Paper No. __
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_______________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_______________________________
`
`LUPIN LTD. and LUPIN PHARMACEUTICALS INC., INNOPHARMA
`LICENSING, INC., INNOPHARMA LICENSING LLC, INNOPHARMA
`INC., INNOPHARMA LLC, MYLAN PHARMACEUTICALS INC., and
`MYLAN INC.
`Petitioners
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD.
`Patent Owner
`
`____________________
`
`Case IPR2015-011001
`Patent 8,927,606
`____________________
`
`
`
`
`
`PETITIONERS’ REPLY TO PATENT OWNER’S
`RESPONSE TO PETITION
`
`
`
`
`1 Case IPR2016-00091 has been joined with this proceeding.
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_______________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_______________________________
`
`LUPIN LTD. and LUPIN PHARMACEUTICALS INC., INNOPHARMA
`LICENSING, INC., INNOPHARMA LICENSING LLC, INNOPHARMA
`INC., INNOPHARMA LLC, MYLAN PHARMACEUTICALS INC., and
`MYLAN INC.
`Petitioners
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD.
`Patent Owner
`
`____________________
`
`Case IPR2015-011001
`Patent 8,927,606
`____________________
`
`
`
`
`
`PETITIONERS’ REPLY TO PATENT OWNER’S
`RESPONSE TO PETITION
`
`
`
`
`1 Case IPR2016-00091 has been joined with this proceeding.
`
`
`
`
`
`TABLE OF CONTENTS
`
`
`I.
`
`A POSA Would Have Combined Ogawa and Sallmann to Arrive at
`the Claimed Invention ..................................................................................... 1
`
`A.
`
`B.
`
`C.
`
`Bromfenac Was an NSAID with Superior Efficacy ............................. 1
`
`A POSA Would Have Considered Ogawa Example 6 ......................... 2
`
`A POSA Would Have Considered Sallmann Example 2 ...................... 3
`
`D. One of ordinary skill would have been motivated to seek to
`replace polysorbate 80, and would have arrived at tyloxapol ............... 4
`
`A.
`
`Ethoxylated Octylphenols Were Known to Solve the
`Complexation Problem ........................................................................ 12
`
`1.
`
`2.
`
`Tyloxapol Falls within the Class of Ethoxylated
`Octylphenols Disclosed in Fu ................................................... 13
`
`Tyloxapol and Polysorbate 80 were Among the Few
`Nonionic Surfactants ................................................................. 14
`
`B.
`
`BAC Was Commonly Used for Ophthalmic Products. ....................... 15
`
`III.
`
`Patent Owner’s Evidence of Alleged Objective Indicia is Not
`Probative of Patentability .............................................................................. 16
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`Patent Owner’s Purported Unexpected Results Relating to
`Tyloxapol were Known in the Art....................................................... 16
`
`The Data Relied Upon by Patent Owner Do Not Demonstrate
`More Chemical Stability Than The Closest Prior Art ......................... 17
`
`The Alleged Unexpected Benefits of The Claimed Invention Do
`Not Support Nonobviousness .............................................................. 18
`
`Patent Owner’s Test Data Should be Disregarded .............................. 19
`
`Evidence of Commercial Success Lacks Factual Support and
`Nexus with the Claims ........................................................................ 20
`
`
`
`i
`
`
`
`
`
`F.
`
`G.
`
`H.
`
`Patent Owner’s Evidence of Secondary Considerations are Not
`Commensurate with the Scope of the Claims ..................................... 22
`
`Patent Owner Did Not Compare the Closest Prior Art ....................... 24
`
`Patent Owner’s Arguments Regarding Licensing and Copying
`are Misplaced ...................................................................................... 24
`
`I.
`
`The Dependent Claims Are Not Separately Patentable ...................... 25
`
`CERTIFICATION OF SERVICE............................................................................ 26
`
`
`
`
`
`
`ii
`
`
`
`
`
`I.
`
`A POSA Would Have Combined Ogawa and Sallmann to Arrive at the
`Claimed Invention
`
`One of skill in the art would have combined the teaching of Ogawa and
`
`Sallmann to arrive at the claims of the ‘606 patent. Based on the prior art, a POSA
`
`would have understood that replacing polysorbate 80 in Ogawa Example 6 with
`
`tyloxapol would have increased the stability of the formulation. Per Dr. Lawrence,
`
`a POSA would have understood that a function of polysorbate 80 in Ogawa
`
`formulation 6 is to stabilize the formulation against precipitation of bromfenac-
`
`BAC complexes known to occur. EX1094, ¶31. It was known that tyloxapol had
`
`improved properties over polysorbate 80, as well as antioxidant activity.
