SENJU EXHIBIT 2020
`LUPIN v. SENJU
`IPR2015-01105
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`Bausch & Lomb
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`Senju Pharmaceutical C0,, Ltd.
`December 15, 2014
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`The application included certifications under § 355(j)(2)(A)(vii)(IV) for
`United States Patent N 0. 8,129,431 ("the '431 patent”), United States Patent No.
`8,669,290 (" the ‘290 patent"), United States Patent No. 8,754,131 ("the ‘131
`patent") and United States Patent No. 8,871,813 ("the '813 patent”). Paddock has
`certified that in its opinion and to the best of its knowledge, the claims of the
`'431, ‘290, '13] and ’813 patents will not be infringed by Paddock's proposed
`manufacture, use, or sale of its product that is the subject of its application,
`and/ or those claims are invalid or unenforceable. According to Bausch and
`Lomb's entry in the FDA’s electronic Orange Book, the ’431 patent expires
`September 11, 2025, the ‘Z90 patent expires January 16, 2024, the ’131 patent
`expires January 16, 2024, and the ’813 patent expires on January 16, 2024.
`
`As required by 21 U.S.C. §355(j)(2)(B)(ii), a detailed statement of the
`factual and legal bases for Paddock's opinion is set forth below. Furthermore,
`this enclosure also contains an offer of confidential access pursuant to 21 U.S.C. §
`355(j)(5)(C)(iii).
`
`Pursuant to 21 CPR. §314.95(e), Paddock requested and received from
`the FDA permission to send this notice to the NDA holder and patent owner by
`means other than registered or certified mail. The FDA granted Paddock’s
`request prior to this notice being sent.
`
`The name and address of an agent authorized to accept service of process
`for Paddock is:
`
`Shane A. Brunner, Edward J. Pardon, Jeffrey S. Ward, or Wendy M. Ward
`Merchant 8: Gould PC
`
`10 E. Doty Street, Suite 600
`Madison, WI 53703-3376
`
`DETAILED STATEMENT
`
`Legal Standards
`
`General legal standards utilized here are discussed below. More detailed
`law is discussed in the analysis sections as needed.
`
`A.
`
`Claim Construction
`
`The first step in an infringement or invalidity analysis is to construe the
`claims. Claim construction is an issue of law, performed by the court, even in a
`jury trial. Mnrkmnn v. Westview Instruments, Inc, 52 F.3d 967, 979 (Fed. Cir. 1995),
`njj“ d, 517 U.S. 370 (1996). The interpretation to be given a claim is formed by the
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`claim language itself, the language of the other claims in the patent, the
`specification of the patent, the prior art, and the prosecution history. SR1 Int‘! 1).
`Matsushita Elec. Corp., 775 F.2d 1107, 1118 (Fed. Cir. 1985). Claim terms are
`generally given their ordinary and established meanings to one of ordinary skill
`in the art. Phillips v. AWH Corp., 415 F.3d 1303, 1312-13 (Fed. Cir. 2005).
`
`The specification is the primary basis for construing the claims, because
`that is where the inventor provides a full and exact description of the invention.
`Phillips, 415 F.3d at 1315-17. The claims themselves, both asserted and
`unasserted, are also a valuable source with respect to claim construction. Id. at
`1314. The prosecution history should also be consulted. Id. at 1317. Review of the
`prosecution history can reveal whether there are any express limitations made
`regarding the scope and meaning of the claims. Bell Atlantic Network Seros., inc. v.
`Covad Commc'ns Group, lnc., 262 F.3d 1258, 1268 (Fed. Cir. 2001). In addition,
`extrinsic evidence such as dictionaries, technical treatises, articles that are
`publicly available at the time the patent issued, and expert testimony may also be
`considered, but this evidence is less significant than the patent itself and its
`prosecution history. Phillips, 415 F.3d at 1317-19.
`
`B.
