(12) United States Patent
`Gamache et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,638,976 B2
`Oct. 28, 2003
`
`US006638976B2
`
`(54) METHOD OF TREATING
`NEURODEGENERATIVE DISORDERS OF
`THE RETINA AND OPTIC NERVE HEAD
`
`GB
`GB
`W0
`W0
`
`2 071 086 A
`2 093 027 A
`W0 00/40087
`WO 01/28474 A1
`
`9/1981
`8/1982
`7/2000
`4/2001
`
`OTHER PUBLICATIONS
`.
`.
`.
`.
`N
`RaW]1 et al., “Quantification of Concanavalin—A Mediated
`Retinal Edema Using Scanning Laser Tomography Derived
`Edema Maps,” Investigative, Ophthalmology. Ana’ Wsaal.
`Science, The Association for Research in Vision and Oph-
`thalmology, vol. 41(4):871 (2000).
`Sancilio et al., “AHR—10037, a non—steroidal anti—inflam-
`matory compound of low gastric toxicity,” Agents and
`Actions, V01, 31(1/2), pp, 117-126 (1990),
`Walsh et al., “Antiinflammatory Agents. 4. Syntheses and
`Biological
`Evaluation
`of
`Potential
`Prodrugs
`of
`2—Amino—3—benzoylbenzeneacetic
`Acid
`and
`2—Amino—3—(4—chlorobenzoyl)benzeneacetic Acid,”
`J.
`Med. Chem., Vol. 33; pp. 2296-2304 (1990).
`Walsh et al.,.“Antiinflammatory Agents. 3. Syntheses and
`Pharmacological
`Evaluation
`of
`2—Amino—3—benzoylphenylacetic Acid and Analogues,” J.
`M a’. Ch
`.,
`1.27 11 ,
`. 1379-1388 1984 .
`Gfaff et :1.” ‘Ti10Vitro(Cliagaioterization of the Oc)ular Bioac-
`tivation arid Permeation of External Ocular Barriers of
`Nepafenac, a Potent Topical Ocular NSAID with Long
`Duration of Action,” Investigative, Ophthalmology. And
`Wsaal. Science, TheAssociatioh for Research in Wsioh and
`0phthalm0l0gy,V01~ 41(4):1892 (2000).
`Kapin et al., “Inhibition of Concanavalin—A Mediated Pan
`Retmai Edema BY Nepafenacaii1”V€‘§”S00V0‘» 0Phlh0im0i'
`ogy. Ana’ Wsual. Science, The Association for Research in
`Vision and Ophthalmology, vol. 41(4):1887 (2000).
`Ke et al. “Nepafenac, A Unique Nonsteroidal Prodrug with
`Potential Utility in the Treatment of Trauma—Induced Ocular
`Inflammation: II. In Vitro Bioactivation and Permeation of
`
`External Ocular Barriers,” Inflammation, V01 24(4), P11
`371-384 (2000)
`Clark et al., “Ocular Angiostatic Agents,” Exp. Opin. Ther.
`Pa[e}1[S,V01. 10(4), pp, 427-448 (2000),
`Gamache et a1.’ “Nepafenac, A Unique Nonsteroidal Ami_
`Inflammatory Prodrug With Potential Utility In The Treat-
`_
`~
`1,
`Emmi t.Oft.TraugnahtI,:1‘iluCe;i ACi2iedO;’,il1arlI“§ia.mmai1"1{;;
`AW“ ig“. ‘V2
`If
`‘i 20.053‘ . ” d
`lcieilicea
`16
`550C“”‘0”f0’
`959079 "1 W0” 0”
`P ’ “"10 0gY>"°~
`41(4)I1892 (2000)
`.
`.
`Gamache et al., “Nepafenac, A Unique Nonsteroidal Pro-
`drug With Potential Utility in the Treatment of Trauma—In-
`duced Ocular Inflammation: I. Assessment of Anti—Inflam-
`Hlatory EffiCaCy”’ Inflammation’ V01
`(2000).
`
`* cited by examiner
`
`.
`.