`
`A. Bromfenac Was an NSAID with Superior Efficacy
`Contrary to Patent Owner’s assertions, one of ordinary skill would have
`
`chosen bromfenac as an ideal active agent for the treatment of ophthalmic
`
`conditions. 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.” (EX1006, 3:2:2). Instead Patent Owner simply ignores
`
`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.” (EX1006, 2:2:5-3:1:1).
`
`
`
`1
`
`
`
`
`
`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.
`
`Other NSAIDs, including diclofenac, were known to have similar issues.
`
`(EX1091, 2300:2:1; EX1092, 3:1:2; EX1093, 1:1:1, 4:2:2). Moreover, an
`
`ophthalmic dosage form of bromfenac was approved by the FDA. (EX2111, 2).
`
`B. A POSA Would Have Considered Ogawa Example 6
`Patent Owner’s allegation that a POSA would not have been motivated to
`
`develop an improved bromfenac formulation is contrary to the prior art and the
`
`basic knowledge of a POSA. (Resp. at 8-10; EX1006, 2:1:2, 2:2:5-3:1:1, 3:2:2).
`
`Patent Owner would lead one to believe that a POSA would have simply stopped
`
`there and would have ignored the abundance of evidence that NSAID formulations
`
`can be further improved by using tyloxapol in place of polysorbate 80. Simply
`
`arguing that a POSA would not seek to improve something merely because it is
`
`“sufficient” is not the standard for obviousness. Moreover, as Dr. Lawrence
`
`
`
`
`
`
`
`testified,
`
` (EX2316, 53:18-54:5).
`
`(EX2316, 53:18-54:5, 148:14-20). By arguing that the formulation taught by
`
`Ogawa Example 6 is “stable” (Resp. at 9) and that one would not seek to improve
`
`
`
`
`2
`
`
`
`
`
`upon it, Patent Owner acknowledges that Ogawa is a good starting point. And
`
`indeed, this is the case. Example 6 of Ogawa exhibited superior stability compared
`
`to other examples disclosed in Ogawa. (EX1010, Tables 8, 10, 11). And, a POSA
`
`would have known based on prior art publications that the formulation of Ogawa
`
`Ex. 6 was a commercially viable one, since it was sold in Japan as Bronuck.
`
`(EX2248, 27-28; EX2111, 2; EX2112, 2; EX1006, 2:1:3; EX1005 ¶ 101).
`
`C. A POSA Would Have Considered Sallmann Example 2
`A POSA seeking to formulate an improved bromfenac formulation would
`
`have been motivated to consider Sallmann Example 2. As Dr. Lawrence testified,
`
`
`
`
`
`
`
`
`
` (EX2316, 263:22-264:7). Thus, Patent Owner’s
`
`argument that Petitioners used hindsight to focus on Sallmann Example 2 is simply
`
`incorrect. (Resp. at 30-31). Patent Owner’s attempt to disparage Dr. Lawrence’s
`
`reliance on Sallmann based on a mischaracterization of her testimony should be
`
`disregarded. Dr. Lawrence testified that
`
` (EX2316, 303:14-305:15).
`
`
`
`
`3
`
`
`
`
`
`
`
`
`
`D. One of ordinary skill would have been motivated to seek to
`replace polysorbate 80, and would have arrived at tyloxapol
`
`First, a POSA would have expected tyloxapol to improve stability and
`
`preservative efficacy. In particular, as discussed infra at 12-13, a POSA would
`
`have expected that inclusion of tyloxapol would have addressed the BAC-NSAID
`
`complexation problem widely described in the art. Moreover, since tyloxapol is an
`
`antioxidant, a POSA would have expected tyloxapol to improve the stability of a
`
`bromfenac formulation, particularly in place of polysorbate 80, as polysorbate 80 is
`
`an oxidizing agent which leads to oxidative degradation of bromfenac. (E.g.,
`
`EX1100, 4:46-61; EX1101, 2:38-48; EX1022, 6:55-7:43, Tables 4 and 5).2
`
`
`
`
`
`
`
` (E.g.,
`
`EX1021, 8:1-15; EX1014, 9:1-40; EX1022, Table 4-5; EX1104, 31:24-32:9).
