1104, ¶¶
`
`35-37). Despite the numerous statements in the prior art, Patent Owner’s experts
`
`have offered no alternative explanation for the identity of the material that is causing
`
`the turbidity in Fu. (EX1067, 154:8-155:25; EX1061, 152:5-153:17).
`
`Although Dr. Davies refuses to accept the numerous statements in the prior
`
`art reporting the BAC-NSAID complex, including in the ’431 patent itself, Dr.
`
`Davies does accept statements in the prior art when they do not conflict with his
`
`assertions. (EX1061, 206:14-207:12; EX1080, 82:13-83:6).3 Dr. Davies even finds
`
`it acceptable to speculate that “Cyclodextrins May Impact the Stability” based on the
`
`2 Dr. Davies provides testimony with respect to EX1062, which corresponds to Fu.
`
`3 More troubling, Dr. Davies did not consider the details of the subject patent in
`
`expressing his opinions. (EX1080, 53:22-54:3; 81:2-3; EX2105 ¶ 97).
`
`3
`
`
`
`general information regarding cyclodextrins and aryl groups.
`
`(EX2105 at 46
`
`(emphasis added); EX1080, 87:11-20, 90:9-16; EX1061, 295:9-298:14).
`
`To put this issue to rest, Patent Owner submitted evidence to the Board
`
`showing that when bromfenac and BAC were combined, they unremarkably formed
`
`a precipitate. (EX2098, 30 “[B]romfenac sodium forms insoluble complexes due to
`
`the addition of quaternary ammonium salt and becomes cloudy.”). There is nothing
`
`unique about how bromfenac interacts with BAC compared to other acidic NSAIDs.
`
`NSAIDs Are Chemically and Structurally Similar
`b)
`It cannot seriously be disputed that acidic NSAIDs, such as diclofenac
`
`(Sallmann) and ketorolac (Fu), in relevant part have similar structures to bromfenac.
`
`(Decision at 13; EX1061, 77:25-78:4; EX2114, 91:14-21, 103:14-18). Dr. Davies
`
`states that these NSAIDs are all weak acids with similar pKa values, and would be
`
`in anionic form at the pH of Ogawa Example 6. (EX1061, 80:19-81:14, 82:7-16).
`
`Articles studying bromfenac note its similarity to other NSAIDs.
`
`(EX1085,
`
`2300:1:5; EX1086, 723:1:1). A patent owned by Patent Owner naming the same
`
`inventor also considers bromfenac and diclofenac together.
`
`(EX1087, 1:21-24).
`
`Even Dr. Williams, Patent Owner’s expert, makes no distinction between these
`
`NSAIDs in one of his prior art patents. (EX1088, 10:33, 10:40).
`
`Moreover, the ’431 patent itself incorporates by reference, Desai ’929, which
`
`along with describing the NSAID-BAC complexation problem, (EX1001, 1:54-2:3,
`
`4
`
`
`
`11:54-57) also lists diclofenac, bromfenac, ketorolac, and several other NSAIDs
`
`together. (EX1005, 3:20-25). Not one of these references suggests the complexation
`
`issue would not have applied to any particular acidic NSAID (i.e., bromfenac). A
`
`POSA would understand that bromfenac interacts with BAC in the same way as the
`
`other acidic NSAIDs. (EX1003, ¶ 96).4
`
`2.
`
`Ethoxylated Octylphenols Were Known to Solve the
`Complexation Problem
`Fu provided a solution to the complexation problem between acidic NSAIDs
`
`and BAC.
`
`(See Pet. at 49-50; EX1011). Fu found that a solution containing
`
`ketorolac and BAC turned turbid when using polysorbate 80, but remained clear
`
`when using octoxynol 40, concluding that ethoxylated octylphenols solved the
`
`complexation issue. (EX1011, 19:1-22). Dr. Williams also acknowledged that Fu
`
`showed that octoxynol 40 “was superior to the other two surfactants [polysorbate 80
`
`and Myrj 52].” (EX1067, 155:13-16). The stabilizing property of ethoxylated
`
`octylphenols described by Fu was recognized in other prior art. (EX1005, 1:35-41;
`
`EX1019, 2:9-24). Dr. Davies’s argument that a POSA would not have added a
`
`surfactant because bromfenac is soluble is irrelevant, because the surfactant was
`
`addressing the complex formed between the acidic NSAID and BAC—not
`
`4 Based on these similarities, bromfenac would have been interchangeable with other
`
`NSAIDs, such as diclofenac. (Pet. 28-29; Ex. 1003 ¶¶ 60-63; Decision at 13).
