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`£33337”.—
`
`MIAMI
`BOCA RATON
`PITTSBURGH
`NEWARK
`
`"’{S “‘6’“
`CHERRY HILL
`W“; TAHOE
`MYANMAR
`OMAN
`A GCC REPRESENTAm’E OFFICE
`0F DUANE MORRIS
`
`MEXJLCIJX
`0
`ALLIANCE WITH
`MIRANDA & ESTAVILLO
`
`| )uane |_\/_|orris°
`
`FIRM anIIAFFIUATE OFFICES
`
`VINCENT L. CAPUANO
`DIRECT DIAL: +1 857 488 4250
`PERSONAL FAX: +1 857 401 3002
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`
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`
`W "RANC'SC?
`““00" V“ L“
`W ”"360
`BOSTON
`HOUSTON
`LOS ANGELES
`HANOI
`
`HO CHI MINH CITY
`ATL
`A
`
`June 26, 20 14
`
`____—
`
`Chief Executive Officer
`
`Bausch & Lomb Incorporated
`1400 North Goodman St.
`
`Rochester, NY 14609
`
`Re: Notification Pursuant to § 505(j)(2)(B)(ii) of the Federal Food, Drug, and
`Cosmetic Act for US. Patent Nos. 8,129,431 and 8,669,290
`
`Dear Sir/Madam:
`
`We represent Coastal Pharmaceuticals, Inc. (“Coastal”). Coastal is providing notice of
`the following information pursuant to Section 505(j)(2)(B)(ii) of the Federal Food, Drug, and
`Cosmetic Act (“the Act”):
`
`1.
`
`In order to obtain approval to engage in the commercial manufacture, use,
`importation, offer for sale or sale of bromfenac sodium ophthalmic solution,
`0.07%, Coastal submitted to the Food and Drug Administration (“FDA”) an
`Abbreviated New Drug Application (“ANDA’ ’), which contains the required
`bioavailability or bioequivalence data or information.
`
`The ANDA number is 206257.
`
`The established name of the proposed drug product that is the subject of Coastal’s
`ANDAlS bromfenac sodium ophthalmic solution, 0.07%, marketed by Bausch &
`Lomb Incorporated (“B&L”) under the name PROLENSA®.
`
`The active ingredient in the proposed drug product that is the subject of Coastal’s
`ANDA No. 206257 is bromfenac sodium; the strength of the proposed drug
`
`Page 1 of 63
`
`SENJU EXHIBIT 2001
`METRICS v. SENJU
`IPR2014-01041
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`

`Bausch & Lomb Incorporated
`June 26, 2014
`Page 2
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`product is 0.07%; and the dosage form of the proposed drug products is an
`ophthalmic solution.
`
`5.
`
`Coastal’s ANDA No. 206257 includes Paragraph IV certifications to U.S. Patent
`Nos. 8,129,431 (“the ’431 patent”) and 8,669,290 (“the ’290 patent”)
`(collectively, the “Orange Book Patents”). These patents were identified to FDA
`and listed in the publication entitled Approved Drug Products with Therapeutic
`Equivalence Evaluation (“Orange Book”). According to the Orange Book, the
`’431 patent expires on September 11, 2025 and the ’290 patent expires on January
`16, 2024.
`
`Coastal contends, as provided in its certifications to FDA, that the claims of the ’431
`patent and the ’290 patent are invalid, unenforceable, and/or will not be infringed by the
`commercial manufacture, use, importation, offer for sale, or sale of the proposed drug product
`that is the subject of Coastal’s ANDA. Pursuant to 21 U.S.C. § 3550)(2)(B)(iv)(Il) and 21
`CPR. § 314.95(c)(6), a detailed statement of the factual and legal bases for the Paragraph IV
`certifications contained in Coastal’s ANDA No. 206257 with respect to the Orange Book Patents
`is attached hereto as Appendix A. This information is supplied for the sole purpose of
`complying with the above-referenced statutes and regulations. Coastal reserves the right to
`challenge the infringement, validity and/or enforceability of the Orange Book Patents on other
`and further grounds, should such grounds appear during any ensuing litigation.
`
`Pursuant to 21 CPR. § 314.95(e), Coastal requested and received from FDA permission
`to send this notice by means other than registered or certified mail.