`
`Patent Owner alleges that tyloxapol unexpectedly maintained preservative
`
`efficacy and that the formulation of Ogawa Ex. 6 modified to include tyloxapol
`
`would not be able to pass European Pharmacopeia (“EP”) standards. (Resp. at 45-
`
`2 Yasueda (EX1022) discloses pranlukast, which has an acidic functional group
`
`that is functionally a replacement for carboxylic acids (EX1105, 6:15, 6:20, 6:26,
`
`6:36, 6:44; EX1106, 3379-3393).
`
`
`
`
`4
`
`
`
`46, 58-59). However, this argument makes no sense,
`
`
`
`
`
`
`
` (EX1104,
`
`146:17-147:9). Furthermore, Ogawa Ex. 6, as modified to include tyloxapol,
`
`would be similar to Compositions A-04, A-05, and A-06 of the ’606 patent, which
`
`all purportedly satisfied the EP criteria B. (EX1004, Table 2, 9:25-30).
`
`There are further reasons why the improved preservative efficacy alleged by
`
`Patent Owner would have been entirely expected. 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 Ex. 6 has.
`
`(EX1012, 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. (EX1107, 878-79, 884; EX1108; EX1109, 973). Per
`
`Desai ’929, by solving the complexation issue between bromfenac and BAC, BAC
`
`would not “lose [its] ability to function.” (EX1012, 1:28-34).
`
`Second, a POSA would be motivated to use tyloxapol instead of polysorbate
`
`80 based on Patent Owner’s own theory that a POSA would have used antioxidants
`
`to stabilize bromfenac. According to Dr. Williams,
`
`
`
` (EX2082, ¶ 57). Dr.
`
`Davies concurs, explaining that “a [POSA] would understand bromfenac to be
`
`
`
`
`5
`
`
`
`
`
`susceptible to degradation by oxidation.” (EX2105, ¶ 60). Dr. Williams also
`
`explains, “polysorbate 80 . . . does not stabilize the bromfenac in Ogawa’s
`
`formulations.” (EX2082, ¶ 125). 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, ¶ 126). According
`
`to Dr. Davies,
`
`
`
` (EX1126, ¶ 73;
`
`see also EX1094, ¶ 31). That would have prompted a POSA to replace
`
`polysorbate 80 with another nonionic surfactant. (EX1094, ¶ 31).
`
`As explained by Dr. Williams, to remedy the problem of oxidative
`
`degradation of bromfenac as described in Ogawa, a POSA would have been led to
`
`Doi (EX2030), which discloses using other antioxidants to stabilize NSAIDs “to
`
`even further improve bromfenac’s chemical stability.” (EX2082, ¶ 141; see also
`
`EX1094, ¶ 32). Doi teaches that alkylphenols are antioxidants for ophthalmic
`
`preparations. (EX2030, 3:7-9). As was known in the art, tyloxapol belongs to the
`
`alkylphenol class of compounds disclosed in Doi. (EX1094, ¶ 33; EX1095, 1:45-
`
`61; EX1096, 9902; EX1051, EX2030, 3:51-52).
`
`Doi, which Dr. Williams concedes provides a relevant teaching to prevent
`
`the oxidation degradation of bromfenac, specifically teaches the presence of
`
`
`
`
`6
`
`
`
`oxygen as the cause of the degradation. (EX2030, 3:57-65; EX2082, ¶ 141).
`
`Tyloxapol inhibits the oxidation caused by oxygen based species. (EX1094, ¶ 37;
`
`
`
`EX1100, 1:27-61; EX1101, 2:38-50; EX1102, 1219-19).
`
`
`
`
`
`
`
` (EX1094, ¶ 31).
`
`In addition to Doi, the prior art is replete with other examples discussing
`
`tyloxapol’s antioxidant property. (EX1096, 9902 (explaining that tyloxapol is an
`
`ophthalmic excipient and is “oxidized by metals”); EX1051, 1415; EX1094, ¶ 31
`
`fn. 5). The ’606 patent and Ogawa similarly involve nasal formulations and Patent
`
`Owner’s expert acknowledges the relevance of looking at such art. (EX1004,
`
`3:64-67, 11:6-9; EX1010, 4:60-63, Example 10; EX1094, ¶ 31 fn. 5; EX1099,
`
`20:13-21). The ’956 application and WO ’610 also teaches that tyloxapol is a
`
`surfactant and an antioxidant. (EX1094, ¶ 31 fn. 5; EX1097, ¶ [0032], EX1098,
`
`6:25-28). Indeed, other art characterizes tyloxapol as a surfactant that is a “potent
`
`antioxidant” and best-known in its class. (EX1100, 4:46-61; see also EX1101,
`
`2:38-48; EX1102, 1219-22; EX1094, ¶ 31 fn. 5). According to Dr. Lawrence, once
`
`in formulation tyloxapol will act as an antioxidant, regardless of where the
`
`formulation is ophthalmic, nasal, or lung. (EX1094, ¶ 31 fn. 5).