`
`5
`
`
`
`bromfenac alone. (EX1104, ¶ 38; see EX1011, 19:19-22; EX2105, ¶ 54; Resp. at
`
`16). In any event, Ogawa Example 6 still found the need to include a surfactant, and
`
`the prior art publications describing Bronuck showed the inclusion of a surfactant
`
`remained necessary. (EX2039, 4; EX2112, 2).
`
`a)
`
`Tyloxapol Falls within the Class of Ethoxylated
`Octylphenols Disclosed in Fu
`Patent Owner inaccurately suggests that a POSA would not have considered
`
`tyloxapol in view of Fu, because Fu does not mention tyloxapol.
`
`(Resp. at 35;
`
`EX2082, ¶ 84; EX2105, ¶ 85). Patent Owner’s expert, however, does not dispute
`
`that (1) tyloxapol is also a nonionic surfactant in the ethoxylated octylphenol class
`
`(EX1080, 56:8-57:1; see also EX2114, 104:4-14); and (2) the class of ethoxylated
`
`octylphenol surfactants disclosed in Fu includes any surfactant that has an ethylene
`
`oxide to octylphenol ratio of between 3:1 and 40:1.
`
`(EX1011, claim 3; EX1067,
`
`112:7-16). Tyloxapol has a corresponding ratio of 9.6:1, failing squarely with the
`
`disclosure of Fu. (EX2105, ¶ 86; EX1104, ¶¶ 2-3; EX1091, 1:45-61 (“A preferred
`
`compound of this group is the product containing ten ether groups per p-tertiary-
`
`octylphenol nucleus which is known . . . generically as tyloxapol”)).
`
`b)
`
`Tyloxapol was One of Two Ethoxylated Octylphenols
`Used in Approved Ophthalmic Solution Products
`There would have been only two ethoxylated octylphenol surfactants within
`
`the series of Fu that a POSA would have considered: octoxynol 40 and tyloxapol.
`
`6
`
`
`
`Patent Owner’s expert, Dr. Williams, acknowledges that these two surfactants were
`
`the only known ethoxylated octylphenols used in commercial ophthalmic solutions,
`
`and that
`
`tyloxapol was used in several commercial ophthalmic formulations.
`
`(EX1067, 51:14-17, 115:5-15; 116:18-25; EX2082, ¶ 78; EX1003, ¶ 36). The
`
`FDA’s Inactive Ingredient Guide from 1996 (“FDA IIG,” EX1057), corroborates Dr.
`
`Williams’s testimony, which he testified a POSA would have used as a “starting
`
`point” for selecting excipients. (EX1067, 31:12-14; see also EX1089, 9902 (“Use
`
`as ophthalmic excipient”)). The FDA IIG shows that the only use of tyloxapol was
`
`for ophthalmic products and there were nine such uses. (EX1057, 151). In contrast,
`
`octoxynol 40 was used in only one ophthalmic formulation. (EX1057, 86).
`
`Patent Owner asserts that a POSA would not have chosen a surfactant in the
`
`ethoxylated octylphenol class despite Fu’s teaching, and instead would have chosen
`
`Sallmann’s Cremophor. (Resp. at 17, 30).
`
`(EX2114, 162:3-6, 196:10-17, 260:5-14; EX1079, 102:13-
`
`104:7; EX1073, 2; EX1074, 475).
`
`It is also undisputed that Sallmann states that
`
`tyloxapol is a preferred solubilizer contrary to Patent Owner’s characterization that
`
`Cremophor is preferable over tyloxapol. (EX1009, 4:62). Furthermore, a POSA
`
`would have used tyloxapol based on the teachings of Fu as discussed above, which
`
`a POSA would have known was more widely used for ophthalmic products
`
`7
`
`
`
`compared to Cremophor.
`
`(EX1057, 110, 151). Sallmann’s disclosure of other
`
`surfactants (i.e., Cremophor) does not amount to teaching away from tyloxapol.
`
`Apple Inc. v. Samsung Elecs. Co., Ltd., No. 2015-1171, 2016 WL 761884, at *8 (Fed.
