Merchant & Gould
`
`An Intellectual Property Law Finn
`
`I 0 E3st Doty Strtct
`Suite 600
`M3dison, WISConsin
`53703 USA
`
`TU 608.280.6750
`fAX 612.332.9081
`www.merchamgould com
`
`A Proltssian.al Corporauon
`
`SENT BY FEDERAL EXPRESS
`
`IJ!mt Canuct 1
`
`Jclli'l:y S Ward
`JWard@mcrchantgould com
`608·280-675 I
`
`January 20, 2015
`
`J. Michael Pearson, CEO
`Bausch & Lomb Incorporated
`1400 North Goodman Street
`Rochester, NY 14609
`
`Yukoh Yoshida, President & CEO
`Senju Pharmaceutical Co., Ltd.
`2-5-8, Hirano-machi, Chuo-ku
`Osaka, Japan
`
`Re:
`
`Paragraph IV certification, notice letter, and offer of confidential access for
`Bromfenac Sodium Ophthalmic Solution/ Drops EQ 0.07% Acid, Paddock
`Laboratories, LLC ANDA No. 207584.
`Dear Sir:
`I am writing to inform you that Paddock Laboratories, LLC ("Paddock")
`has submitted an abbreviated new drug application to the United States Food
`and Drug Administration (FDA) containing one or more "paragraph IV"
`certifications in order to obtain approval to engage in the commercial
`manufacture, use, or sale of bromfenac sodium ophthalmic solution/ drops, EQ
`0.07% acid ("the Paddock product").
`Paddock's abbreviated new drug application ("Paddock's ANDA" or "the
`application") was submitted pursuant to 21 U.S.C. § 3550) and received by the
`FDA. Paddock's ANDA contains any required bioavailability or bioequivalence
`data or information.
`Paddock's ANDA has been assigned No. 207584.
`The established name of the drug product is bromfenac sodium
`ophthalmic solution/ drops. The active ingredient, strength, and dosage forms of
`the proposed drug product are: bromfenac sodium EQ 0.07% acid, ophthalmic
`solution/ drops.
`
`Knoxville
`
`Madison
`
`Minneapolis
`
`New York
`
`~alllc:
`
`Washington DC
`
`Page 1 of 26
`
`SENJU EXHIBIT 2021
`LUPIN v. SENJU
`IPR2015-01099
`
`

`
`Bausch & Lomb
`Senju Pharmaceutical Co., Ltd.
`January 20, 2015
`Page2
`
`The application included a certification under§ 3550)(2)(A)(vii)(IV) for
`United States Patent No. 8,927,606 ("the '606 patent"). Paddock has certified that
`in its opinion and to the best of its knowledge, the claims of the '606 patent 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 '606 patent expires on January 16, 2024.
`
`As required by 21 U.S.C. § 3550)(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. §
`3550)(5)(C)(iii).
`
`Pursuant to 21 C.F.R. § 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]. Pardon, JeffreyS. Ward, or Wendy M. Ward
`Merchant & Gould PC
`10 E. Doty Street, Suite 600
`Madison, WI 53703-3376
`
`DETAILED STATEMENT
`
`I.
`
`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. Markman v. Westview Instruments, Inc., 52 F.3d 967, 979 (Fed. Cir. 1995),
`affd, 517 U.S. 370 (1996). The interpretation to be given a claim is formed by the
`claim language itself, the language of the other claims in the patent, the
`specification of the patent, the prior art, and the prosecution history. SRI Int'l v.
`Matsushita Elec. Corp., 775 F.2d 1107, 1118 (Fed. Cir. 1985). Claim terms are
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`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. I d. at
`1314. The prosecution history should also be consulted. I d. 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 1ns Group, Inc., 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 claim1s 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 lnt' l, Inc. v.