`
`Through routine experimentation,
`
`
`
`
`
`
`7
`
`
`
`
`
`
`
` (EX1094, ¶
`
`31; EX2030, 2:1-4 (showing more than one antioxidant used), 5:1-2. Thus, by
`
`Patent Owner’s own reasoning,
`
`
`
`
`
` (EX1094, ¶ ¶ 31, 37-40).
`
`Dr. Davies—who has never worked with tyloxapol (EX1103, 48:19-21)—
`
`asserts that tyloxapol, much like polysorbate 80, is an oxidizing agent. (EX1126,
`
`¶¶ 73-74. Dr. Davies points to two references in support, EX2097 and EX2120 –
`
`neither of which makes any reference to tyloxapol. (EX1094, ¶ 33). Dr. Davies’s
`
`assertion conflicts with the experimental data presented in Yasueda, (EX1094, ¶
`
`33), and the statements in the prior art which describe tyloxapol’s antioxidant
`
`properties. (EX1094, ¶ 33).
`
`The stability issues raised in Ogawa provide further motivation to use
`
`substitute tyloxapol for polysorbate 80. Ogawa discusses “red insoluble matters,”
`
`without explaining the source of these matters. Dr. Williams argues
`
`
`
` (EX 2082, ¶174; EX1094, ¶ 37). As Dr. Lawrence
`
`
`
`explains, if Dr. Williams is correct and this issue is resolved in Ogawa by inclusion
`
`of sodium sulfite, a POSA would have then focused on the separate stability
`
`
`
`
`8
`
`
`
`problem of the complexes that form between BAC and NSAIDs with a –COOH
`
`group taught by Fu, and would have substituted typloxapol for polysorbate 80 to
`
`prevent formation of these complexes. (EX1094, ¶ 37). However,
`
`
`
`
`
`
`
`
`
` (EX1094, ¶ 37).
`
`II.
`
`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, (EX1012, 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 Dr. Lawrence’s testimony as based on hindsight.3
`
`First, complexation of acidic NSAIDs and BAC was already known. Patent
`
`Owner suggests that
`
`
`
` (Resp. at 5; EX2105, ¶¶ 32, 69; EX2082, ¶ 115). Not true,
`
`
`3 Patent Owner’s “evidence” to support its statements that Dr. Lawrence’s
`
`testimony was based on hindsight falls flat. Dr. Lawrence merely noted that
`
`
`
`
`
` (EX2316, 15:18-22).
`
`
`
`
`9
`
`
`
`
`
`as 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
`
`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.” (EX1014, 2:14-
`
`15, 2:33-35). There is no dispute that Bromfenac would be an anionic compound
`
`at the relevant pH. (EX1103, 80:19-81:3). This same caution about the
`
`incompatibility of NSAIDs and quaternary ammonium compounds (“QACs”) was
`
`expressed multiple times in the art. (EX1039, 2:18-30; EX1012, 1:27-37, 3:20-25;
`
`EX1013, 1:15-21; EX1027, 2:2-3:2; EX1110, 1:29-38; EX1064, 1:31-61; EX1111,
`
`2:34-39; EX1112, 4:39-44). It even appeared in Remington, which states BAC “is
`
`not compatible with anionic compounds.” (EX1113, 831), and as Dr. Williams
`
`testified,
`
` (EX1099,
`
`24:8-15). Significantly, the ’606 patent expressly discusses this same
`
`incompatibility issue, citing to the corresponding Japanese patent application of
`
`prior art Desai ’929 (EX1012). (EX1004, 1:48-63).
`
`Patent Owner cannot explain why a POSA would ignore this teaching. Dr.
`
`Davies contends only that the statements in the prior art do not include
`
`experimental evidence confirming the identity of the BAC-NSAID complex.