`
`Cir. Feb. 26, 2016) (stating that the presence of alternatives, even if more preferred,
`
`does not amount to teaching away).
`
`c)
`
`Tyloxapol and Polysorbate 80 were Among the Few
`Nonionic Surfactants for Ophthalmic Formulations at
`the Time, with Tyloxapol Being More Common
`Patent Owner argues that a POSA would not consider polysorbate 80 and
`
`tyloxapol to be interchangeable.
`
`(Resp. at 23-24). As the Board found, that is
`
`inaccurate.
`
`(Decision at 9; EX1003, ¶ 38). Furthermore, POSAs were already
`
`comparing polysorbate 80 and tyloxapol in ophthalmic formulations. For example,
`
`Yasueda compared polysorbate 80 and tyloxapol in a formulation containing the
`
`acidic drug pranlukast. (EX1012, 7:35-43). Kawabata also identified tyloxapol and
`
`polysorbate 80, and no others, as suitable surfactants in an ophthalmic formulation
`
`containing an acidic drug. (EX1043, 13:10-11, 14:1-2).
`
`There were a limited number of nonionic surfactants that were considered for
`
`ophthalmic solutions at the time. (See, e.g., EX1090, 4:44-45 (“The tyloxapol and
`
`[polysorbate] surfactants are preferred because they are FDA approved for human
`
`use.”)). Even Patent Owner’s expert testified that, other than tyloxapol, octoxynol
`
`8
`
`
`
`40 and polysorbate 80, he could not name a single other surfactant in commercial
`
`ophthalmic products in 2003. (EX1067, 115:4-116:25).
`
`BAC Was Commonly Used for Ophthalmic Products
`3.
`Patent Owner argues that since BAC is toxic and causes complexation, and
`
`thus a POSA would have been motivated to develop a preservative free formulation
`
`or used a different preservative. (Resp. at 9-10). As Remington states, however,
`
`BAC was “by far, the most common preservative used in ophthalmic preparations.”
`
`(EX1059, 831:1:3; EX2089, 205, 207). Further, the FDA IIG lists no less than 77
`
`ophthalmic products contained BAC.
`
`(EX1057, 8). Even the ‘431 patent states
`
`“[BAC] is a widely used preservative in ophthalmic solutions.” (EX1001, 1:63-64).
`
`a)
`
`Patent Owner’s Experts Rely on Hearsay Statements
`from an Unrelated Case to Mischaracterize BAC
`Patent Owner’s experts adopt the hearsay statement of another expert in an
`
`unrelated case stating that BAC is a purported “natural-born killer” that was “from
`
`Satan.” (EX2082 ¶ 65; EX2116 ¶ 43; EX1067, 179:16-181:3). Patent Owner’s
`
`reliance on such statements is misguided. (EX2134, 16-17 (noting that a POSA
`
`would have avoided using a “higher concentration of BAK . . . especially when 50
`
`ppm BAK was known to be an adequate preservative.”)). Even Patent Owner’s
`
`expert acknowledges that the concentration of BAC at issue in the Allergan case was
`
`four times that found in Ogawa Example 6.
`
`(EX1081, 95:20-97:1). Moreover,
`
`Patent Owner’s own expert advocated the use of BAC as a preservative at the
`
`9
`
`
`
`relevant time indicating no toxicity with its use. (EX1088, 7:61, 9:54, 10:33, 14:35,
`
`15:22; EX1079, 68:5-8; see also EX1059, 831:1:35 (“Certain early negative reports
`
`[of the use of BAC] have been shown to be quite erroneous . . . .”); EX2064, 107:3
`
`(reporting “no significant difference in the intensity of pathological effects” between
`
`BAC and four other preservatives); EX1079, 57:18-58:16).