`Specifically, Coastal
`requested that it be allowed to send this notice by FedEx®. FDA granted Coastal’s request prior
`to this notice being sent. Consequently, the operative date for determining the start of the 45-day
`clock gnder 21 U.S.C. §355(i)(5)(B)(iii) began from the receipt of this notice, as sent via
`FedEx .
`
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`

`Bausch & Lomb Incorporated
`June 26, 2014
`Page 3
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`An Offer of Confidential Access and Confidentiality Agreement (OCA) is attached
`hereto as Appendix B. Coastal does not waive any attomey-client privilege or work product
`immunity concerning the subject matter of this communication. Questions related to the OCA
`should be directed to the undersigned at (857) 488-4250 or vcapuano@duanemorris.com.
`
`Sincerely,
`
`W KY Putnam
`
`Vincent L. C puano
`
`Page 3 of 63
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`

`

`APPENDIX A
`
`COASTAL PHARMACEUTICALS, INC.’S DETAILED FACTUAL AND LEGAL BASIS
`IN SUPPORT OF ITS PARAGRAPH IV CERTIFICATIONS FOR
`
`BROMFENAC SODIUM OPHTHALMIC SOLUTION, 0.07%
`
`INTRODUCTION
`
`This document is the detailed factual and legal basis for Coastal’s certification that, in its
`opinion and to the best of its knowledge, US. Patent Nos. 8,129,431 (“the ’431 patent”) and
`8,669,290 (“the ’290 patent”) (collectively, the “Orange Book Patents”) are invalid,
`unenforceable, and/or will not be infringed by the commercial manufacture, use, or sale of the
`drug product described in Coastal’s ANDA. The right to raise additional noninfringement,
`invalidity, and unenforceability defenses is expressly reserved.
`
`COASTAL’S ANDA PRODUCT
`
`Coastal’s ANDA Product consists of an ophthalmic solution containing bromfenac
`sodium as the active pharmaceutical ingredient (0.07%). Coastal seeks approval for the use of its
`ANDA Product for the treatment of postoperative inflammation and reduction of ocular pain in
`patients who have undergone cataract surgery.
`
`The composition of Coastal’s ANDA Product may be disclosed pursuant to the terms set
`forth in the Offer of Confidential Access attached hereto as APPENDIX B.
`
`111.
`
`THE ORANGE BOOK LISTED PATENTS
`
`The Orange Book listing for PROLENSA® (Bromfenac Sodium Ophthalmic Solution,
`0.07%) contains the following patents:
`
`
`
`
`
`
`
`
`US. Patent No.
`
`8,129,431
`
`8,669,290
`
`GOVERNING LAW
`
`A.
`
`Claim Construction
`
`Ex iration Date
`
`Se ntember 11, 2025
`
`
`
`16, 2024
`Janu
`
`
`A court must first construe claims before determining whether they are valid or infringed.
`Amazon.com, Inc. v. Barnesandnoble.c0m, Inc., 239 F.3d 1343, 1351 (Fed. Cir. 2001); Markman
`v. Westview Instruments, Inc., 52 F.3d 967, 976, 996 n. 7 (Fed. Cir. 1995) (en banc). Claims
`must be construed the same way for determining validity and infringement. Id.
`
`The claim construction inquiry begins in all cases with the actual words of the claims.
`Phillips v. AWH Corp., 415 F.3d 1303, 1312 (Fed. Cir. 2005) (en banc). Claim terms are to be
`given their ordinary and customary meanings as they would have been understood by a person of
`
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`ordinary skill in the art in the context of the patent at the time of the invention, i.e., as of the
`effective filing date of the patent application. Id. at 1312—14. To properly interpret claim terms,
`the “intrinsic” record, including the claims, the specification, and the prosecution history must be
`considered. Id. at 1314—24. The claims must be read “in view of” and “so as to be consistent
`
`with” the specification, which is the “single best guide to the meaning of a disputed term.” Id. at
`1315-1316. The importance of the specification in claim construction derives from its statutory
`role of providing a “full” and “exact” description of the claimed invention. Id. at 1316.
`
`B.