`
`Infringement
`
`After the claim is interpreted, it must be compared to the accused device
`or process to determine whether the claim's scope encompasses the accused
`device or process. North Am. Vaccine, Inc. v. American Cyanamid Co., 7 F.3d 1571,
`1574 (Fed. Cir. 1993). If the properly interpreted terms of the claim read on the
`accused device or process, literal infringement is established. Morton Int'l, Inc. :2.
`Cardinal Chem. Co., 5 F.3d 1464, 1468 (Fed. Cir. 1993). Because each element of a
`claim is material and essential, the patent owner must show the presence of each
`and every element in the accused device to establish literal infringement. Charles
`Greiner 8 Co. v. Mari-Med Mfg., Inc., 962 F.2d 1031, 1034 (Fed. Cir. 1992). The
`patentee has the burden to show infringement by a preponderance of the
`evidence. SnzithI<Iine Diagnostics, Inc. 2). Helena Laboratories Corp., 859 F. 2d 878,
`889 (Fed. Cir. 1988).
`
`Absent literal infringement, a legal doctrine termed the doctrine of
`equivalents may apply to bring an accused device or process under the web of
`infringement. Hughes Aircraft Co. v. United States, 717 F.2d 1351, 1361 (Fed. Cir.
`1983). Under the doctrine of equivalents, a patent owner may be successful in an
`infringement action, even if the claims are not literally infringed, if "the accused
`product or process contain[s] elements identical or equivalent to each claimed
`element of the patented invention." Warner-jenkinson Co. 1:. Hilton Davis Chem.
`Co., 520 U.S. 17, 40 (1997). In applying the doctrine of equivalents, one considers
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`if the differences between the claimed structure or process and the accused
`device or process are insubstantial from the vantage point of one of ordinary skill
`in the relevant art. Hilton Davis Chem. Co. v. Warner-jenkinson Co., 62 F.3d 1512,
`1517-18 (Fed. Cir. 1995), rev‘d on other grounds and remanded, 520 U.S. 17 (1997). It
`is often enough to assess whether the accused device or process performs
`substantially the same function in substantially the same way to obtain
`substantially the same result as the claim element(s) missing from the accused
`structure or process under the literal infringement analysis. Hilton Davis, 62 F.3d
`at 1518. Furthermore, a patent owner must show the presence of every element
`or its substantial equivalent in the accused device or process to prove
`infringement under the doctrine of equivalents. Pennzaalt Corp. v. Durand-
`Wayland, Inc., 833 F.2d 931, 935 (Fed. Cir. 1987).
`
`Application of the doctrine of equivalents can be precluded in certain
`situations as a matter of law. For example, a patent owner cannot obtain, under
`the doctrine of equivalents, coverage that could not lawfully have been obtained
`from the USPTO by literal claims. Pennwalt, 833 F.2d at 938. In other words, a
`claim cannot be read to cover an accused device under the doctrine of
`
`equivalents if that claim would then be unpatentable in view of prior art. Wilson
`Sporting Goods Co. 12. David Geoflrey and Assocs., 904 F.2d 677, 684 (Fed. Cir. 1990).
`In addition, a patentee is precluded from capturing subject matter under the
`doctrine of equivalents that was disclosed in the patent specification but not
`claimed by the patentee. jolmson 5' Iolmston Assocs., Inc. v. R.E. Sero. Co., 285 F.3d
`1046 (Fed. Cir. 2002) (en banc). Furthermore, a patentee cannot assert the
`doctrine of equivalents where to do so would "vitiate" or completely read a
`limitation out of a claim. Warner-jenkinson Co., 520 US. at 39 n.8; DePuy Spine, Inc.
`v. Medtronic Sofamor Danek, Inc, 469 F.3d 1005, 1017 (Fed. Cir. 2006).
`
`Where an accused activity does not include particular limitations of an
`independent claim or their substantial equivalents, it follows that, for the same
`reason, the dependent claims will not be infringed. Jeneric/Pentron, Inc. v. Dillon
`Co., 205 F.3d 1377, 1383 (Fed. Cir. 2000) ("dependent claims cannot be found
`infringed unless the claims from which they depend have been found to have
`been infringed") (citation omitted).