`Cardinal Cllem. 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 & 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. SmithKline Diagnostics, Inc. v. 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 11the accused
`product or process contain[s] elements identical or equivalent to each claimed
`element of the patented invention. 11 Wamer-Jenkinson Co. v. Hilton Davis Chem.
`Co., 520 U.S. 17, 40 (1997). In applying the doctrine of equivalents, one considers
`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. Wamer-jenkinson Co., 62 F.3d 1512,
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`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. Penmoalt Corp. v. Durand(cid:173)
`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. Pemzwnlt, 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. v. David Geoffrey 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. johnson & johnston Assocs., Inc. v. R.E. Serv. Co., 285 F.3d
`1046 (Fed. Cir. 2002) (en bane). Furthermore, a patentee cannot assert the
`doctrine of equivalents where to do so would "vitiate" or completely read a
`limitation out of a claim. Wamer-]enkinson Co., 520 U.S. 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).
`
`Obviousness
`C.
`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. ]olzn Deere Co., 383 U.S. 1, 17-18
`(1966). These fact issues are: (1) the scope and content of the prior art; (2) the
`differences between the claimed invention and the prior art; (3) the level of
`ordinary skill in the art; and (4) secondary considerations, including unexpected
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`results and commercial success. KSR lnt'l 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. at418-19. 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. !d. 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. Jd. at 421.
`
`II.
`
`Description of the '606 Patent
`
`Background
`A.
`The '606 patent is entitled 11 Aqueous Liquid Preparation Containing 2-
`Amino-3(4-Bromobenzoyl)Phenylacetic Acid." The patent issued on January 6,
`2015 from U.S. application No. 14/ 493,903(11 the '903 application"). The '903
`application was a divisional of U.S. Application No. 14/261,720 ("the '720
`application"), now U.S. Patent No. 8,871,813, which was filed on April 25, 2014 as
`a divisional of the U.S. Application No. 14/165,976 ("the '976 application"), now
`the U.S. Patent No. 8,754,131. The '976 application was filed on January 28, 2014,
`as a divisional of U.S. Application No. 13/687,242 ("the '242 application"), now
`U.S. Patent No. 8,669,290. The '242 application was filed on November 28, 2012 as
`a divisional of U.S. Application No. 13/353,653 ("the '653 application"), now U.S.
`Patent No. 8,497,304. The '653 application was filed on January 19, 2012 as a
`divisional of the U.S. Application No. 10/525,006 ("the '006 application"), which
`became U.S. Patent No. 8,129,431. The '006 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 '606 patent lists Shirou Sawa and Shuhei Fujita as
`inventors. It is assigned to Senju Pharmaceutical Co., Ltd. (11Senju"). The '813
`patent expires January 16, 2024, according to the entry in the Orange Book.
`Claims
`B.
`The '606 patent contains thirty claims, three of which are independent:
`claims 1,11 and 19. These claims are reproduced below.
`1. A method for treating an inflammatory disease of an eye,
`the method comprising administering to said eye a stable
`aqueous liquid preparation that comprises: (a) a first
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`component; and (b) a second component; wherein the first
`component is 2-amino-3-( 4-bromobenzoyl)phenylacetic
`acid or a pharmacologically acceptable salt thereof or a
`hydrate thereof, wherein the hydrate is at least one selected
`from a 1/2 hydrate, 1 hydrate, and 3/2 hydrate; the first
`component is the sole pharmaceutical active ingredient
`contained in the preparation; the second component is
`tyloxapol and is present in said liquid preparation in an
`amount sufficient to stabilize said first component; wherein
`said stable liquid preparation is fonnulated tor ophthalmic
`administration; and wherein said liquid preparation is
`administered to said eye at a dose and a frequency effective
`to treat said inflammatory disease.