`
`b)
`
`The Alleged Alternatives to BAC and Bromfenac Do Not
`Change the Obviousness Conclusion
`Equally without merit is Patent Owner’s suggestion that the use of BAC is
`
`nonobvious because a POSA could have used other preservatives, such as “stabilized
`
`oxychloro complex” (“SOC”), lauralkonium chloride (“LAC”), Polyquad®, and
`
`parabens. (Resp. at 11-12; EX2082, ¶¶ 69-71). Patent Owner’s arguments directly
`
`contradict the teaching in Remington that “[g]iven the alternative it would be
`
`preferable to modify a formulation to remove the incompatibility [of BAC], rather
`
`than include a compatible but less effective preservative.” (EX1059, 831:1:3); see
`
`also EX1057, 8 (identifying BAC in 77 ophthalmic solutions). Patent Owner also
`
`fails to consider the teachings in the prior art or common knowledge of a POSA in
`
`making these allegations. (EX2089, 207-208 (noting that SOC is an oxidizing agent
`
`making it unfavorable), EX2089, 211 (Polyquad® shown to cause more corneal
`
`epithelial damage over SOC), EX1059, 831:2:6 (parabens unacceptable as
`
`ophthalmic preservative), EX1067, 103:21-25). See also Apple, 2016 WL 761884,
`
`at *8 (stating that the presence of alternatives does not amount to teaching away).
`
`10
`
`
`
`Patent Owner’s alternate suggestion that a POSA would have used a less
`
`proven derivative of bromfenac as discussed in Yanni (EX1033) should similarly be
`
`dismissed. (Resp. at 12; EX2082, ¶ 73). Indeed, even after December 12, 1995, the
`
`date of issuance of Yanni, bromfenac continued to be discussed as an NSAID with
`
`favorable properties. (EX2039, 27-28; EX1002, 2:1:2-2:2:1; EX2111, 2-3; EX2112,
`
`2-3). Moreover, after the date of Yanni, Dr. Williams’s own patent discusses
`
`bromfenac as a suitable NSAID, and bromfenac was used in Bronuck. (EX1088,
`
`7:61, 9:54, 10:33, 14:35, 15:22; EX1079, 57:18-58:16; EX2112, 2; EX2039, 4).
`
`B.
`
`The Claims are Obvious under Patent Owner’s Theory that a
`POSA Would Have Used Antioxidants to Stabilize Bromfenac
`Even under Patent Owner’s experts’ theory, a POSA would still have
`
`substituted polysorbate 80 with tyloxapol. According to Dr. Williams, “a [POSA]
`
`would have readily understood that oxidation caused bromfenac’s degradation.”
`
`(EX2082, ¶ 44). Dr. Davies concurs, explaining “Ogawa Example 6 is a bromfenac
`
`formulation, and bromfenac is susceptible to oxidation.” (EX2105, ¶ 72). Dr.
`
`Williams also explains, “polysorbate 80 . . . does not stabilize the bromfenac in
`
`Ogawa’s formulations.” (EX2082, ¶ 100). Dr. Williams states further that “[t]he
`
`data in Ogawa’s Experimental Examples 4-6 . . . establish[] that polysorbate does
`
`not stabilize bromfenac, let alone prevent the oxidative degradation of bromfenac or
`
`otherwise maintain bromfenac’s chemical stability.” (EX2082, ¶ 103).
`
`11
`
`
`
`According to Dr. Davies, polysorbate 80 degrades to form hydroperoxides and
`
`peroxides,
`
`leading to chemical stability problems associated with bromfenac.
`
`(EX2105, ¶ 72; see also EX1104, ¶ 8). That would have prompted a POSA to replace
`
`polysorbate 80 with another nonionic surfactant. (EX1104, ¶¶ 5, 7). As explained
`
`by Patent Owner’s expert, to remedy the problem of oxidative degradation of
`
`bromfenac as described in Ogawa, a POSA would have been led to Doi (EX2025),
`
`which discloses using other antioxidants to stabilize NSAIDs “to even further
`
`improve bromfenac’s chemical stability.” (EX2082, ¶ 114; see also EX1104, ¶ 9).
`
`Tyloxapol is in the Class of Alkylphenols Disclosed in Doi
`1.
`Doi teaches that alkylphenols are antioxidants for ophthalmic preparations.
`
`(EX2025, 3:7-9). As Dr. Laskar explains, tyloxapol belongs to the alkylphenol class
`
`of compounds disclosed in Doi.
`
`(EX1104, ¶¶ 15-18, 23-24; EX1091, 1:45-61;
`
`EX1089, 9902; EX1106, EX2025, 3:51-52).
`
`157:13-15).
`
`(EX2114,
`
`(EX2114, 156:6-157:22).
`
`2.