`
`C.
`
`Obviousness
`
`A claimed invention in an issued patent is invalid if it would have been
`obvious to one of ordinary skill in the art at the time the invention was made
`when viewed in light of the prior art. 35 U.S.C. § 103. Obviousness is a question
`of law, based on underlying fact issues. Graham v. [elm Deere Co., 383 U.S. 1, 17-18
`(1966). These fact issues are: (1) the scope and content of the prior art; (2) the
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`differences between the claimed invention and the prior art; (3) the level of
`ordinary skill in the art; and (4) secondary considerations, including unexpected
`results and commercial success. KSR Int’! Co. v. Teleflex, Inc., 550 U.S. 398, 406
`(2007).
`
`To prove obviousness based on a combination of references, it can be
`helpful to identify whether there must be some reason to combine those
`references. KSR, 550 U.S. at 418-19. The reason to combine references can be
`provided by any need or problem that is known in the field of endeavor at the
`time of the invention and addressed by the patent at issue. Id. at 420. In addition,
`where there is a need to solve a problem, and there are a finite number of
`identified, predictable solutions, a person of ordinary skill in the art has good
`reason to pursue those solutions. If this leads to anticipated success, it is likely
`the product of ordinary skill and common sense, and is not inventive. Id. at 421.
`
`II.
`
`Description of the ’431 Patent
`
`A.
`
`Background
`
`The '431 patent is entitled "Aqueous Liquid Preparation Containing 2-
`Amino-3(4-Bromobenzoy1)Phenylacetic Acid." The patent issued on March 6,
`2012 from U.S. application No. 10/ 525,006 (” the ‘O06 application"). The ‘O06
`application was the U.S. national phase of PCT application PCT/ JP2004/ 000350,
`filed on January 16, 2004. The PCT application claimed priority to a Japanese
`patent application filed on January 21, 2003. The ‘431 patent lists Shirou Sawa
`and Shuhei Fujita as inventors. It is assigned to Senju Pharmaceutical Co., Ltd.
`("Senju”). The ’431 patent expires September 11, 2025, according to the entry in
`the Orange Book.
`
`B.
`
`Claims
`
`The ’431 patent contains twenty-two claims, two of which are
`independent: claims 1 and 18. These claims are reproduced below.
`
`1. An aqueous liquid preparation consisting essentially of
`the following two components, where the first component
`is [bromfenac] or a pharmaceutically acceptable salt or a
`hydrate thereof, where the hydrate is at least one selected
`from a V2 hydrate, 1 hydrate and 3/ 2 hydrate and the
`second component is tyloxapol, wherein said liquid
`preparation is formulated for ophthalmic administration,
`and wherein when a quaternary ammonium compound is
`included in said liquid preparation, the quaternary
`ammonium compound is benzalkonium chloride.
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`18. An aqueous liquid preparation consisting essentially
`of:
`
`(a) [bromfenac] or a pharmaceutically acceptable salt or
`a hydrate thereof, where the hydrate is at least one selected
`from a 132 hydrate, 1 hydrate and 3/ 2 hydrate;
`
`(b) tyloxapol;
`
`(c) boric acid;
`
`(cl) sodium tetraborate;
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`(e) EDTA sodium salt;
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`(f) benzalkonium chloride;
`
`(g) polyvinylpyrrolidone;
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`(h) sodium sulfite;
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`wherein said liquid preparation is formulated for
`ophthalmic administration, and wherein benzalkonium
`chloride is the only quaternary ammonium compound
`which is included in said liquid preparation.
`
`Claims 2-17 are ultimately dependent on claim 1. Claim 2 requires that
`bromfenac sodium be used, while claim 3 limits the tyloxapol concentration and
`the bromfenac sodium concentration to from about 0.01 w/ v% to about 0.5
`w/ v%. Claims 4 and 5 further limit the bromfenac sodium concentration, while
`claim 6 specifies that the tyloxapol concentration is about 0.02 w/ v%. Claim 7
`states that the formulation further includes one or more additives selected from
`
`certain excipient groups, while claim 8 specifies a single excipient from each
`group. Claims 9 and 10 are dependent on claim 8, and specify certain pH ranges.
