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`SENJU EXHIBIT 2022
`LUPIN v. SENJU
`IPR2015-01100
`
`

`
`Pursuant to 21 U.S.C. § 355(i)(2)(B)(iv)(I) and 21 C.F.R. § 314.95(c)(1), we advise you
`that the FDA has received an Abbreviated New Drug Application (“ANDA”) from
`Apotex for Apotex’s Bromfenac sodium 0.07% ophthalmic solution/drops (“the Apotex
`Product”). The ANDA contains the required bioavailability and/or bioequivalence data
`and/or bioequivalence waiver. The ANDA was submitted under 21 U.S.C. §§ 355(j)(I)
`and (2)(A), and contains a paragraph IV certification to obtain approval to engage in the
`commercial manufacture, use or sale of the Apotex Product, before the expirations of the
`‘43 1,
`‘290, ‘I31, and ‘813 patents which are listed in the Patent and Exclusivity
`Information Addendum of the FDA’s Orange Book.
`
`Pursuant to 21 C.F.R. § 3 I4.95(c)(2), we advise you that the ANDA submitted by Apotex
`has been assigned the number 20-7334 by the FDA.
`
`Pursuant to 21 C.F.R. § 314.95(c)(3), we advise you that the established name of the drug
`product that is the subject of Apotex’s ANDA is Bromfenac ophthalmic solution (0.07%).
`
`Pursuant to 21 C.F.R. § 3l4.95(c)(4), we advise you that the active ingredient in the
`proposed drug product is known as bromfenac sodium; the strength of the proposed drug
`product is 0.07%; and the dosage form of the proposed drug product is ophthalmic
`solution/drops.
`
`Pursuant to 21 C.F.R. § 314.95(c)(5), we advise you that the patents alleged to be invalid
`and/or not infringed in the paragraph IV certification are the ‘431, ‘290, ‘I31, and ‘813
`patents, which are listed in the FDA’s Orange Book in connection with NDA N203168
`for PROLENSA® (bromfenac) 0.07% ophthalmic solution/drops.
`
`According to the electronic records of the FDA’s Orange Book, the ‘431 patent will
`expire on or about September 11, 2025; the ‘290, ‘I31 and ‘813 patents will expire on or
`about January 16, 2024.
`
`Apotex alleges, and has certified to the FDA, that in Apotex’s opinion and to the best of
`its knowledge, the ‘431, ‘290, ‘I31 and ‘813 patents are each invalid, unenforceable
`and/or will not be infringed by the commercial manufacture, use or sale of the drug
`product described in Apotex’s ANDA.
`Therefore, pursuant
`to
`21 U.S.C.
`§355(j)(2)(B)(iv)(II) and 21 C.F.R. §314.95(c)(6), Apotex’s detailed statement of the
`legal and factual basis for the paragraph IV certification set forth in Apotex’s ANDA is
`attached hereto and made a part hereof.
`
`A detailed statement of the factual and legal bases of our opinion that the claims of the
`‘431, ‘290, ‘ 131, and ‘813 patents are invalid, unenforceable and/or will not be infringed
`follows and is made part hereof
`In addition, Apotex reserves the right to demonstrate
`additional
`factual
`and legal bases
`concerning non-infringement,
`invalidity, or
`unenforceability should future information so warrant.
`
`Service of Process and Courtesy Copies:
`
`The following person is authorized to accept service of process for any patent infringement
`complaint that may result from this notification (and limited to such a complaint only):
`
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`
`Mr. Kiran Krishnan
`
`Vice-President, U.S. Regulatory Afi°airs
`Apotex Corp.
`2400 N. Commerce Parkway
`Weston, FL 33326
`Tel: (954) 384-8007
`
`As a professional courtesy, please send a copy of any such complaint:
`
`Mr. Robert Shapiro, Esq.
`Senior Global Lead Patent Attorney
`Global Intellectual Property Dept.
`Apotex Inc.
`150 Signet Drive
`Toronto, Ontario, Canada M9L 1T9
`Tel: (416) 401-7311
`
`Reservation of Legal Right
`Apotex reserves the right to assert the same, similar, different or new theories of non-
`rnfringement, invalidity and/or unenforceability and nothing in this Notice Letter or Detailed
`Statement shall be construed as to limit Apotex’s right to make any allegation in any
`subsequent litigation regarding any issue.