`
`Infringement
`
`To literally infringe a United States Letters Patent, an accused product or process must
`meet each and every limitation of the patent claim exactly, including any functional limitations.
`See Corning Glass Works v. Sumitomo Elec., 868 F.2d 1251, 1258 (Fed. Cir. 1989). Any
`deviation from the claim precludes a finding of literal infringement. See, e. g., Cole v. Kimberly-
`Clark Corp., 102 F.3d 524, 532 (Fed. Cir. 1996).
`
`An analysis of literal infringement requires two inquiries: first, the claims must be
`construed to resolve their proper scope and meaning; and second, it must be determined whether
`the accused product or process falls exactly within the scope of the properly construed claims.
`See Markman, 52 F.3d at 976; see also Novo Nordisk ofN. Am., Inc. v. Genentech, Inc., 77 F.3d
`1364, 1368 (Fed. Cir. 1997). The first inquiry is a legal question for the court; the second
`inquiry is a factual determination for the fact-finder. See Markman, 52 F.3d at 976—80.
`
`Infringement may also be found under the doctrine of equivalents if the accused product
`or method includes features that are identical or equivalent to each claimed element. Warner—
`Jenkinson Co., Inc. v. Hilton Davis Chem. Co., 520 US. 17, 21, 40 (1997). The determination of
`equivalency, which is evaluated as of the time of infringement, is an objective inquiry applied on
`an element-by-element basis taking into account the role of each claim element in the context of
`the claim. Id. at 18, 29, 37, 40.
`
`The Supreme Court has not mandated any specific approach to evaluate equivalency. Id.
`at 39—40. Among the recognized approaches that may be applied, including the function-way-
`result test and the insubstantial differences test. Id. at 19—20, 25, 36, 39—40.
`
`There are a number of limitations on the application of the doctrine of equivalents. For
`example, the doctrine of equivalents cannot be applied so as to effectively eliminate a claim
`limitation in its entirety. Id. at 29. Moreover, limitations may not be afforded a scope of
`equivalency that effectively results in a claim that does not patentably distinguish the prior art.
`See, e.g., Wilson Sporting Goods Co. v. David Geoffrey & Assocs., 904 F.2d 677, 683 (Fed. Cir.
`1990), overruled on other grounds by Cardinal Chem. Co. v. Morton Int’l, 508 US. 83 (1993).
`Additionally, prosecution history estoppel operates to prevent recapture, through the doctrine of
`equivalents, of coverage of subject matter that was relinquished by amendment or argument
`during prosecution. Festo Corp. v. Shoketsu Kinzoku Kogyo Kabushiki Co., 535 US. 722, 733—
`34 (2002).
`
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`Although the sale of an apparatus to perform a patented method or process is not a direct
`infringement of a method or process claim, such a sale may nevertheless constitute an active
`inducement of infringement under 35 U.S.C. § 271(b) and/or a contributory infringement under
`35 U.S.C. § 271(c). See Joy Techs, Inc. v. Flakt, Inc., 6 F.3d 770, 774 (Fed. Cir. 1993).
`“Liability for either active inducement of infringement or for contributory infringement is
`dependent upon the existence of direct infringement.” Id. at 774; see also C.R. Bard, Inc. v.
`Advanced Cardiovascular Sys., Inc., 911 F.2d 670, 673 (Fed. Cir. 1990).
`
`Inducement of infringement is actively and knowingly aiding and abetting another’s
`direct infringement of a patent claim. See C.R. Bard, 911 F.2d at 675; DSU Med. Corp. v. IMS
`Co., Ltd., 471 F.3d 1293, 1306 (Fed. Cir. 2006). In order to find induced infringement, a
`patentee must show (i) direct infringement, either literally or under the doctrine of equivalents,
`(ii) that the alleged indirect infringer actually intended to cause another to directly infringe, (iii)
`that the alleged indirect infringer knew of the allegedly infringed patents, and (iv) that the
`accused inducer has knowledge that the induced acts constitute patent infringement. See 35
`U.S.C. § 271(b); see also Global-Tech Appliances Inc. v. SEB, 131 S. Ct. 2060 (May 31, 2011);
`DSU Med. Corp., 471 F.3d at 1304—05 (Fed. Cir. 2006) (en banc) (quoting Metro-Goldwyn-
`Mayer Studios, Inc. v. Grokster, Ltd., 545 US. 913, 936 (2005)). Also, “a good-faith belief of
`invalidity is evidence that may negate the specific intent to encourage another’s infringement,
`which is required for induced infringement.” Commil USA, LLC v. Cisco Systems, Inc., 720 F.3d
`1361, 1368 (Fed. Cir. 2013).