`Claim 11 is dependent on claim 4, and specifies that the concentration of the
`brornfenac sodium is about 0.02%, while claim 12 is also dependent on claim 4,
`and requires the tyloxapol concentration to be about 0.3 w/ v%. Claims 13-17 are
`dependent on claims 12, 13, 11, 15 and 16, respectively, and relate to the presence
`of further excipients (claims 13, 14, 16 and 17) or a specific tyloxapol
`concentration (claim 15).
`
`Claims 19-20 are ultimately dependent on claim 18, and require brornfenac
`sodium (claim 19), and that the bromfenac sodium and tyloxapol concentrations
`are from about 0.01 w/v% to about 0.5 w/ V923 and about 0.02 w/ v%,
`respectively. Claims 21 and 22 are also ultimately dependent on claim 18, and
`require that the bromfenac sodium concentration is about 0.01 w/ v% and about
`0.1 w/v%, respectively.
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`C.
`
`Specification
`
`The ‘A131 patent specification states that benzalkonium chloride and other
`quaternary ammonium compounds are generally considered to be incompatible
`with ophthalmic drug compositions with acidic groups, such as nonsteroidal
`anti-inflammatory drugs (NSAIDS), because the preservatives form complexes
`with the drug compounds and lose their ability to function. (’431 patent at col. 1,
`1. 62 - col. 2, 1. 3.) Accordingly, the specification states that it is an object of the
`invention to provide an aqueous liquid preparation comprising bromfenac or a
`salt or hydrate thereof that is stable within a pH range that is not irritating to the
`eye and when a preservative such as benzalkonium chloride is used, the
`preservative effect of that compound does not substantially deteriorate. (Id. at
`col. 2, 1]. 14-22.)
`
`The specification then claims that the inventors have discovered that by
`adding an alkyl aryl polyether alcohol type polymer such as tyloxapol or a
`polyethylene glycol fatty acid ester such as polyethylene glycol monostearate to
`an aqueous liquid preparation comprising bromfenac or its salts or hydrates, the
`preparation is stable in a non-irritating pH range. (Id. at col. 2, 11. 34-43.) The
`specification also states that in this preparation, the change in bromfenac over
`time can be inhibited, and where the preparation contains a preservative, the
`deterioration of the preservative can also be inhibited for a long period of time.
`(’431 patent at col. 2, 1]. 43-49.)
`
`The specification contains several Examples. In Experimental Example 1,
`various aqueous preparations containing brornfenac sodium and other
`excipients, including benzalkonium chloride and one of polysorbate 80,
`tyloxapol, or po1yoxyl40 stearate (a polyethylene glycol monostearate) were
`tested for stability at 60°C at pH 7 for four weeks. According to the specification,
`the preparations containing tyloxapol were the most stable, the preparation with
`polyoxyl 40 stearate was the second most stable, and the preparation with
`polysorbate 80 was the least stable. (ld.at col. 7, 1]. 10-64.) The inventors also
`concluded that the preparation containing 0.02 w/ v% tyloxapol was more stable
`than that containing 0.15 w/ V96 tyloxapol. (Id. at col. 7, I. 65 - col. 8, l. 2.)‘
`
`1 The preparations containing polysorbate 30 contained it in a concentration of 0.15
`w/ v%, while the preparation containing po1yoxyl40 stearate also contained that
`compound in a concentration of 0.15 w/ v%.
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`Experimental Example 2 tested the stability of various liquid preparations
`containing bromfenac sodium and other excipients, including benzalkonium
`chloride and one of tyloxapol or polyoxyl 40 stearate for four weeks at 60°C and
`a pH of about 8.15. Varying amounts of tyloxapol (0.02 g, 0.03 g, or 0.05 g)3 or
`polyoxyl 40 stearate (0.02 g or 0.05 g) were used. The specification stated that all
`of the preparations had more than 90% of the bromfenac remaining at the end of
`the test, which indicates that compositions have sufficient stability for eye drops.