`
`Yours very truly,
`Apotex Inc.
`
`Dr. Ross Maclean
`
`Senior Vice-President, Scientific & Regulatory Affairs
`Apotex Inc.
`150 Signet Drive
`Toronto, Ontario, Canada M9L 1T9
`Tel : (416)401-7601
`Fax: (416)401-3808
`
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`I. Detailed Statement For ANDA 20-7334
`
`A.
`
`Introduction
`
`Pursuant to 21 U.S.C. § 355(j)(2)(B)(iv)(II) and 21 C.F.R. § 314.95(c)(6), this document
`is the detailed factual and legal bases for the paragraph IV certification of Apotex that, in
`its opinion and to the best of its knowledge, the claims of the ‘431, ‘290, ‘ 13 1, and ‘813
`patents are invalid, unenforceable and/or will not be infringed by the commercial
`manufacture, use or sale of the drug product described in Apotex’s ANDA 20-7334.
`Apotex reserves the right to raise additional factual and legal bases concerning non-
`infringement, invalidity, and/or unenforceability in any litigation or other proceeding.
`
`A.l
`
`The Apotex ANDA Product
`
`is an ophthalmic solution/drops containing as active
`The Apotex ANDA Product
`ingredient bromfenac. The strength of the proposed ANDA product is 0.07%.
`
`B.
`
`B.1
`
`Legal Standards
`
`Claim Construction
`
`It is a “bedrock principle” of patent law that “the claims of a patent define the invention
`to which the patentee is entitled the right to exclude.” Phillips v. AWH Corp., 415 F.3d
`1303, 1312 (Fed. Cir. 2005). The first step, claim construction, “is simply a way of
`elaborating the normally terse claim language in order to understand and explain, but not
`to change, the scope of the claims.” DeMarini Sports, Inc. v. Worth, Inc., 239 F.3d 1314,
`1322 (Fed. Cir. 2001) (citation omitted).
`
`The words of a claim “are generally given their ordinary and customary meaning,” i. e.,
`the meaning that the term would have to a person of ordinary skill in the art in question as
`of the effective filing date of the patent application. Phillips, 415 F.3d at 1312-13
`(citations omitted). Because the meaning of a claim term as understood by persons of
`skill in the art is often not immediately apparent, and because patentees frequently use
`terms idiosyncratically, courts look to “those sources available to the public that show
`what a person of skill in the art would have understood disputed claim language to
`mean,” which include “the words of the claims themselves,
`the remainder of the
`specification,
`the prosecution history, and extrinsic evidence concerning relevant
`scientific principles, the meaning of technical terms, and the state of the art.” Phillips,
`415 F.3d at 1314 (citations omitted).
`
`When construing a patent claim, a court first analyzes the intrinsic evidence of record—
`the claims, the specification, and the prosecution history, as such evidence is the most
`significant source of the legally operative meaning of a claim. Phillips, 415 F.3d at 1314-
`17; Markman v. Westview Instruments Inc., 52 F.3d 967, 980 (Fed. Cir. 1995) (en banc),
`a ’d 517 U.S. 370 (1996). While “words in a claim are generally given their ordinary
`and customary meaning, a[n] applicant may choose to be his own lexicographer and use
`tenns in a manner other than their ordinary meaning, as long as the special definition is
`
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`clearly stated in the patent specification or file history.” Vitronics Corp. v. Conceptronic,
`Inc., 90 F.3d 1576, 1582 (Fed. Cir. 1996); Phillips, 415 F.3d at 1316.
`
`The Federal Circuit has recognized that a court construing a patent claim may also utilize
`extrinsic evidence, such as expert testimony and technical dictionaries. Phillips, 415 F.3d
`at 1317. While extrinsic evidence on the issue of claim construction may be referenced,
`the Federal Circuit has held that it
`is “less significant than the intrinsic record in
`determining ‘the legally operative meaning of claim language.’”
`Id. On several
`occasions, the Federal Circuit has admonished courts construing patent claims for relying
`on extrinsic evidence because it “poses the risk that [the extrinsic evidence] will be used
`to change the meaning of claims in derogation of the ‘indisputable public records
`consisting of the claims,
`the specification and the prosecution history,’
`thereby
`undermining the public notice function of patents.”