`
`Contributory infringement is knowingly making and/or selling a product for use in
`practicing a patented method or process, when that product is specifically designed for use in
`infringement of the patented method or process and has no substantial non-infringing uses. See
`Preemption Devices, Inc. v. Minn. Mining & Mfg. Co., 803 F.2d 1170, 1174 (Fed. Cir. 1986).
`
`C.
`
`Invalidity For Failure to Comply with 35 U.S.C. § 103(a)
`
`A patent may be proven invalid by a showing of clear and convincing evidence.
`Microsoft Corp. v. i4i Ltd. P’ship, 131 S. Ct. 2238, 2251 (2011).
`
`In the absence of a single anticipatory prior art reference, a claim may be invalidated by
`one or a combination of multiple prior art references 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.” 35 U.S.C. § 103(a). In determining obviousness, the
`following four factors must be considered: (1) the scope and content of the prior art; (2) any
`differences between the prior art and the claims at issue; (3) the level of ordinary skill in the
`pertinent art; and, (4) any secondary considerations evidencing nonobviousness, such as
`commercial success, copying, long felt but unsolved needs, failures of others, unexpected results,
`etc. See KSR, 550 US. at 406 (citing Graham v. John Deere Co. ofKan. City, 383 US. 1, 17—18
`(1966)).
`
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`In KSR, the U.S. Supreme Court confirmed that, in evaluating obviousness, “an
`expansive and flexible” approach is to be taken, i. e., “rigid and mandatory formulas” are
`improper. Id. at 419. More specifically, the Court stated that “[t]he combination of familiar
`elements according to known methods is likely to be obvious when it does no more than yield
`predictable results.” Id. at 416. Additionally, it is likely obvious to: (1) substitute one known
`element for another in a known structure to yield no more than a predictable result, (2) arrange
`old elements with each performing its same known function to yield no more than one would
`expect from the arrangement, (3) make a predictable variation in a known work, when there are
`design incentives or other market forces prompting the variation (either in the same or a different
`field) and a person of ordinary skill could have implemented the variation, and (4) use a known
`technique for improving one device to improve similar devices in the same way, if such use of
`the technique would be recognized by and within the capability of a person of ordinary skill in
`the art. Id. at 416—417. In these situations, a court must ask “whether the improvement is more
`than the predictable use of prior art elements according to their established functions.” Id.
`
`Relevant factors in determining the level of ordinary skill in the art include the
`educational level of active workers in the field, the type of problems encountered in the art, prior
`art solutions to such problems, the rapidity of innovations in the art, and the sophistication of the
`technology. See In re GPAC, Inc., 57 F.3d 1573, 1579 (Fed. Cir. 1995).
`
`In order for evidence of secondary considerations to be given substantial weight, the
`patentee must demonstrate that there is a nexus between such evidence and the merits of the
`claimed invention. Ormco Corp. v. Align Tee/1., Inc., 463 F.3d 1299, 1311—13 (Fed. Cir. 2006).
`In other words, such evidence must arise from the claimed invention, rather than from extrinsic
`influences such as unclaimed features, prior art features, marketing activities, FDA requirements,
`etc. Id.
`
`U.S. PATENT No. 8,129,431
`
`A.
`
`Overview
`
`1.
`
`The ’431 Patent
`
`The claims of the ’431 patent are directed to aqueous liquid preparations for ophthalmic
`administration. Claim 1 is reproduced 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
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`compound is included in said liquid preparation, the quaternary
`ammonium compound is benzalkonium chloride.
`
`(’431 patent, 11:66-12:101) (emphasis added).