`
`(EX1103, 86:16-87:3, 89:25-90:11, 134:24-136:10). Fu, however, states that the
`
`
`
`
`10
`
`
`
`
`
`precipitate is “between the Ketorolac moiety and [BAC].” (EX1014, 9:35-36).
`
`There are only four components in Example 5 of Fu: water; ketorolac; BAC; and
`
`one of three surfactants, thus, the BAC-NSAID complex is the only logical
`
`conclusion. (EX1014, 3:50-54, 9:1-15; EX1094, ¶ 26). Patent Owner’s experts
`
`have offered no alternative explanation for
`
`
`
` (EX1104, 154:8-156:2; EX1103, 152:5-153:13).
`
`It cannot seriously be disputed that
`
`
`
`
`
` (Decision at 13; EX1103, 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 Ex. 6. (EX1103, 80:19-81:14,
`
`82:7-16). Articles studying bromfenac note its similarity to other NSAIDs.
`
`(EX1115, 720; EX1091, 2299-2300). A patent owned by Patent Owner naming
`
`the same inventor also considers bromfenac and diclofenac together. (EX1116,
`
`1:21-24). Even Dr. Williams, Patent Owner’s expert, makes no distinction
`
`between these NSAIDs in one of his prior art patents. (EX1117, 10:33, 10:40).
`
`The ‘606 patent itself incorporates by reference Desai ’929, which along with
`
`describing the NSAID-BAC complexation problem, (EX1004, 1:48-63, 11:6-9)
`
`also lists diclofenac, bromfenac, ketorolac, and several other NSAIDs together.
`
`
`
`
`11
`
`
`
`
`
`(EX1012, 3:20-25). A POSA would understand that bromfenac interacts with
`
`BAC in the same way as the other acidic NSAIDs. (EX1005, ¶¶ 83, 102, 129).4
`
`A. Ethoxylated Octylphenols Were Known to Solve the
`Complexation Problem
`
`Fu provided a solution to the complexation problem between acidic NSAIDs
`
`and BAC. (Petition at 13-16; EX1014). 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. (EX1014, 9:1-40).
`
` (EX1104, 155:13-16). The stabilizing property of ethoxylated
`
`octylphenols described by Fu was recognized in other prior art. (EX1012, 1:35-41;
`
`EX1039, 2:9-24). Dr. Davies’s argument that
`
`
`
`
`
`
`
` (EX1094, ¶ 62; EX1014, 9:35-36; EX2105, ¶ 66). 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
`
`4 Based on these similarities, bromfenac would have been interchangeable with
`
`other NSAIDs, such as diclofenac. (Pet. 34-37; EX1005 ¶¶ 95, 195, 197, 257).
`
`
`
`
`12
`
`
`
`necessary. (EX2248, 4; EX2112, 2).
`
`1.
`
`Tyloxapol Falls within the Class of Ethoxylated
`Octylphenols Disclosed in Fu
`
`Patent Owner inaccurately suggests that
`
`
`
`
`
`EX2082, ¶ 158; EX2105, ¶ 78). Patent Owner’s expert, however, does not dispute
`
` (Resp. at 26;
`
`
`
`
`
`
`
` (EX1014, claim 3; EX1104,
`
`that
`
`112:7-16).
`
` (EX2105, ¶ 79; EX1094, ¶ 69; EX1095, 1:45-61).
`
`There would have been only two ethoxylated octylphenol surfactants within
`
`the series of Fu that a POSA would have considered: octoxynol 40 and tyloxapol.
`
`Patent Owner’s expert, Dr. Williams, acknowledges that
`
`
`
`
`
`
`
` (EX1104, 51:14-17, 115:4-15; 116:18-25; EX2082, ¶ 93; EX1005, ¶
`
`89). The FDA’s Inactive Ingredient Guide from 1996 (“FDA IIG,” EX1118),
`
`corroborates Dr. Williams’s testimony, which he testified
`
`
`
`
`
`
` (EX1104, 31:12-14; see also
`
`13
`
`
`
`
`
`EX1096, 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.
`
`(EX1118, 151). In contrast, octoxynol 40 was used in only one ophthalmic
`
`formulation. (EX1118, 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, 31). As Dr. Lawrence explains,
`
`Cremophor has a tendency to form solids, thus making it less preferable compared
`
`to liquid based materials like tyloxapol. (EX1094, ¶ 61). 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. (EX1021, 4:64).