`Id. at 1319 (citation omitted).
`Likewise, extrinsic evidence may not correct errors, erase limitations, or otherwise
`diverge from the description of the invention as contained in the patent documents.
`Aqua-Aerobic Sys., Inc. v. Aerators, Inc., 211 F.3d 1241, 1245 (Fed. Cir. 2000).
`
`A patentee carmot recapture in litigation claim scope surrendered, either by amendment
`or argument, during the prosecution of the patent. Pharmacia & Upjohn Co. v. Mylan
`Pharms., Inc., 170 F.3d 1373, 1376-77 (Fed. Cir. 1999). Because “[c]laims may not be
`construed one way in order to obtain their allowance and in a different way against
`accused infringers,” Southwall Techs., Inc. v. Cardinal IG Co., 54 F.3d 1570, 1576 (Fed.
`Cir. 1995), if a claim must be construed in a particular way to make the claimed subject
`matter patentable, it carmot be construed differently to cover an accused device if that
`construction would simultaneously include the prior art. This principle prevents a
`patentee from claiming that its patent claims cover subject matter for which the PTO was
`unwilling to issue a patent.
`It also gives courts guidance as to what claims or claim
`elements warrant a narrow scope. When a patentee urges a court to broadly construe or
`effectively “read out” claim limitations which, if so broadly construed or eliminated,
`would fail to differentiate a claim from the prior art, courts have a basis for rejecting such
`claim constructions. Id. at 1580-82; DeMarini, 239 F.3d at 1332.
`
`B.2.
`
`Infringement Analysis
`
`The first step to determining whether infringement exists is to construe the patent claim
`language. Second, the properly construed claims are compared to the accused product or
`process to determine whether it falls within the scope of the claims. Markman v.
`Westview Instruments, Inc., 52 F.3d 967, 976 (Fed. Cir. 1995), afi”d, 517 U.S. 370
`(1996).
`
`Literal infringement of a patent claim requires that the accused product contain each
`limitation of the claim. Litton Sys., Inc. v. Honeywell, Inc., 140 F.3d 1149, 1454 (Fed.
`Cir. 1998). Each limitation of the claim is essential; if one or more limitations or its
`equivalent carmot be found in the accused product or process, the claim is not infringed.
`London v. Carson Pirie Scott & C0,, 946 F.2d 1534, 1538-39 (Fed. Cir. 1991).
`
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`Infringement under the doctrine of equivalents requires the accused product to contain
`elements identical or equivalent to Q claim limitation recited in a claim of a patent.
`See Warner-Jenkinson Co. v. Hilton Davis Chemical Co., 520 U.S. 17, 29 (1997). Two
`primary approaches have been used for determining equivalents:
`(1) the “triple identity”
`approach; and (2) the “insubstantial differences” approach. The triple identity approach
`focuses on whether the substitute element of the accused product or process performs
`substantially the same function, in substantially the same way, to achieve substantially
`the same result as the claim limitation for which equivalents is at issue. Id at 1054. The
`insubstantial differences approach focuses on “whether the substitute element plays a role
`substantially different from the claimed element.” Id.
`
`Further, “the concept of equivalency cannot embrace a structure that is specifically
`excluded from the scope of the claims.” Dolly, Inc. v. Spaulding & Evenflo Co., Inc., 16
`F.3d 394, 400 (Fed. Cir. 1994). Once a patent issues, all limitations in a claim are
`material and must be met
`in the accused device or method — either exactly or
`equivalently. See Becton Dickinson and Co. v. C.R. Bard Inc., 922 F.2d 792, 798 (Fed.
`Cir. 1990). “There can be no infringement as a matter of law if a claim limitation is
`totally missing from the accused device.” London, 946 F.2d at 1539. “The doctrine of
`equivalents cannot be used to erase meaningful structural and functional limitations of the
`claim on which the public is entitled to rely in avoiding infringement.” Conopco, Inc. v.
`May Department Stores Co., 46 F.3d 1556, 1562 (Fed. Cir. 1994), cert. denied, 514 U.S.
`1078 (1995).