`
`In pertinent part, claim 1 is directed to an aqueous liquid preparation for ophthalmic
`administration consisting essentially of just two components: (1) bromfenac (or its salts and
`hydrates); and (2) tyloxapol.2
`
`In the context of the ’431 patent, the “consisting essentially of” transitional phrase is
`construed to mean that the claimed ophthalmic formulations may include additional unrecited
`ingredients provided they do not materially affect the stability of the formulation “within a pH
`range giving no irritation to eyes, and change Of the [bromfenac] over time can be inhibited, and
`when the aqueous solution contains a preservative, deterioration in the preservative effect of
`said preservative can be inhibited for a long period of time.” (’431 patent, 2:34-47 & Abstract).
`The ’431 patent specification expressly allows for other ingredients to be present in the
`formulation, including a preservative, buffer, thickener, stabilizer, chelating agent, and pH
`controlling agent, or an additional active ingredient. (’431 patent, claims 7 and 8 and 6:42-44).
`
`2.
`
`Noninfringement
`
`As explained in more detail below, claims 5, 11-17, 21 and 22 of the ’431 patent do not
`claim Coastal’s proposed ANDA Product, and neither the filing of Coastal’s ANDA nor the
`manufacture, use, sale, offer for sale of Coastal’s ANDA Product would infringe these claims,
`either literally or under the doctrine of equivalents.
`
`3.
`
`Obviousness
`
`Claims 1-22 of the ’431 patent are unpatentable for failing to satisfy the nonobviousness
`requirement of 35 U.S.C. § 103. The alleged “inventions” involve no more than the (i) “simple
`and obvious substitution Of one known element for another to obtain predictable results” over
`what was already taught and used in the prior art; (ii) “choosing from a finite number of
`identified, predictable solutions,” with a reasonable expectation of success; and/or (iii) obvious
`modification of prior art teachings, with a reasonable expectation of success. As such, these
`claims fall squarely, and fatally, under KSR Int’l Co. v. Teleflex Inc., 550 US. 398, 417 (2007).
`
`1 Citations are as follows: X:YY-ZZ (col:lines; patent); X:Y:Z (page:col:para; journal article);
`X:Y (page:para; journal article).
`2 Claim 1 also recites that it may optionally include the commonly used preservative
`benzalkonium chloride (“BAC”). Because BAC is optional, prior art which shows that it was
`known or would be obvious to combine the two required components: (1) bromfenac (or its salts
`and hydrates); and (2) tyloxapol, would invalidate claim 1 without regard to the presence of
`BAC.
`
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`

`In essence the claims all are directed to an aqueous formulation of bromfenac (a non-
`steroidal anti-inflammatory drug (NSAID)) with tyloxapol (a non-ionic surfactant). Tyloxapol
`was a known non-ionic surfactant in aqueous formulations of NSAIDS and bromfenac was a
`known NSAID previously formulated with another non-ionic surfactant, polysorbate 80. Thus,
`the inventors of the aqueous preparations of the challenged claims of the ’431 patent simply
`switched tyloxapol for polysorbate 80 (both well-known non-ionic surfactants). Or viewed
`another way, the inventors of the challenged claims of the ’431 patent merely switched
`bromfenac for diclofenac (both well-known structurally similar NSAle). Swapping known
`alternatives from the prior art, according to their known functions to achieve predictable results,
`is not innovation.
`
`a.
`
`The Scope and Content of the Prior Art
`
`i.
`
`Aqueous Ophthalmic Preparations of Bromfenac
`
`Bromfenac, like diclofenac and ketorolac, was a well-known NSAID useful for treating
`inflammation in the eye. (See, e. g., Hara, Yoshiyuki , "Bromfenac sodium hydrate," Clinics &
`Drug Therapy 19:1014-1015 (2002) (“Hara”), 1014:1:2). Each of bromfenac, diclofenac and
`ketorolac are in the class of NSAIDs possessing a carboxylic acid group (—COOH), and as
`discussed below this class of NSAIDs was known to interact with BAC in aqueous ophthalmic
`formulations in a way that weakens the preservative efficacy of BAC. By January 21, 2003,
`bromfenac had been formulated with BAC along with non-ionic surfactants in aqueous
`preparations for ophthalmic delivery. As discussed in more detail below, the class of non-ionic
`surfactants includes tyloxapol and polysorbate 80, among others.