`
`11. A method for treating an inflammatory disease of an
`eye, the method comprising administering to said eye a
`stable aqueous liquid preparation that comprises: (a) a first
`component; and (b) a second component; wherein the first
`component is 2-amino-3-( 4-bromobenzoyl)phenylacetic
`acid or a phannacologically acceptable salt thereof or a
`hydrate thereof, wherein the hydrate is at least one selected
`from a 1/2 hydrate, 1 hydrate, and 3/2 hydrate; the first
`component is the sole phannaceutical active ingredient
`contained in the preparation; the second component is
`tyloxapol; wherein said stable liquid preparation is
`fonnulated for ophthalmic administration; wherein the
`stable aqueous liquid preparation is characterized in that
`greater than about 90% of the original amount of the first
`component remains in the preparation after storage at about
`60.degree. C. for 4 weeks; and wherein said liquid
`preparation is administered to said eye at a dose and a
`frequency effective to treat said inflammatory disease.
`
`19. A method for treating an inflammatory disease of an
`eye, the method comprising administering to said eye a
`stable aqueous liquid preparation that comprises: (a) a first
`component; and (b) a second component; wherein the first
`component is 2-amino-3-( 4-bromobenzoyl)phenylacetic
`acid or a pharmacologically acceptable salt thereof or a
`hydrate thereof, wherein the hydrate is at least one selected
`from a 1/2 hydrate, 1 hydrate, and 3/2 hydrate; the first
`component is the sole pharmaceutical active ingredient
`contained in the preparation; the second component is
`tyloxapol; wherein said stable liquid preparation is
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`formulated for ophthalmic administration; provided that the
`liquid preparation does not include mannitol; and wherein
`said liquid preparation is administered to said eye at a dose
`and a frequency effective to treat said inflammatory
`disease.
`Claims 2-10 and 28 are ultimately dependent on claim 1. Claim 2 requires
`that the inflammatory disease is a disease of the interior or posterior segment of
`the eye, while claim 3 requires that the disease is postoperative inflammation.
`Claim 4 requires that bromfenac sodium be used, while claim 5 limits the
`tyloxapol concentration to from about 0.01 w I v % to about 0.5 w I v% and the
`bromfenac sodium concentration to from about 0.01 wlv% to about 0.2 w lv %.
`Claims 6 and 8 further limit the bromfenac sodium concentration, while claim 7
`requires that the preparation include a quaternary ammonium compound. Claim
`9 adds additional excipients and specifies the same bromfenac sodium
`concentration as claim 6. Finally, claim 28 requires that the liquid preparation
`meet certain preservative efficacy standards of EP-criteria B of the European
`Pharmacopoiea.
`Claims 12-18 and 29 are ultimately dependent on claim 11. Claim 12
`requires that greater than about 92% of the bromfenac remains in the preparation
`after storage at about 60°C. for four weeks. Claim 13 requires that the
`inflammatory disease is a disease of the interior or posterior segment of the eye,
`while claim 14 requires that the disease is postoperative inflammation. Claim 15
`limits the tyloxapol concentration to from about 0.01 w lv% to about 0.5 w lv%
`and the brornfenac sodium concentration to from about 0.05 w I v% to about 0.2
`w lv%. Claim 16 further limits the bromfenac sodium concentration, while claim
`17 requires that the preparation include a quaternary ammonium compound.
`Claim 18 adds additional excipients and specifies the same bromfenac sodium
`concentration as claim 16. Finally, claim 29 requires that the liquid preparation
`meet certain preservative efficacy standards of EP-criteria B of the European
`Pharmacopoiea.