`
`Experimental Example 3 tested the preservative effect of three liquid
`preparations from Experimental Example 2. Two of the preparations contained
`0.02 w/ v% or 0.05 w/ v% tyloxapol, while the other contained 0.02 w/v%
`polyoxyl 40 stearate. The specification states that these results showed that the
`preparations met various EP preservative criteria. (‘431 patent at col. 8,1. 51 - col.
`9,1. 52.)
`
`The specification also contains three example eye drop preparations, all of
`which contain bromfenac sodium, benzalkonium chloride and other excipients,
`and one of tyloxapol or polyoxyl 40 stearate. (ld. at col. 10, 1. 51 - col. 11, 1. 43.)
`
`D.
`
`Prosecution history
`
`The ‘O06 application as originally filed contained eighteen claims. Claims
`1-14 related to aqueous liquid preparations, with claim 1 being the only
`independent claim in that group. It claimed "[a]n aqueous liquid preparation
`comprising [bromfenac] or a pharmacologically acceptable salt or hydrate
`thereof, and an alkyl aryl polyether alcohol type polymer or a polyethylene
`glycol fatty acid ester." Claims 15 and 16 were both independent and claimed an
`eye drop comprising bromfenac sodium and either 0.01 to 0.5 w/ v% tyloxapol
`(claim 15) or 0.02 to 0.1 w/v% polyethylene glycol monostearate (claim 16).
`Claims 17 and 18 were also both independent and related to a method for
`stabilizing bromfenac or its salts for hydrates by incorporating tyloxapol or
`polyethylene glycol monostearate (claim 17) or a method for inhibiting the
`decrease in preservative effect of a preservative in an aqueous liquid preparation
`of bromfenac or its salts or hydrated by incorporating tyloxapol or polyethylene
`glycol monostearate.
`
`These claims were then cancelled in a preliminary amendment, and new
`claims 19-40 were added. Claim 19 was identical to original claim 1, and the only
`
`2 According to the specification, these amounts equate to w / v96, e.g., 0.02 g tyloxapol is
`equal to 0.02 w/ v% tyloxapol.
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`other independent claims, claims 39 and 40, were similar to original claims 17
`and 18, respectively.
`
`In response to a restriction requirement, the applicants elected claims 19-
`38. These claims were rejected as being anticipated and obvious. With respect to
`the obviousness rejections, various claim combinations were rejected over (1)
`W0 01/ 15677 to Gamache et al. (”Gamache”) in view of publicly available
`information regarding Xibrom or Nolan, Agents and Actions, 1988 Aug; 25(1-
`2):77-85, abstract (”Nolan"), (2) "New Drugs in Japan," 2001 and U.S. Patent No.
`6,369,112 to Xia (”Xia"), or (3) New Drugs in Japan and Xia in View of Nolan.
`
`The applicants subsequently conducted an interview with the examiner
`and discussed the various prior art references listed above. Shortly thereafter, on
`March 26, 2008, the applicants submitted an amendment. There, they amended
`the claims to require two components, the first being bromfenac or a salt thereof,
`and the second being an alkyl aryl polyether alcohol type polymer or a
`polyethylene glycol fatty acid ester. Certain claims specified tyloxapol as the
`alkyl aryl polyether alcohol type polymer as well as various concentration ranges
`of the two components.
`
`The applicants also added new claims 41-63. Claims 41-60 tracked claims
`19-38, except the new claims contained the phrase "consisting essentially of”
`instead of "comprising.” New claims 61-62 related to a method for stabilizing
`bromfenac or its salts or hydrates claim (claim 61) or a method for inhibiting
`decrease in preservative effect of a preservative (claim 62) comprising
`incorporating tyloxapol or polyethylene glycol monostearate, to obtain a
`composition consisting essentially of those two components. New claim 63 was
`similar to claim 19, used the phrase “consisting of" and added optional
`components.