`
`For example, Ogawa et al., US. Patent No. 4,910,225 "Locally Administrable
`Therapeutic Composition for Inflammatory Disease" (“Ogawa”) described (and exemplified) an
`aqueous ophthalmic formulation containing (1) bromfenac, (2) polysorbate 80, and (3) BAC.
`(Ogawa, 925-10: 19; for other prior art references describing aqueous bromfenac ophthalmic
`preparation; see also Hara, Desai et al., US. Patent No. 5,603,929, "Preserved Ophthalmic Drug
`Compositions Containing Polymeric Quaternary Ammonium Compounds" (“Desai I”), Desai, et
`al., US. Patent No. 5,558,876, "Topical Ophthalmic Acidic Drug Formulations" (“Desai II”),
`"Bromfenac sodium hydrate" in the Japanese Pharmacopoeia 2001 Edition: 27-29, Yakuji
`Nippo Limited (2001) (“Bromfenac JP Pharmacopoeia”), FDA approved "BROMDAYTM
`(bromfenac ophthalmic solution, .09%) Product Label," U.S. Approval: March 24, 2005, ISTA
`Pharmaceuticals, Inc.) (“Bromday Label”).
`
`ii.
`
`Tyloxapol and Related Surfactants in NSAID Aqueous
`Ophthalmic Preparations
`
`By January 21, 2003, tyloxapol and related alkylaryl polyether surfactants were well-
`known non-ionic surfactants formulated in the prior art with NSAIDs. For example, Sallmann et
`al., US. Patent No. 6,107,343, "Ophthalmic And Aural Compositions Containing Diclofenac
`Potassium" (“Sallmann”) described liquid ophthalmic formulations containing (1) diclofenac
`sodium (an NSAID), (2) tyloxapol surfactant, and (3) BAC. (Sallmann, 8: 1-15).
`
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`Tyloxapol, like polysorbate 80, was successfully used to stabilize aqueous ophthalmic
`formulations as early as the 1960’s. (Sallmann, 4:62; Guttman et al., "Solubilization of Anti—
`inflammatory steroids by Aqueous Solutions of Triton—WR-1339," Journal ofPharnzaceutical
`Sciences 50: 305—307 (1961) (“Guttman”), 306:4-8). Notably, the prior art taught that tyloxapol
`was effective in stabilizing NSAIDs, like bromfenac. (Fu et al., Australian Patent No. AU—B—
`22042/88, "Preservative System For Ophthalmic Formulations" (“Fu”)). The prior art also
`disclosed examples where tyloxapol is a preferred non-ionic surfactant for use in ophthalmic
`formulations containing acidic NSAIDs, like bromfenac (Sallmann, 4:62), and where tyloxapol
`was superior to polysorbate 80 as a surfactant in aqueous liquid formulations of an acidic
`compound. (Yasueda et al., US. Patent No. 6,274,609, "Aqueous Liquid Pharmaceutical
`Composition Containing as Main Component Benzopyran Derivative" (“Yasueda”), 7:20-43). In
`the prior art a finite number of non-ionic surfactants, including tyloxapol and polysorbate 80, had
`been used in approved ophthalmic formulations (Yasueda, 4:51-63; Sallmann, 4:52—62).
`
`b.
`
`The Differences Between the Claims and the Prior Art
`
`The claims of the ’431 patent are obvious in view of the combination of primary prior art
`references, Ogawa and Sallmann. Each of Ogawa and Sallmann discloses a prior art
`ophthalmic formulation of an NSAID, BAC and a non-ionic surfactant, similar to what is
`claimed in the ’431 patent. The claims of the ’431 patent differ from prior art aqueous liquid
`ophthalmic formulations of an NSAID only in the replacement of bromfenac for another NSAID,
`or alternately, in the replacement of tyloxapol for another non-ionic surfactant (polysorbate 80),
`as illustrated in the following chart comparing the components of claim 1 of the ’431 patent with
`Example 6 from the Ogawa patent and Example 2 from the Sallmann patent.