`“It
`is important
`to insure that
`the application of the doctrine [of
`equivalents], even as to an individual element,
`is not allowed such broad play as to
`effectively eliminate that element in its entirety.” Warner-Jenkinson, 520 U.S. at 29
`(1997); see Cooper Cameron Corp. v. Kvaerner Oilfield Products, Inc., 291 F.3d 1317,
`1321-22 (Fed. Cir. 2002) (There can be no infringement under the doctrine of equivalents
`when a limitation of a claim is missing—the claim required a port to be positioned
`“between” two plugs so there was no infringement by equivalents where the accused
`positioned the port “above” the two plugs). The scope of equivalents also may not
`encompass the prior art. Wilson Sporting Goods Co. v. David Geofiey & Assocs., 904
`F.2d 677, 684 (Fed. Cir. 1990) (“[S]ince prior art always limits what an inventor could
`have claimed, it limits the range of permissible equivalents of a claim”)).
`
`The patentee, as the author of the claim language, may be expected to draft claims
`encompassing readily known equivalents. Festo Corp. v. Shoketsu Kinzoku Kogyo
`Kabushiki Co., Ltd, 535 U.S. 722, 740 (2002). A patentee who narrows a claim by
`amendment during prosecution to satisfy a requirement of the Patent Act is presumed to
`have surrendered any equivalents in the territory between the original claim and the
`amended claim.
`Id.; see Deering Precision Instruments, LLC v. Vector Distributing
`Systems, Inc., 347 F.3d 1314, 1325 (Fed. Cir. 2003); Ranbaxy Pharmaceuticals Inc. v.
`Apotex, Inc., 350 F.3d 1235, 1241 (Fed. Cir. 2003). The presumption can be overcome if
`the equivalent was unforeseeable at the time of the application, the rationale underlying
`the amendment bears no more than a tangential relationship to the equivalent in question,
`or there was some other reason suggesting that the patentee could not reasonably be
`expected to have described the insubstantial
`substitute in question.
`Ranbaxy
`Pharmaceuticals, 350 F.3d at 1241 (citing and quoting in part, Festo Corp., 535 U.S. at
`
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`740-41). The question of whether the presumption has been rebutted is a question of law
`for a court.
`
`Prosecution history estoppel is premised upon the notion that “a patentee should not be
`able to obtain,
`through litigation, coverage of subject matter relinquished during
`prosecution.” Zenith Lab., Inc. v. Bristol-Myers Squibb Co., 19 F.3d 1418, 1424 (Fed.
`Cir. 1994). A patentee is estopped from recapturing coverage relinquished by argument
`or amendment during prosecution by application of the doctrine of equivalents. See
`Hormone Research Foundation, Inc. v. Genentech, Inc., 904 F.2d 1558, 1564 (Fed. Cir.
`1990), cert. dismissed, 49 U.S. 955 (1991); Loctite Corp. v. Ultraseal Ltd, 781 F.2d 861,
`870 (Fed. Cir. 1985); Southwall Techs., Inc. v. Cardinal IG C0., 54 F.3d 1570, 1582-84
`(Fed. Cir. 1995). cert, denied, 516 U.S. 987 (1995); Canton Bio-Medical,
`Inc. v.
`Integrated Liner Technologies, Inc., 216 F.3d 1367, 1371 (Fed. Cir. 2000) (patentee was
`barred from asserting that a single prior art component was an equivalent where the
`patentee had argued that its invention was a “particular primer solution” distinguished by
`its use of three specific components from the prior art); PODS, Inc. v. Porta Star, Inc.,
`484 F.3d 1359, 1368 (Fed. Cir. 2007) (arguments made to distinguish prior art as lacking
`a rectangular-shaped frame created a clear and unmistakable surrender of coverage for
`frames that were not rectangular or four-sided).
`
`. the prosecution history must evince a clear and
`.
`“To invoke argument-based estoppel .
`unmistakable surrender of subject matter.” PODS Inc. , 484 F.3d at 1368. Clear assertions
`made in support of patentability may create an estoppel, regardless of whether or not they
`were actually required for allowance of a claim.
`Id. The relevant inquiry is “whether a
`competitor would reasonably believe that the applicant had surrendered the relevant
`subject matter.” Id. Once an argument-based estoppel is created with regard to a claim
`term, the estoppel applies to that term in other claims. Id.
`
`B.3.