`
`Addressing the obviousness rejections, the applicants argued that
`Gamache discloses 5-I-IT agonist compositions with a great number of other
`possible ingredients, and does therefore not suggest the claimed composition.
`The applicants also argued that the presence of the 5-HT agonist was beyond the
`scope of the claims having the "consisting essentially of" language. With respect
`to the publicly available information regarding Xibrom, the applicants stated
`Xibrom has a different composition from that claimed, in that it does not include
`the required alkyl aryl polyether alcohol type polymer or polyethylene glycol
`fatty acid ester. They also argued that Nolan also does not disclose this
`component. Regarding "New Drugs in Japan," the applicants provided a
`complete translation and argued that it did not teach the use of tyloxapol. The
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`applicants also contended that Xia was not relevant, because it relates to adding
`a biguanide to a contact lens solution containing tyloxapol.
`
`The examiner issued another Office Action on July 18, 2008. There, claims
`61 and 62 were withdrawn, and the rejections based on Gamache were
`maintained. The rejections based primarily on "New Drugs in Japan" were not
`maintained, but the examiner made a new obviousness rejection based on U.S.
`Patent No. 5,998,465 to Hellberg ("Hellberg") in view of Nolan.
`
`The applicants responded on January 15, 2009. There, they amended
`claims 19, 41 and 63 to require that the claimed liquid preparation be in the form
`of an eye drop. They then again argued that Gamache did not disclose or suggest
`the specific combination of bromfenac or its salts or hydrates in combination
`with an alkyl aryl polyether alcohol type polymer or polyethylene glycol fatty
`acid ester. To the extent that Gamache did disclose the use of tyloxapol with a 5-
`HT agonist, the applicants contended that there was no explanation why it was
`added to the exemplified composition. The applicants also argued that Gamache
`did not disclose eye drops.
`
`With respect to the rejection based on Hellberg, the applicants stated that
`Hellberg related to compositions having anti-inflammatory and antioxidant
`activity, and that the active agent, unlike brornfenac, had to have both properties.
`As a result, the applicants contended, substitution of bromfenac in the Hellberg
`compositions would render those compositions unsatisfactory for their intended
`purpose.
`
`A new examiner issued an Office Action on June 3, 2009, and again
`rejected all of the pending claims. The examiner maintained the rejections based
`on Gamache and Hellberg, and made them final.
`
`The applicants then submitted a Request for Continuing Examination
`("RCE”) on October 5, 2009. There, they amended claims 19, 41 and 63 to remove
`the language that the compositions be in the form of an eye drop, and instead
`added language that the compositions be formulated for ophthalmic
`administration. This amendment had been suggested by the examiner in the
`previous Office Action. Shortly thereafter, the applicants conducted an interview
`with the examiner and again asserted that there would be no motivation to use
`brornfenac in the Hellberg compositions.
`
`The examiner issued another Office Action on December 24, 2009. There,
`
`she maintained the previous rejections. The applicants then had another
`interview with the examiner, and explained that the tyloxapol in Hellberg was
`not used as a cosolvent. They then submitted an amendment on March 24, 2010.
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`There, they cancelled claims 19-40 and 63, among others, leaving the "consisting
`essentially of" claims in issue. They also added new claims 64-68. Claim 64 was
`independent and specified that the claimed aqueous liquid preparation consist
`essentially of brornfenac or a salt or hydrate, tyloxapol, boric acid, sodium
`tetraborate, EDTA sodium salt, benzalkonium chloride, polyvinylpyrrolidone,
`and sodium sulfite, where it is formulated for ophthalmic administration. The
`applicants then stated that the examiner had agreed to withdraw the rejection
`based on Gamache. and that there was no motivation to replace the bifunctional
`Compounds of Hellberg with bromfenac.
`
`The examiner responded on June 24, 2010. There, she rejected the claims
`as anticipated by U.S. Patent No. 5,603,929 to Desai (“Desai”) and obvious over
`Desai in view of U.S. Patent N0. 5,475,034 to Yanni ("Yanni") and Hellberg. She
`again made the rejection final.