`
`
`
`
`
`
`’43] Patent
`Claim 1
`
`Ogawa
`Example 6
`
`Sallmann
`Example 2
`
`Tyloxapol
`
`Polysorbate 80 Tyloxapol
`
`
`
`
`
`
`When viewed against the prior art, what becomes clear is that the inventors of the ’431
`patent did nothing more than swap one well-known component from a prior art formulation with
`another component known to be used for the same purpose. Thus, the inventors of the aqueous
`preparations of the claims of the ’431 patent simply switched tyloxapol for polysorbate 80 (both
`well-known non-ionic surfactants). Alternately, the inventors of the claims of the ’431 patent
`merely switched bromfenac for diclofenac (both well—known structurally similar NSAIDs).
`Swapping known alternatives from the prior art is not innovation. All the inventors of the ’431
`patent accomplished was the mere obvious replacement of known components, according to their
`known functions, to achieve predictable results. A person of ordinary skill in the art (“POSA”)
`
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`

`

`could have readily performed these simple component substitutions—tyloxapol for polysorbate
`80 or bromfenac for diclofenac—because the functions of these components were well known in
`the art and the results of the substitutions were predictable.
`
`And, finally, the prior art disclosed only a finite number of non—ionic surfactants for
`ophthalmic formulations, such that it would have been obvious to try substituting any of these
`known non-ionic surfactants (including tyloxapol) for polysorbate 80 to modify the teachings of
`Ogawa to arrive predictably at the claimed inventions, with a reasonable expectation of success.
`
`Sallmann disclosed ophthalmic formulations containing NSAIDs including diclofenac
`and ketorolac together with ethoxylated octylphenol surfactants including tyloxapol as the non-
`ionic surfactant. Sallmann’s ophthalmic formulation also included the preservative BAC. A
`POSA, therefore, would have been motivated to substitute bromfenac for diclofenac in
`
`Sallmann’s ophthalmic formulations to obtain predictable results because of the structural and
`functional similarities between bromfenac and diclofenac (Hara, 1015:2z2), including their
`similar interaction with BAC, and the known preference for bromfenac over diclofenac (Hara).
`The prior art also only disclosed a finite number of NSAIDs for ophthalmic application, such that
`it would have been obvious to try substituting any of these known anti—inflammatory compounds
`(including bromfenac) for diclofenac to modify the teachings of Sallmann and to arrive
`predictably at the claimed inventions, with a reasonable expectation of success. (Hara, 1014:2z3-
`1015 :1: 1).
`
`While some dependent claims of the ’431 patent recite more particular excipients,
`concentration ranges, and pH ranges, these nominal differences fall far short of imparting
`patentability as discussed below.
`
`B.
`
`The ’431 Patent and Claim Construction
`
`The ’431 patent issued on March 6, 2012, from US. App]. No. 10/525,006, a US.
`National Stage patent application of Patent Cooperation Treaty Appl. No. PCT/JP2004/000350,
`filed on January 16, 2004. Accordingly, the effective filing date (“EFD”) of the ’431 patent is
`January 16, 2004. The earliest possible priority date for the ’431 patent is January 21, 2003, the
`filing date of Japanese App]. No. 2003-12427. The ’431 patent specification is directed to
`aqueous liquid preparations containing 3-(4-bromobenzoyl)phenylacetic acid (“bromfenac”; the
`’431 patent, 1:24-36), tyloxapol, and optionally BAC. (the ’431 patent, 2:50—3:21).
`
`The following terms/phrases from the claims of the ’431 patent should be construed:
`“consisting essentially ofi ” “about,” and “ophthalmic.”
`
`1.
`
`“consisting essentially of”
`
`The phrase “consisting essentially 0]” applies to claims 1-22. Properly interpreted, this
`phrase includes the components recited in the claims and is also “open to unlisted ingredients
`that do not materially affect the basic and novel properties of the invention.” Ecolab, Inc. v.
`FMC Corp., 569 F.3d 1335, 1343 (Fed. Cir. 2009). According to the ’431 patent specification,
`
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`those properties are that “the [claimed] aqueous solution becomes stable within a pH range
`giving no imitation to eyes, and change Of the 2-amino-3—(4-bromobenzoyl)phenylacetic acid
`over time can be inhibited, and
`when the aqueous solution contains a preservative,
`deterioration in the preservative effect Of said preservative can be inhibited for along period of
`time” through the addition of tyloxapol. (the ’431 patent, 2:34-47 & Abstract). Thus, the
`claimed ophthalmic formulations may include additional unrecited ingredients provided they do
`not materially affect these properties.