`
`Patent Invalidity
`
`Patent invalidity is a complete defense to a charge of infringement. See TypeRight
`Keyboard Corp. v. Microsoft Corp., 374 F.3d 1151, 1157 (Fed. Cir. 2004) (holding that a
`finding of invalidity is a complete defense to infringement); Viskase Corp. v. Am. Nat ’l
`Can C0., 261 F.3d 1316, 1323 (Fed. Cir. 2001) (same); see also Weatherchem Corp. v.
`JL. Clark, Inc., 163 F.3d 1326, 1335 (Fed. Cir. 1998) (“[I]nvalidity operates as a
`complete defense to infringement for any product, forever.”). A patent is invalid if it fails
`to satisfy any of the conditions for patentability found in 35 U.S.C. §§ 101 et seq.
`Furthermore, a patent claim may be invalid for being an obvious variation of a prior
`patented claim under
`the judicially-created doctrine of obviousness-type double
`patenting.
`
`B.4.
`
`Burden of Proof and Presumption of Validity
`
`“A patent, though
`The burden of proving invalidity rests with the party asserting it.
`presumed valid, 35 U.S.C. § 282 (1988), is actually a fragile entity, and must be propped
`up by a myriad of supports, each representative of one of the legal requirements of
`validity.
`If even a single one of these supports is removed, the patent will fall. For
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`. if it is found to be anticipated by a prior art
`.
`example, a patent may be declared invalid .
`reference, see id. § 102; if it is rendered obvious by a combination of the prior art, see id.
`§ 103; or if it fails to satisfy any one of a variety of other conditions.” Morton Int ’l, Inc.
`v. Cardinal Chem. Co., 5 F.3d 1464, 1471-72 (Fed. Cir. 1993) (Mayer, J., concurring.)
`
`The statutory presumption of validity merely assumes the PTO properly did its job by
`considering all prior art or other evidence material to patentability. See Lannom Mfg. Co.
`v. US. Int’l Trade Comm ’n, 799 F.2d 1572, 1575 (Fed. Cir. 1986). “[W]here the PTO
`has not considered facts relevant to an issue in suit, there is no reason to give deference to
`its action in issuing the patent and a court may find those facts controlling in determining
`whether the burden of proof has been sustained.” Kalman v. Kimberly-Clark Corp., 713
`F.2d 760, 773 n.3 (Fed. Cir. 1983), overruled on other grounds by SRI Int ’l v. Matsushita
`Elec. Corp. of Am., 775 F.2d 1107 (Fed. Cir. 1985). Thus, “[t]he courts are the final
`arbiter of patent validity and, although courts may take cognizance of, and benefit from,
`the proceedings before the patent examiner, the question is ultimately for the courts to
`decide, without deference to the rulings of the patent examiner.” Quad Envtl. Techs.
`Corp. v. Union Sanitary Dist., 946 F.2d 870, 876 (Fed. Cir. 1991).
`
`B.5.
`
`35 U.S.C. § l02—Anticipation
`
`Under 35 U.S.C. § 102, a person shall be entitled to a patent unless “the invention was
`known or used by others in this country, or patented or described in a printed publication
`in this or a foreign country, before the invention thereof by the applicant for patent,” 35
`U.S.C. § l02(a), or “the invention was patented or described in a printed publication in
`this or a foreign country .
`.
`. more than one year prior to the date of the application for
`patent in the United States,” Id. § 102(b).
`
`A patent claim is said to be anticipated (i.e., not novel) if comparison of the claim with a
`prior art reference reveals that every element of the claim is described, either expressly or
`inherently, in the prior art reference. See In re King, 801 F.2d 1324, 1326 (Fed. Cir.
`1986); Rockwell Int’l Corp. v. United States, 147 F.3d 1358, 1363 (Fed. Cir. 1998);
`Schering Corp. v. Geneva Pharms., 339 F.3d 1373, 1377 (Fed. Cir. 2003). “Under the
`principles of inherency, if the prior art necessarily fimctions in accordance with, or
`includes, the claimed limitations, it anticipates.” Mehl/Biophile Int ’l Corp. v. Milgraum,
`192 F.3d 1362, 1365 (Fed. Cir. 1999).
`
`B.6.