`
`The applicants then submitted a second RCE on October 25, 2010. There,
`the applicants amended claims 41 and 64 to require that when a quaternary
`ammonium compound is added to the claimed liquid preparation, it is
`benzalkonium chloride. The applicants then argued that Desai disclosed using
`polymeric quaternary ammonium compounds as preservatives and taught that
`benzalkonium chloride is incompatible with NSAIDS, because the benzalkonium
`chloride forms complexes with the charged drug compounds and loses its ability
`to function as a preservative. As a result, the applicants argued that Desai taught
`away from the claimed formulations, which require the use of benzalkonium
`chloride if a quaternary ammonium compound is used.
`
`The applicants further discussed this issue with the examiner in an
`interview held on Ianuary 14, 2011. In response, the examiner issued an Office
`Action on May 6, 2011. There, she withdrew the rejection based on Desai, but
`rejected the pending claims over Yanni in view of US. Patent No. 5,540,930 to
`Guy (”Guy") and in some instances in further view of Gamache.
`
`The applicants responded on September 6, 2011. There, they contended
`that Yanni did not disclose brornfenac, but instead disclosed an amide derivative
`
`in combination with polysorbate 80, and that Yanni was not directed to the use of
`bromfenac. The applicants also argued that Guy did not teach the equivalency of
`tyloxapol and polysorbate 80, as it was directed to a different problem, and in
`addition, that as shown in applicants’ application, tyloxapol was unexpectedly
`superior as a stabilizer to polysorbate 80 in a brornfenac composition subjected to
`stability testing at pH 7.0 at 60°C for four weeks.
`
`The examiner was not convinced, and maintained the rejections in an
`Office Action dated November 15, 2011. The rejection was again made final.
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`However, inexplicably, on December 23, 2011, the examiner reversed
`course and issued a Notice of Allowance. The examiner stated that the prior art
`did not teach or suggest the claimed liquid preparations, and that the applicants
`had discovered that tyloxapol was not equivalent to polysorbate 80 when
`combined with brornfenac, based on the information in the specification. The
`examiner also stated that Desai taught that only polymeric quaternary
`ammonium compounds should be used with brornfenac, while the amended
`claims require that the quaternary ammonium compound be benzalkonium
`chloride.
`
`The '431 patent then issued on March 6, 2012.
`
`III.
`
`Claims 1-10, 18-20 and 22 of the '43] Patent are Invalid as Obvious
`
`Claims 1-10, 18-20 and 22 of the ‘431 patent are invalid under § 103 as
`obvious over US. Patent No. 4,910,225 ("the '225 patent") or New Drugs in Japan
`in view of U.S Patent No. 6,107,343 ("the ‘343 patent”), U.S. Patent N0. 5,457,126
`("the ‘126 patent"), European Patent No. 0443766 ("EP ’766”), U.S. Patent No.
`6,274,609 ("the '609 patent") and/ or Guy. The ‘225 patent discloses brornfenac
`ophthalmic compositions including benzalkonium chloride and polysorbate 80,
`as well as other components. New Drugs in Japan discloses an approved
`ophthalmic composition containing bromfenac sodium hydrate, along with
`polysorbate 80 and benzalkonium chloride. The ’343 patent, the ‘126 patent and
`EP ‘766 disclose the use of tyloxapol with drug substances (including NSAIDS)
`having acidic groups in combination with quaternary ammonium compounds,
`such as benzalkonium chloride, and the '609 patent and Guy disclose the
`substitutability of tyloxapol for polysorbate 80 in ophthalmic compositions and
`the benefits thereof, including improved stability and antimicrobial effect.
`
`Accordingly, one of ordinary skill in the art would have understood that
`the polysorbate 80 in the brornfenac formulations of the ’225 patent or New
`Drugs in Japan could be replaced with tyloxapol, and would have had a
`reasonable expectation of success that the resulting product would be stable,
`sterile and useful for ophthalmic administration. Further, while Senju argued
`that bromfenac compositions containing tyloxapol were unexpectedly more
`stable than those containing polysorbate 80, the alleged evidence of unexpected
`result is insufficient to render the claims non-obvious, when all four Gmhmn
`
`factors are considered together. This conclusion is explained in more detail
`below.