`
`2.
`
`Tyloxapol and Polysorbate 80 were Among the Few
`Nonionic Surfactants
`
`Indeed, there were a limited number of nonionic surfactants that were
`
`generally considered for ophthalmic solutions at the time. (E.g., EX1065, 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,
`
`
`
`
`
` (EX1104, 115:4-
`
`116:25). Prior to the ‘606 patent, POSAs were already comparing polysorbate 80
`
`and tyloxapol in ophthalmic formulations. Yasueda compared polysorbate 80 and
`
`
`
`
`14
`
`
`
`
`
`tyloxapol in a formulation containing the acidic drug pranlukast. (EX1022, 7:35-
`
`43). Kawabata also identified tyloxapol and polysorbate 80, and no others, as
`
`suitable surfactants in an ophthalmic formulation containing an acidic drug.
`
`(EX1119, 13:10-11, 14:1-2).
`
`BAC Was Commonly Used for Ophthalmic Products.
`
`B.
`Patent Owner argues that 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 10-11). As Remington states, however,
`
`BAC was “by far, the most common preservative used in ophthalmic
`
`preparations.” (EX1113, 831; EX2089, 205, 207). Further, the FDA IIG lists no
`
`less than 77 commercial ophthalmic products contained BAC. (EX1118, 8). Even
`
`the ‘606 patent states “[b]enzalkonium chloride is a widely used preservative in
`
`ophthalmic solutions.” (EX1004, 1:57-58).
`
`Patent Owner’s experts adopt the hearsay statement of another expert in an
`
`unrelated case stating
`
`
`
` (EX2082 ¶ 76; EX2116 ¶ 42; EX1104, 179:16-181:3). Even Patent
`
`Owner’s expert acknowledges that the concentration of BAC at issue in the
`
`Allergan case was four times that found in Ogawa Ex. 6. (EX1120, 95:20-97:1).
`
`Moreover, Patent Owner’s own expert advocated the use of BAC as a preservative
`
`at the relevant time indicating no toxicity with its use. (EX1117, 7:61, 9:54, 10:33,
`
`
`
`
`15
`
`
`
`14:35, 15:22; EX1099, 68:5-8; see also EX1113, 831 (“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); EX1099, 57:18-58:16).
`
`Equally without merit is Patent Owner’s suggestion that
`
`
`
`
`
`
`
`(Resp. at 11-13; EX2082, ¶¶ 80-82). 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.” (EX1113, 831); see also EX1118, 8
`
`(identifying BAC in 77 ophthalmic solutions).
`
`III. Patent Owner’s Evidence of Alleged Objective Indicia is Not Probative
`of Patentability
`A.
`
`Patent Owner’s Purported Unexpected Results Relating to
`Tyloxapol were Known in the Art
`
`Where the feature that allegedly supports the objective indicia was known in
`
`the prior art, there is no nexus between that feature and the claims. Tokai Corp. v.
`
`Easton Enters., Inc., 632 F.3d 1358, 1369 (Fed. Cir. 2011) (“If commercial success
`
`is due to an element in the prior art, no nexus exists.”).
`
`Increased chemical stability and preservative efficacy for tyloxapol-
`
`
`
`
`16
`
`
`
`
`
`containing preparations as compared to polysorbate 80-containing preparations was
`
`known in the art. As discussed above, supra at 8-9, it was entirely expected that
`
`tyloxapol would provide a stabilizing effect on bromfenac over polysorbate 80,
`
`even at lower concentrations.
`
`Patent Owner incorrectly argues that a POSA would have expected that
`
`0.15% tyloxapol would be required in a bromfenac-containing preparation, simply
`
`because that is the concentration of polysorbate 80 is used in prior art bromfenac-
`
`containing preparations. (Resp. at 39-41).
`
`
`
`
`
`
`
` (EX1094, ¶ 77). This is further supported by the
`
`evidence in the prior art that concentrations of 0.02 w/v% or lower of an
`
`ethoxylated octyphenol compound was sufficient to stabilize a preparation
`
`containing an NSAID and BAC. (EX1094, ¶ 80; EX1014, Ex. 5). Moreover, it
`
`was understood in the art that using too much non-ionic surfactant could reduce the
`
`effectiveness of the BAC, which would inform the POSA in 2003 that lower levels
`
`of tyloxapol would indeed be effective. (EX1094, ¶81).
`
`B.