`
`35 U.S.C. § l03(a)—Obviousness
`
`Under 35 U.S.C. § 103(a), “[a] patent may not be obtained though the invention is not
`identically disclosed or described as set forth in section 102 of this title, if the differences
`between the subject matter sought to be patented and the prior art are such that the subject
`matter as a whole would have been obvious at the time the invention was made to a
`person having ordinary skill in the art to which said subject matter pertains.” See also
`KSR Int ’l Co. v. Teleflex Inc., 550 U.S. 398, 406 (2007).
`
`Obviousness is ultimately a legal conclusion, based upon underlying factual inquiries.
`McNeil-PPC, Inc. v. L. Perrigo Co., 337 F.3d 1362, 1368 (Fed. Cir. 2003). The required
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`(1) what is the level of ordinary skill in the pertinent art; (2)
`factual inquiry considers:
`what was the scope and content of the prior art; and (3) what are the differences between
`the prior art and the asserted claims. Graham v. John Deere Co., 383 U.S. 1, 17 (1966).
`Objective evidence of nonobviousness, i. e., so-called “secondary considerations,” if any,
`is considered where relevant. See id at 17-18; see also Stratoflex, Inc. v. Aeroquip Corp.,
`713 F.2d 1530, 1538-39 (Fed. Cir. 1983).
`
`in the art, the differences
`When, from the perspective of a person of ordinary skill
`between the prior art and the claimed invention as a whole would be obvious, a prima
`facie case of obviousness is established under § 103, thus rendering the subject claim
`invalid. See In re Dillon, 919 F.2d 688, 692-93 (Fed. Cir. 1990).
`
`Obviousness may be based on one or more references. However, either the prior art as a
`whole, or knowledge generally available to one of ordinary skill in the art, should suggest
`the desirability, and thus, the obviousness of combining and modifying the prior art to
`arrive at the claimed invention. See SIBIA Neurosciences, Inc. v. Cadus Pharm. Corp.,
`225 F.3d 1349, 1356 (Fed. Cir. 2000). This requirement for a showing of motivation to
`combine references ensures that a combination is not improperly made in hindsight. See
`In re Gartside, 203 F.3d 1305, 1318-19 (Fed. Cir. 2000). However, it is not necessary
`that the references be combined for the same reasons as the inventor.
`In re Beattie, 974
`F.2d 1309, 1312 (Fed. Cir. 1992) (“As long as some motivation or suggestion to combine
`the references is provided by the prior art taken as a whole, the law does not require that
`the references be combined for the reasons contemplated by the inventor”). Moreover, a
`“combination of familiar elements according to known methods is likely to be obvious
`when it does no more than yield predictable results.” KSR, 550 U.S. at 416. More
`specifically, “if a technique has been used to improve one device, and a person of
`ordinary skill in the art would recognize that it would improve similar devices in the
`same way, using the technique is obvious unless its actual application is beyond his or her
`skill.” Id at 417.
`
`Yet, the mere fact that results are not entirely predictable in advance, and must be
`confirmed through testing, does not mean that subject matter is non-obvious. “[A] rule of
`law equating unpredictability to patentability” is improper because “the expectation of
`success need only be reasonable, not absolute.” See Pfizer, Inc. v. Apotex, Inc., 480 F.3d
`1348, 1364 (Fed. Cir. 2007). That is, “obviousness carmot be avoided simply by a
`showing of some degree of unpredictability in the art so long as there was a reasonable
`probability of success.” Id
`
`Where “there is a design need or market pressure to solve a problem and there are a finite
`number of identified, predictable solutions, a person of ordinary skill has good reason to
`pursue the known options within his or her technical grasp.” KSR, 550 U.S. 421. “If this
`leads to the anticipated success, it is likely the product not of innovation but of ordinary
`skill and common sense.” Id In such instances “the fact that a combination was obvious
`to try might show that it was obvious under § 103.” Id.
`
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`C.
`
`C.l.
`
`The Orange Book Patents with a Paragraph IV Certification
`
`U.S. Patent No. 8,129,431
`
`is entitled: “Aqueous Liquid Preparation Containing 2-Amino-3-(4-
`The ‘431 patent
`Bromobenzoyl)-Phenylacetic Acid,” assigned to Senju Pharmaceutical Co, Ltd., was filed
`on February 17, 2005, as a national
`stage application of International Appl. No.