`
`Tyloxapol’s General Antioxidant Properties Were Known
`
`12
`
`
`
`In addition to Doi, the prior art is replete with other examples discussing
`
`tyloxapol’s antioxidant property.
`
`(EX1089, 9902 (explaining that tyloxapol is an
`
`ophthalmic excipient and is “oxidized by metals”); EX1106, 1415; EX1104, ¶ 14,
`
`19, 21-22). The ’956 application and WO ’610, which disclose liquid preparations
`
`for nasal and/or pharyngeal applications, also teaches that tyloxapol is a surfactant
`
`and an antioxidant. (EX1105, ¶ [0032], EX1104, ¶¶ 23-24; EX1148, 6:25-28). The
`
`’431 patent and Ogawa similarly involve nasal formulations and Patent Owner’s
`
`expert acknowledges the relevance of looking at such art. (EX1001, 4:10-13, 11:48-
`
`51; EX1004, 4:60-62, Example 10; EX1104, ¶ 25; EX1079, 20:13-21). Indeed, other
`
`art
`
`investigating tyloxapol’s antioxidant property characterize tyloxapol as a
`
`surfactant that is a “potent antioxidant” and best-known in its class. (EX1092, 4:46-
`
`61; see also EX1093, 2:38-48; EX1094, 3:2:2, 5:2:2-6:1:1; EX1104, ¶¶ 20, 26-29).
`
`Moreover, Doi, which Patent Owner’s expert concedes provides a relevant
`
`teaching to preventing the oxidation degradation of bromfenac, teaches the presence
`
`of oxygen as the cause of the degradation. (EX2025, 3:57-65; see EX2082, ¶ 114).
`
`As Kennedy teaches, tyloxapol inhibits the oxidation caused by oxygen based
`
`species. (EX1092, 1:27-61; EX1104, ¶¶ 26-29; EX1093, 2:38-50; EX1094, 3:2:2).
`
`Patent Owner’s experts cannot dispute that a POSA would be motivated to replace
`
`polysorbate 80, which they explain was leading to oxidative degradation in Ogawa,
`
`with a surfactant having antioxidant properties, such as tyloxapol. (EX1104, ¶¶ 4-
`
`13
`
`
`
`9, 13-20, 23-24). And through routine experimentation, a POSA would have
`
`determined the optimal antioxidant combination of tyloxapol and sodium sulfite to
`
`address the oxidation degradation problem explained by Patent Owner’s experts.
`
`(EX1104, ¶ 33-34; EX2025, 2:1-4 (showing that there can be more than one
`
`antioxidant used), 5:12 (disclosing PVP). Thus, by Patent Owner’s own reasoning,
`
`a POSA would have expected tyloxapol, a known antioxidant, to stabilize bromfenac
`
`and would have been motivated to replace polysorbate 80 with tyloxapol for that
`
`reason. (EX1104, ¶¶ 7-9).
`
`Dr. Davies—who has never worked with tyloxapol (EX1061, 48:19-21)—
`
`asserts that tyloxapol, much like polysorbate 80, is an oxidizing agent. (EX2105, ¶¶
`
`71-72). Dr. Davies points to two references in support, EX2097 and EX2120,
`
`neither of which makes any reference to tyloxapol.
`
`(EX1104, ¶¶ 11-13). Dr.
`
`Davies’s assertion conflicts with the experimental data presented in Yasueda,
`
`(EX1104, ¶ 30-32), and the statements in the prior art which describe tyloxapol’s
`
`antioxidant properties. (EX1104, ¶¶ 13-29). In contrast, Dr. Williams, who: (1) has
`
`worked with tyloxapol; and (2), cites to a reference (Doi, EX2025) that shows that
`
`tyloxapol belongs to a class of compounds that has antioxidant activities and
`
`explains that he would use this class of compounds to modify Ogawa, conveniently
`
`takes no position on whether tyloxapol is an antioxidant. (EX1067, 44:24-45:7).
`
`C.
`
`A POSA Would Have Expected Tyloxapol to Improve Stability and
`Preservative Efficacy
`
`14
`
`
`
`Patent Owner alleges that there is no reasonable expectation of improving
`
`stability by substituting tyloxapol in place of polysorbate 80. (Resp. at 19-20, 26-
`
`27, 28, 31, 48). As discussed above, the inclusion of tyloxapol would have addressed
`
`the BAC-NSAID complexation problem widely described in the art and Patent
`
`Owner’s own data shows complexation occurs between bromfenac and BAC.