`Claims 20-27 and 30 are ultimately dependent on claim 19. Claim 20
`requires that the inflammatory disease is a disease of the interior or posterior
`segment of the eye, while claim 21 requires that the disease is postoperative
`inflammation. Claim 22 requires that bromfenac sodium be used, while claim 23
`limits the tyloxapol concentration to from about 0.01 wlv% to about 0.5 wlv%
`and the bromfenac sodium concentration to from about 0.01 w lv% to about 0.2
`w lv%. Claim 24 further limits the brornfenac sodium concentration, while claim
`25 adds additional excipients and specifies the same bromfenac sodium
`concentration as claim 24. Claim 26 requires that greater than about 90% of the
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`bromfenac remains in the preparation after storage at about 60°C. for four weeks,
`while claim 27limits the tyloxapol concentration to from about 0.01 w /v% to
`about 0.5 w jv% and the bromfenac sodium concentration to from about 0.01
`w jv% to about 0.2 w jv%. Finally, claim 30 requires that the liquid preparation
`meet certain preservative efficacy standards of EP-criteria B of the European
`Pharmacopoiea.
`
`C.
`
`Specification
`
`The Background Section of the '606 patent specification states that
`bromfenac and its salts and hydrate are known as nonsteroidal anti(cid:173)
`inflammatory drugs (NSAIDs), and are effective against inflammatory diseases
`of the anterior or posterior segment of the eye, as well as postoperative
`inflammation of the eye. ('606 patent at col. 1, 11. 19-39.) It also states that
`bromfenac sodium has been used in the form of eye drops. (I d. at col. 1, 11. 39-41.)
`The specification further states that benzalkonium chloride and other quaternary
`ammonium compounds are generally considered to be incompatible with
`ophthalmic drug compositions with acidic groups, such as NSAIDs, because the
`preservatives form complexes with the drug compounds and lose their ability to
`function. (I d. at col. 1, 11. 57-63.) 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, 11. 6-14.)
`
`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. (I d. at col. 2, 11. 26-35.) 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.
`(Id. at col. 2, 11. 35-41.)
`
`The specification contains several Examples. In Experimental Example 1,
`various aqueous preparations containing bromfenac sodium and other
`excipients, including benzalkonium chloride and one of polysorbate 80,
`tyloxapol, or polyoxyl40 stearate (a polyethylene glycol monostearate) were
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`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
`polyoxyl40 stearate was the second most stable, and the preparation with
`polysorbate 80 was the least stable. ('606 patent at col. 6, l. 46- col. 7, l. 17.) The
`inventors also concluded that the preparation containing 0.02 w I v% tyloxapol
`was more stable than that containing 0.15 w /v% tyloxapol. (I d. at col. 7, I. 18-22.)1
`
`Experimental Example 2 tested the stability of various liquid preparations
`containing bromfenac sodium and other excipients, including benzalkonium
`chloride and one of tyloxapol or polyoxyl40 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)2 or
`polyoxyl40 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 wjv% tyloxapol, while the other contained 0.02 w jv%
`polyoxyl40 stearate. The specification states that these results showed that the
`preparations met various EP preservative criteria. ('606 patent at col. 8, l. 30- col.
`9, 1. 50.)
`
`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 polyoxyl40 stearate. (ld. at col. 9, 1. 51 -col. 10, I. 59.)
`
`D.
`
`Prosecution history
`1.
`The '006 Application
`
`The '006 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
`
`1 The preparations containing polysorbate 80 contained it in a concentration of 0.15
`w /v%, while the preparation containing polyoxyl40 stearate also contained that
`compound in a concentration of 0.15 w jv %.
`
`~ According to the specification, these amounts equate tow/ v%, e.g., 0.02 g tyloxapol is
`equal to 0.02 wjv % tyloxapol.
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`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 wfv% 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
`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)
`WO 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.
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`Addressing the obviousness rejections, the applicants argued that
`Gamache discloses 5-HT 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
`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 bromfenac, 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
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`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
`bromfenac 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.
`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 bromfenac or a salt or hydrate, tyloxapol, boric acid, sodium
`tetraborate, EDT A 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 No. 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 January 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 U.S. Patent No. 5,540,930 to
`Guy ("Guy") and in some instances in further view of Gamache.
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`The applicants responded on September 6, 2011. There, they contended
`that Yanni did not disclose bromfenac, 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 bromfenac 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.
`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 prep