`PCT/JP04/00350, filed on January 16, 2004 and claiming priority to Japanese Appl. No. JP
`2003-12427, filed January 21, 2003. The ‘431 patent was allowed December 23, 2011 and
`issued on March 6, 2012. The ‘431 patent will expire on September 11, 2025 based on a
`term of 20 years from the international filing date (January 16, 2004) and an allotted Patent
`Term Adjustment of 604 days. The ‘431 patent lists Shirou Sawa and Shuhei Fujita as
`inventors.
`
`(4-
`is directed to stable aqueous liquid preparations of 2-amino-3-
`The ‘431 patent
`bromobenzoyl)phenylacetic acid (bromfenac) or its salts or hydrates in combination with an
`alkyl aryl polyether alcohol type polymer such as tyloxapol, or a polyethylene glycol fatty
`acid ester, such as polyethylene glycol monostearate.
`
`According to the Background of the Invention, bromfenac and its salts and hydrates were
`known in the art as NSAIDs effective against inflammatory diseases of the eye such as
`blepharitis, conjunctivitis, scleritis, and postoperative inflammation. The ‘431 patent admits
`that eye drop compositions containing the sodium salt of bromfenac were known from U.S.
`Patent No. 4,910,225, where the bromfenac was stabilized in solution with a water soluble
`polymer (e.g., polyvinylpyrrolidone, polyvinyl alcohol, etc.) and a sulfite (e.g., sodium
`sulfite, potassium sulfite, etc.). Additionally,
`the ‘431 patent notes that a bromfenac
`ophthalmic composition containing antibacterial quaternary ammonium polymers and boric
`acid was also known. However, the ‘431 patent states that the prior art is silent regarding
`the ability of alkyl aryl polyether alcohol type polymers and a polyethylene glycol fatty
`acid esters to stabilize aqueous liquid preparations of bromfenac or its salts or hydrates.
`
`The aqueous compositions of the ‘431 patent, which include bromfenac or its salts or
`hydrates in combination with alkyl aryl polyether alcohol type polymers, are said to be
`stable within a pH range giving no irritation to the eyes such that
`the decrease of
`bromfenac in the composition over time is reduced. Additionally, the alkyl aryl polyether
`alcohol
`type polymers are said to inhibit the decrease in preservative effects of, e.g.,
`benzalkonium chloride when it is also included in the aqueous composition.
`
`Pharmaceutically acceptable salts of bromfenac are said to include alkali metal salts such as
`the sodium salt and the potassium salt, and alkali earth metal salts such as the calcium salt
`and the magnesium salt. The ‘431 patent also discloses bromfenac obtained as its hydrate,
`including its U2 hydrate, 1 hydrate, and 3/2 hydrate. The concentration of bromfenac (or its
`salts or hydrates) in the aqueous compositions is said to be usually about 0.01 to 0.5 wfv %,
`preferably about 0.05 to 0.2 %, and especially about 0.1 wlv %.
`
`type polymer. The
`is noted as a preferred alkyl aryl polyether alcohol
`Tyloxapol
`concentration of tyloxapol incorporated into the aqueous compositions of the ‘431 patent is
`
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`said to be from a minimum of 0.01 w/v % to a maximum of 0.5 w/v %, with the range of
`0.02 to 0.05 w/v % being preferred.
`
`The preservatives to be used in the compositions of the ‘431 patent include quaternary
`ammonium salts, of which benzalkonium chloride is said to be especially preferred.
`Additionally, according to the ‘431 patent, “so long as the purpose of the present invention is
`achieved, conventional various additives such as isotonics, buffers, thickeners, stabilizers,
`chelating agents, pH controlling agents, perfumes and the like may be appropriately
`added to the aqueous liquid preparation.” The isotonics to be used include boric acid; the
`buffers
`include
`borate
`buffers,
`boric
`acid,
`and
`borax;
`the
`thickeners
`include
`polyvinylpyrrolidone and polyvinyl alcohol; the stabilizers include sulfites such as sodium
`sulfite; the chelating agents include sodium edetate; and the pH controlling agents include
`sodium hydroxide.