`
`Moreover, tyloxapol is an antioxidant and thus a POSA would have expected
`
`tyloxapol to improve the stability of a bromfenac formulation, particularly in place
`
`of polysorbate 80—polysorbate 80 is an oxidizing agent which leads to oxidative
`
`degradation of bromfenac. (See, e.g., EX1092, 4:46-61; EX1093, 2:38-48; EX1012,
`
`6:55-7:43, Tables 4 and 5).5 And a POSA would have had a reasonable expectation
`
`that tyloxapol would work in an aqueous bromfenac formulation, because tyloxapol
`
`and similar surfactants were successfully used in other acidic drug formulations
`
`including Sallmann. (See, e.g., EX1009, 8:1-15; EX1011, 19:1-27; EX1012, Table
`
`4-5; EX1067, 31:24-32:9).
`
`Patent Owner also alleges
`
`that
`
`tyloxapol unexpectedly maintained
`
`preservative efficacy.
`
`(Resp. at 54-55). Patent Owner’s suggests that Ogawa
`
`5 Yasueda (EX1012) discloses pranlukast, which has an acidic functional group that
`
`is functionally a replacement for carboxylic acids (See EX1095, 6:15, 6:20, 6:26,
`
`6:36, 6:44; EX1096, 3379-3393).
`
`15
`
`
`
`Example 6 exhibited poor preservative efficacy, but the commercial products
`
`Bronuck and Bromday® passed the Japanese Pharmacopeia (“JP”) and U.S.
`
`Pharmacopeia (“USP”), respectively.
`
`(EX1067, 146:17-147:9). Furthermore,
`
`Ogawa Example 6 modified to include tyloxapol would be similar to Compositions
`
`A-04, A-05, and A-06 of the ’431 patent, which all purportedly satisfied the EP
`
`criteria B.
`
`(EX1001, Table 2, 9:48-52). Additionally, Desai ’929 states that “an
`
`ophthalmic formulation of an acidic drug” can pass both the USP and EP “using a
`
`combination of a polymeric [QAC] and boric acid,” which Ogawa Example 6 has.
`
`(EX1005, 5:32-37). Furthermore, a POSA would expect switching polysorbate 80
`
`with tyloxapol to improve preservative efficacy because polysorbate 80 was known
`
`to neutralize BAC.
`
`(EX1075, 878-79, 884; EX1098; EX1076, 973:1:5-973:2:1).
`
`Similarly, as explained by Desai ’929, by solving the complexation issue between
`
`bromfenac and BAC, BAC would not “lose [its] ability to function.” (EX1005, 1:28-
`
`35). Thus, the alleged improved preservative efficacy would have been expected.
`
`Dr. Williams relies on test data contained in Mr. Sawa’s declaration, (see, e.g.,
`
`EX2082, ¶ 163, 167-69), but Mr. Sawa could not accurately recount how the test
`
`was conducted and how the data was calculated, including explaining inconsistent
`
`data, (EX1084, 27:11-28:16, 32:6-21; 38:17-40:15, 42:8-43:6, 43:20-44:19, 66:4-
`
`67:21, 73:10-74:22), and thus should be given no weight under 37 C.F.R. 42.65(a).
`
`D.
`
`A POSA Would Have Considered Ogawa Example 6 and Sallmann
`Example 2
`
`16
`
`
`
`1.
`
`Bromfenac Was an NSAID with Superior Efficacy and a
`POSA Would Have Considered Ogawa Example 6
`Patent Owner’s allegation that there was no reason to develop a bromfenac
`
`formulation is also contrary to the prior art and the knowledge of a POSA. (Resp.
`
`at 8-9; Petition at 28-29; EX1002, 2:1:2, 2:2:5-3:1:1, 3:2:2). The ’431 patent
`
`recognizes the known efficacy of bromfenac eye drops. (EX1001, 1:24-47). Patent
`
`Owner does not dispute that Hara, which compared bromfenac sodium to
`
`pranoprofen, indomethacin, and diclofenac sodium, concluded that bromfenac
`
`“shows superior efficacy in treating anterior eye inflammation and post-operative
`
`inflammation.” (EX1002, 3:2:2). Instead, Patent Owner simply argues that Hara
`
`shows that “diclofenac could treat anterior uveitis, while bromfenac was expressly
`
`not approved for this indication,” (Resp. at 10), while conveniently ignoring the
`
`statement in Hara that “the range of applications [for diclofenac] is limited because
`
`the drug is indicated only for use in treating inflammation following cataract
`
`surgery.” (EX1002, 2:2:5-3:1:1).