`
`The Data Relied Upon by Patent Owner Do Not Demonstrate
`More Chemical Stability Than The Closest Prior Art
`
`Patent Owner’s piecemeal presentation of data that only supports its position
`
`does not change the fact
`
`
`
`
`
`
`17
`
`
`
`
`
` (EX1094, ¶ 82;
`
`
`
`
`
`
`
`EX1090, 58:8-63:11; 90:21-95:12). Patent Owner inexplicably compares its
`
`tyloxapol-containing formulation to one of the least stable preparations described
`
`in Ogawa and states that its formulation is unexpectedly more stable. (Resp. at 39-
`
`41; EX2082 at ¶ 189; EX1094, ¶ 84). However,
`
` (Resp. at 43; EX2082, ¶ 193; EX1094, ¶ 85-86).
`
`Patent Owner’s further attempt to
`
`
`
`
`
`
`
`
`
` (Resp. at 43; EX2082, ¶ 192; EX1094, ¶¶ 87-88).
`
`C. The Alleged Unexpected Benefits of The Claimed Invention Do
`Not Support Nonobviousness
`
`Tyloxapol is not the reason for the ability to formulate the claimed
`
`preparation at a pH of 7.8 while retaining stability. Patent Owner would lead one
`
`to believe that,
`
`
`
`
`
`
`
`
` (Resp. at 46-48; EX2082, ¶ 201;
`
`18
`
`
`
`EX1094, ¶ 89). However, the prior art teaches that
`
`
`
`
`
`
`
`
`
` (EX1094, ¶ 91). Furthermore, the claims are not limited to
`
`preparations having a pH of 7.8, but instead encompass any pH in the broadest
`
`claims, and encompass a pH of from 7.5-8.5 in the most narrow range. (EX1094, ¶
`
`92).
`
`With respect to the purported clinical benefits of the invention, the Patent
`
`Owner relies on mere conclusory statements made by their expert that a reduction
`
`in pH and lower concentration of surfactant are responsible for the elimination of
`
`burning and stinging upon administration of Prolensa. (Resp. at 46-48). However,
`
`Patent Owner’s expert, Dr. Trattler, acknowledged that certain adverse reactions
`
`were reported with lower incidence rates during Phase III clinical trials for
`
`Prolensa that were ultimately not reported in Prolensa’s prescribing information.
`
`(EX1120, 40:7-48:23; EX2113, 969-70).
`
`Patent Owner’s Test Data Should be Disregarded
`
`D.
`Dr. Williams relies on information contained in Mr. Sawa’s declaration.
`
`However, Mr. Sawa admitted that he did not compile the data reported in his
`
`declaration, but instead, the data was provided to him. (EX1090, 58:8-63:11). He
`
`further admitted that data on related formulations existed but was not provided to
`
`
`
`
`19
`
`
`
`him, calling into question the completeness and reliability of the evidence.
`
`(EX1090, 90:21-95:12). Under 37 C.F.R. 42.65(a) the declarations should be
`
`given no weight.
`
`Neither Dr. Myer’s nor Dr. Paulson’s testing is referenced in the Patent
`
`Owner’s Response, and for good reason. For example,
`
`
`
`
`
`
`
` (E.g.,
`
`EX1123, 54:21-55:14, 67:11-14, 69:7-17, 70:14-19, 77:15-78:9, 113:1-114:18,
`
`137:4-19, 139:5-140:1; see also EX1124, 732 (“At 46 °C, the growth of S.aureus
`
`was depressed to 50%, and the production of coagulase and methicillin resistance
`
`were diminished. . . .”)). Indeed, Dr. Paulson could barely recognize his
`
`declaration. (EX1123, 52:18-54:10, 55:16-60:14). Likewise, Dr. Myers
`
`inexplicably decided to compare samples that were aged at 60°C for 4 weeks
`
`against samples that were aged at ambient conditions for 4 weeks rather than
`
`compare it to samples prior to aging, (EX1125, 43:6-44:11), and failed to control
`
`for moisture evaporation for all samples during aging, which would affect any %
`
`measurement. (EX1125, 58:5-59:2, 61:19-63:6).
`
`E.