`
`For example, claim 8 ultimately depends from claim 1. Accordingly, each of the specific
`additional ingredients recited in claim 8—boric acid, sodium borate, sodium sulfite, sodium
`edetate, polyvinylpyrrolidone, and sodium hydroxide—may be present in the liquid ophthalmic
`formulation of claim 1 and according to the ’431 patent would not be considered to materially
`affect the basic and novel properties of the invention. Likewise, claim 7, which also depends
`from claim 1, recites further permissible additives—“a preservative, buffer, thickener, stabilizer,
`chelating agent, and pH controlling agent”——each of which may also be present in the liquid
`ophthalmic preparation of claim 1 consistent with achieving the purpose of the invention, i. e., the
`purportedly novel features are not materially affected by the addition of the additives recited in
`claim 7. (the ’431 patent, 6: 1 1-30). Finally, the ’431 patent expressly states that “[510 long as
`the purpose of the present invention is achieved, other same or different kind of active
`ingredients may be appropriately added,” and thus contemplates that the claimed formulations
`may contain active ingredients in addition to bromfenac without materially affecting the novel
`features of the invention. (the ’431 patent, 6:42-44).
`
`2.
`
`“about”
`
`A POSA would understand that the term “about” as used in claims of the ’431 patent
`means that the values are as precise as the number of significant figures dictates. Therefore, to a
`POSA, “about 0.1 w/v%” includes a w/v% between 0.05-0.15 w/v%. Similarly, “about 0.2
`w/v%” includes a w/v% between 0.15-0.25 w/v%. A POSA would understand that these
`
`percentage values are derived from the weights and volumes measured to prepare the aqueous
`preparations, and without any special definition of “about” in the ’431 patent, a POSA would use
`the number Of significant figures to determine the precision of the claimed w/v% and the
`meaning of “about.”
`
`3.
`
`“ophthalmic”
`
`The claim term “ophthalmic” means “of or relating to the eyes.”
`
`C.
`
`The Person of Ordinary Skill in the Art (“POSA”)
`
`A POSA is a hypothetical person who is presumed to be aware Of all pertinent art, thinks
`along conventional wisdom in the art, and is a person of ordinary creativity. KSR, 550 US. at
`420. With respect to the ’431 patent, a POSA would have had education and/or experience in the
`field Of ophthalmic formulations and drug delivery, and knowledge of the scientific literature
`concerning the same, specifically pharmaceutical formulations for ophthalmic administration,
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`including those comprising anti—inflammatory compounds (such as NSAIDs) as of 2003. The
`education and experience levels may vary between persons of ordinary skill, with some persons
`holding a basic Bachelor’s degree, but with 5—10 years of relevant work experience, or others
`holding more advanced degrees—e.g., Pharm.D., Ph.D., or M.D.——but having fewer years of
`experience.
`
`A POSA may work as part of a multi—disciplinary team and draw upon not only his or her
`own skills, but also take advantage of certain specialized skills of others in the team, to solve a
`given problem.
`
`As of January 21, 2003, the state of the art pertinent to the ’431 patent was such that
`aqueous liquid preparations containing NSAIDs (including bromfenac) and tyloxapol were
`disclosed. For example, Desai I disclosed a formulation that included bromfenac and tyloxapol,
`and BAC, in addition to other ingredients. (Desai I, Abstract; 2: 18-23, 3:30-45, 6: 13—16 & 6: 25—
`28; see also, Kapin, et al., International Patent No. WC 2002/ 13804, "Method For Treating
`Angiogenesis-Related Disorders Using Benzoyl Phenylacetic Acid" (“Kapin”), 3: 1-23, 528-9 &
`7: 13-22, Formulation 3). It was also known that NSAID compounds were known to be suitable
`and desirable for ophthalmic administration (Flach, Allan, "Topical Nonsteroidal
`Antiinflammatory Drugs for Ophthalmic Uses," Ophthalmic NSAIDS: 77-83 (1996) (“Flach”),
`77: 1-10), and that the NSAlD bromfenac was specifically described in ophthalmic formulations
`in the prior art. (Hara). Likewise, ethoxylated octylphenol surfactants, including tyloxapol