`
`Further, Patent Owner’s allegation that the adverse events observed with the
`
`oral form of bromfenac would encourage a POSA to use diclofenac, is of little merit
`
`since other NSAIDs, including diclofenac, were known to have similar issues. (See
`
`EX1086, 2300:2:1; EX1101, 3:1:2; EX1102, 1:1:1, 4:2:2). Indeed, an ophthalmic
`
`dosage form of bromfenac was approved despite the alleged concern with the oral
`
`17
`
`
`
`form. (EX2111, 2 (stating the adverse effects with the “oral agent were due to long-
`
`term administration exceeding the approved usage and dosages”)).
`
`Patent Owner inaccurately argues that there were no reasons to focus on
`
`Ogawa Example 6. (Resp. at 4-5, 11-12). A POSA would have considered Ogawa
`
`Example 6, because it exhibited superior stability compared to other examples
`
`disclosed in Ogawa. (EX1004, Tables 8, 10, 11). And a POSA would have known
`
`based on prior art publications that the formulation of Ogawa Example 6 was a
`
`commercially viable one, sold in Japan as Bronuck. (EX2039, 27-28; EX2111, 2;
`
`EX2112, 2; EX1002, 2:1:3; EX2114, 258:24-259:13).
`
`A POSA Would Have Considered Sallmann Example 2
`2.
`Patent Owner alleges that InnoPharma used hindsight to focus on Sallmann
`
`Example 2.
`
`(Resp. at 31). As discussed above and as
`
`. (EX2114, 195:18-196:17, 259:19-260:14; see supra §§ II.A.2.b),
`
`II.A.3).
`
`E.
`
`A POSA Would Have Arrived at the Appropriate Concentration of
`Tyloxapol through Routine Optimization
`
`18
`
`
`
`Patent Owner inaccurately asserts that there is no prior art teaching or
`
`suggestion for a concentration of 0.02 w/v %. (Response at 40-45). Sallmann itself
`
`discloses tyloxapol concentrations of 0.1 and 0.01 w/v % that encompass the claimed
`
`range. (Pet. at 42; EX1009, 8:10, 4:65-67; EX1003, ¶ 71). Fu discloses a non-ionic
`
`surfactant in the same class as tyloxapol used at 0.02 w/v %. (Decision at 16-17;
`
`Pet. at 44-47; EX1011, 18:5-28, Examples 2 & 5; EX1003, ¶¶ 33–35). The prior art
`
`also taught that “[t]he decreases in hydroxylation of salicylate associated with
`
`tyloxapol also were concentration dependent” and thus a POSA would have known
`
`that the concentration of tyloxapol was a result effective variable. (EX1094, 3:2:2).
`
`A POSA modifying Ogawa Example 6 to include tyloxapol instead of
`
`polysorbate 80 would have optimized the concentration through routine
`
`optimization. Patent Owner’s expert admits as much, stating that a POSA using
`
`different surfactants would have expected to adjust the concentration through routine
`
`experimentation. (EX1079, 90:14-22). Indeed, to show how little experimentation
`
`was required, Patent Owner has submitted evidence showing that as few as five
`
`concentrations of tyloxapol were tested by the inventor to arrive at 0.02% w/v %:
`
`0.02; 0.03; 0.05; 0.1; and 0.15 w/v %. (EX2098 at 86, 88, 173, 175, 393, 395, 474).
`
`As the Board previously observed, and as confirmed by Patent Owner’s
`
`expert, because the concentrations of surfactants were known as result effective
`
`19
`
`
`
`variables with respect to solubility and stability of an aqueous formulation, it would
`
`have been obvious to manipulate and optimize that variable. (Decision at 17).
`
`F.
`
`Patent Owner’s Evidence of Alleged Objective Indicia is Not
`Probative of Patentability
`1.
`Patent Owner Did Not Compare to the Closest Prior Art
`“To be particularly probative, evidence of unexpected results must establ
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