`
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`Senju Pharmaceutical Co., Ltd.
`December 15, 2014
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`Page 13
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`A. Claim Construction
`
`Here, the claims will be construed in accordance with their ordinary
`meaning to one of ordinary skill in the art. For the purposes of this notice letter,
`there are no claim terms needing further construction.
`
`B. The Scope and Content of the Prior Art
`
`The ’225 patent discloses ophthalmic compositions for use in treating
`inflammatory eye diseases. Specifically, Examples 6 and 8 disclose ophthalmic
`solutions containing bromfenac sodium monohydrate as the active ingredient,
`along with other components, including polysorbate 80 and benzalkonium
`chloride, where the composition has a pH of 8. (’225 patent at col. 10, 11. 4-17; col.
`10, 11. 35-48.) The '225 patent also discloses that these compositions were "stable,
`excellent for a long period of time." (Id. at col. 10, 11. 50-57.)
`
`Likewise, New Drugs in Japan also discloses an approved ophthalmic
`composition for use in treating inflammatory eye diseases. The composition,
`trade named Bronuck, contains bromfenac (0.1%) as brornfenac sodium
`sesquihydrate, along with other components, including polysorbate 80 and
`benzalkonium chloride. One of ordinary skill in the art would understand that
`this product is both sterile and stable for a pharmaceutically acceptable amount
`of time— otherwise it would not have been approved.
`
`The '343 patent discloses ophthalmic compositions comprising diclofenac
`potassium (a NSAID) for the treatment of inflammatory conditions of the eye.
`(’343 patent at col. 1, 11. 8-11.) It also discloses that the composition can contain a
`solubilizer and a preservative, with one of the preferred solubilizers being
`tyloxapol and one of the preferred preservatives being benzalkonium chloride.
`(Id. at col. 4,11. 52-67; col. 5, II. 28-38.) Finally, in Example 2, the ’343 patent
`discloses an eye drop formulation comprising diclofenac potassium, tyloxapol,
`and benzalkonium chloride. (Id. at col. 8, 11. 1-15.)
`
`The '126 patent discloses ophthalmic compositions for the treatment of
`ocular allergic responses, including inflammation, such as from conjunctivitis.
`Specifically, it discloses ophthalmic formulations containing lodoxamide
`tromethamine, which is a phenylene dioxamic acid. (‘I26 patent at col. 1, 1]. 14-43;
`col. 2, 11. 39-49.) The formulations also contain tyloxapol and benzalkonium
`chloride, among other excipients. (Id. at col. 2, 11. 39-49.)
`
`EP '766 relates to ophthalmic compositions comprising an antiallergic
`compound, such as lodoxamide, and an antihistamine. The compositions can
`also contain a preservative, such as benzalkonium chloride, as well as other
`components. (EP ‘766 at 3.) EP '766 provides an example formulation containing
`
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`December 15, 2014
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`Page 14
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`lodoxamide trornethamine and pheniramine maleate as active agents, as well as
`tyloxapol and benzalkonium chloride, among other things. (Id. at 4.)
`
`The ’609 patent discloses aqueous solutions, including eye drops, that
`contain pranlukast as the active ingredient. The ’609 patent discloses that
`tyloxapol is a good solubilizing agent for pranlukast. (’609 patent at col. 4, 1. 55 -
`col. 5, l. 32.) It also discloses that a pranlukast aqueous solution containing
`_
`tyloxapol and benzalkonium chloride (formulation A) had superior stability to a
`formulation containing polysorbate 80 and either no preservative or the stabilizer
`EDTA or BHT (formulations D, E and F). (Id. at col. 6, I. 47 — col. 7, l. 45.)
`
`Guy relates to suspensions for ophthalmic and other uses that contain
`corticosteroids, such as loteprednol etabonate as an active agent. These
`formulations contain additional excipient