`
`The compositions of the ‘431 patent can be prepared by dissolving the above-mentioned
`components in, for example, distilled water or sterile purified water. The ‘431 patent states
`that these compositions can be made into the form of an eye drop which can be used for the
`treatment of inflammatory diseases in the anterior or posterior segment of the eye such as
`blepharitis, conjunctivitis, scleritis, postoperative inflammation, and the like. The dose of the
`aqueous
`composition
`containing
`0.1
`w/v % of
`sodium
`2-amino-3-(4-
`bromobenzoyl)phenylacetate hydrate is said to be, for example, administered to an adult 3 to
`6 times daily in an amount of 1 to 2 drops per administration.
`
`to stabilize bromfenac in solution, eye drop
`To demonstrate the ability of tyloxapol
`compared with a
`composition containing
`compositions containing tyloxapol were
`polysorbate 80 instead. The make-up of these eye drop compositions is listed in Table 1:
`
`TABLE 1
`
`
`Comparison
`Component
`Example 1
`A-01
`A-02
`A-03
`
`
`0.1 g
`
`Sodium 2-amino-3-(4-
`bromobenzoyl)
`phenylacetate
`1.5 g
`Boric acid
`Benzalkonium chloride 0.005 g
`Polysorbate 80
`0.15 g
`Polyoxyl 40 stearate
`—-
`Tyloxapol
`—
`Sterile purified water
`q.s.
`Total volume
`100 mL
`
`0.1 g
`
`0.1 g
`
`0.1 g
`
`1.5 g
`0.005 g
`—
`0.15 g
`—
`q.s.
`100 mL
`
`1.5 g
`0.005 g
`—
`—-
`0.15 g
`q.s.
`100 mL
`
`1.5 g
`0.005 g
`-
`—
`0.02 g
`q.s
`100 mL
`
`pH
`Remaining rate
`(%) at 60° C.
`after 4 weeks
`
`
`7.0
`73.8
`
`7.0
`89.6
`
`7.0
`51.3
`
`7.0
`63.7
`
`With reference to Table 1, the ‘431 patent states that compositions containing tyloxapol
`(i.e., A-02 and A-03) were more stable than those containing polysorbate 80 with regard to
`bromfenac loss when those compositions were heated to 60 °C for 4 weeks. Additional
`
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`Page 11 of 63
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`

`
`formulations said to be stable in the ‘431 patent are shown in Table 2, of which
`composition A-04 (below) was shown to be the most stable of those containing tyloxapol:
`
`
`
`
`
`
`
`
`
`
`
`(%)
`
`
`
`
`
`
`Com osition A-04
`I'Il:—
`I: oric Acid
`l'.Il:—
`
`
`
`
`
`
`Ez-
`
`Composition A-04 was tested against several bacteria and fungi to study its preservative
`effect. The composition is said to be compatible with EP-criteria A in the European
`Pharmacopeia. The
`‘006 specification concludes with three examples of eye drop
`compositions, of which the composition of Example 1
`is formulated using the same
`ingredients and amounts as that of composition A~04 above.
`
`C.1.1.
`
`The Claims of the ‘431 Patent
`
`The ‘431 patent issued with twenty-two claims. Claims 1 and 18 are the sole independent
`claims and are provided below:
`
`1. An aqueous liquid preparation consisting essentially of the following
`two components, wherein the first component
`is 2-amino-3-(4-
`bromobenzoyl)phenylaceticacid 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 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.
`
`18. An aqueous liquid preparation consisting essentially of: (a) 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, (b) tyloxapol,
`(c) boric acid,
`((1) sodium tetraborate, (e) EDTA sodium salt, (f)
`benzalkonium chloride, (g) polyvinylpyrrolidone, (h) sodium sulfite,
`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.
`
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`
`C.1.2.
`
`Prosecution History of the ‘431 Patent
`
`The ‘431 patent was filed in the United States as a national stage application of
`PCT/JP04/00350 (published as WO 2004/094828); it contained 18 claims. In a March 20,
`2007 Preliminary Amendment, the original claims were cancelled and replaced with claims
`directed to aqueous liquid preparations (claims 19-38), methods for stabilizing bromfenac by
`incorporating tyloxapol or polyethylene glycol monostearate into an aqueous
`liquid
`preparation (claim 39), and methods for inhibiting a decrease in the preservative effect of a
`preservative
`in
`an
`aque