`
`Evidence of Commercial Success Lacks Factual Support and
`Nexus with the Claims
`
`Patent Owner provides no evidentiary support for its claim that Prolensa’s
`
`purported commercial success is attributable specifically to tyloxapol’s stabilizing
`
`
`
`
`20
`
`
`
`
`
`effect on bromfenac. (Resp. at 48-49). In support, Patent Owners cite to the
`
`declaration of Mr. Jarosz, who is neither a pharmacist nor a chemist (EX1089,
`
`59:7-17; EX1121, 49:15-19), and who opines only as to the purported benefits of
`
`Prolensa relative to other NSAID formulations, and as to the revenues and
`
`prescription volumes of Prolensa since its introduction. (EX2130, ¶¶ 81, 147).
`
`Notably, however, in neither of these paragraphs from Mr. Jarosz’s declaration
`
`does Mr. Jarosz mention that any purported success is directly the result of
`
`tyloxapol’s stabilizing effect on bromfenac, or any other claimed and allegedly
`
`novel aspect of the ’606 patent. (EX2130, ¶¶ 81, 147); Wyers v. Master Lock Co.,
`
`616 F.3d 1231, 1246 (Fed. Cir. 2010) (“For objective evidence of secondary
`
`consideration to be accorded substantial weight, its proponent must establish a
`
`nexus between the evidence and the merits of the claimed invention.” (emphasis in
`
`original, quotation omitted)).
`
`Moreover, Patent Owner’s claims of Prolensa’s “substantial marketplace
`
`success” are factually unfounded. The performance of Prolensa in the marketplace
`
`is primarily attributable to the life-cycle management strategy employed by Patent
`
`Owner for its bromfenac product franchise. (EX1122, ¶¶ 7-8, 43, 55-80); see also
`
`ISTA Pharms., Inc. v. FDA, 898 F. Supp. 2d 227, 232 (D.D.C. 2012) (noting Patent
`
`Owner’s predecessor’s attempt to “maintain a monopoly over the bromfenac
`
`eyedrop market.”). As the data relied upon by Mr. Jarosz illustrates, Prolensa’s
`
`
`
`
`21
`
`
`
`
`
`prescription volumes reflect a capturing of prescriptions of prior bromfenac
`
`formulations that were discontinued, consistent with a life-cycle management
`
`strategy. (EX1122, ¶¶ 60, 66-70; EX2130, Appendix 5). Additionally, significant
`
`evidence proves that Prolensa’s marketplace performance is highly dependent on
`
`extrinsic factors, such as extensive and strategic marketing efforts. (EX1122, ¶¶
`
`61, 81-96).
`
`Importantly, however, Patent Owner overstates the purported success of
`
`Prolensa by relying exclusively on its gross sales. Prolensa’s gross sales (which do
`
`not take into account rebates, discounts, allowances, coupons, chargebacks, and
`
`returns) exceed the net sales of Prolensa
`
` (EX1122, ¶¶ 35-36;
`
`EX1121, 76:16-78:7). After considering other expenses under a proper analysis,
`
`the performance of Prolensa
`
`
`
` which far from illustrates any
`
`cognizable commercial success. (EX1122, ¶¶ 37-40).
`
`F.
`
`Patent Owner’s Evidence of Secondary Considerations are Not
`Commensurate with the Scope of the Claims
`
`The stability data presented using 0.02% w/v % tyloxapol is not
`
`commensurate in scope with the purported claimed invention of the ’606 patent.
`
`Patent Owner relies on testing under “harsh pH” conditions (i.e., pH 7), outside the
`
`scope of even the most narrowly claimed pH range (i.e., pH 7.5-8.5). (Resp. at 39-
`
`41; EX1002, Claims 5, 11, 17, 23). To remedy this defect, Patent Owner cites to
`
`
`
`
`22
`
`
`
`
`
`further stability testing at a pH of 8.2-8.3, which shows a marginal difference in
`
`degree of stability that Patent Owner admits evidences “comparable stabilization
`
`results to Ogawa’s Example 6.” (Resp. at 42-44); see also In re Harris, 409 F.3d
`
`1339, 1344 (Fed. Cir. 2005) (difference between 32% and 43% increase in stress-
`
`rupture life, a property of claimed alloy, constitutes mere difference in degree, not
`
`in kind, and therefore not sufficient to establish unexpected results). Patent Owner
`
`simply fails to provide a basis or trend from which a POSA may determine that any
`
`unexpected results would extend across the entire claimed range. In re Peterson,
`
`315 F.3d 1325, 1329-31 (Fed. Cir. 2003).
`
`Moreover, Patent Owner contends that Prolensa’s formulation at pH 7.8 i
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