`Primary Examiher—Phy111s G. Spivack
`(74) Attorney, Agent, or Firm—Teresa J. Schultz
`
`(57)
`
`ABSTRACT
`
`The use of 3-benzolphenylacetic acids and derivatives,
`including nepafenac, to treat neurodegenerative retinal dis-
`orders is disclosed
`'
`
`12 Claims, N0 Drawings
`
`LUPIN EX 1035
`
`(75)
`
`Inventors: Daniel A. Gamache, Arlington, TX
`(US); Gustav Grafi', Cleburne, TX
`(US); John M, Yanni, Bnrleson, TX
`(US); Michael A, Kapin, Arlington, TX
`(US)
`
`(73) Assignee: Alcon, Inc., Hunenberg (CH)
`
`(*) Notice:
`
`Subject to any disclaimer, the term Of this
`patent is extended or adjusted under 35
`U30 154(1)) by 0 days.
`
`(21) Appi, No; 09/929,704
`.
`F0003
`
`(22)
`(65)
`
`A“8- 13: 2001
`Prim. Publication Data
`
`(oo)
`
`Us 2002/0049255 A1 APr~ 25; 2002
`Reiaied US‘ Application Data
`Piovisioiiai appiioaiioii No‘ oo/225>i32> flied on Aug‘ i4>
`2000'
`Int. Cl.7 ............................................ .. A61K 31/216
`(51)
`(52) U.s. Cl.
`..................... .. 514/532; 514/534; 514/561;
`514/562; 514/563; 514/564; 514/617; 514/618;
`514/619
`(58) Field of Search ............................... .. 514/532, 534,
`514/561, 562, 563, 564, 617, 618, 619
`
`(56)
`
`References Cited
`
`U'S' PATENT DOCUMENTS
`
`............... .. 260/469
`8/1974 Bays et al.
`3,828,093 A
`8/1977 Welstead, Jr. etal.
`.... .. 424/309
`4,045,576 A
`11/1978 Welstead, Jr. et al.
`.... .. 562/441
`4,126,635 A
`1/1980 Welstead, Jr. et al.
`.... .. 424/309
`4,182,774 A
`3/1981 Walsh . ...................... .. 424/309
`4,254,146 A
`§‘i]iatiii‘ti)iii> ii‘ oi ai' "
`2
`a er ury ................ ..
`,
`,
`3/1985 Walsh et al.
`.. 514/539
`4,503,073 A
`2/1986 Moran et al.
`.. 514/648
`4,568,695 A
`7/1987 Poser
`....................... .. 514/539
`4,683,242 A
`11/1988 Brune ...................... .. 514/563
`4,783,487 A
`7/1939 Brune ,,,,,,,,, N
`514/553
`4,351,443 A
`3/1990 Ogawa et al.
`.. 514/561
`4,910,225 A
`12/1991 Bundgaard et al.
`560/56
`5,073,641 A
`Dollerup . . . . . . . . . . ..
`A
`.. 514/619
`12/1995 Yanni et al.
`..... ..
`5,475,034 A
`.. 514/458
`9/1998 Hellberg et al.
`5,811,438 A *
`514/399
`9/1998 Thomas .............. ..
`5,811,446 A
`.. 514/210
`2/2000 Masferrer et al.
`.
`6,025,353 A
`5/2000 Yanni et al.
`.............. .. 514/619
`6,066,671 A
`5/2000 Kuriyama et al.
`........ .. 514/100
`6,069,139 A
`1/2002 Hellberg et al.
`.......... .. 514/530
`6,342,524 B1
`FOREIGN PATENT DOCUMENTS
`
`
`
`DE
`EP
`EP
`EP
`EP
`
`*
`
`3026402
`0 320 015 A1
`1 064 949 A2
`1 064 964 A2
`1 064 965 A2
`
`2/1982
`0/1000
`1/2001
`1/2001
`1/2001
`
`Page 1 of7
`
`LUPIN EX 1035
`
`Page 1 of 7
`
`

`
`US 6,638,976 B2
`
`1
`METHOD OF TREATING
`NEURODEGENERATIVE DISORDERS OF
`THE RETINA AND OPTIC NERVE HEAD
`
`below.
`
`This application claims priority to U.S. Provisional
`Application, Serial No. 60/225,132, filed Aug. 14, 2000.
`
`FIELD OF THE INVENTION
`
`This invention relates to the treatment of retinopathy. In
`particular,
`this invention relates to the use of certain
`3-benzoylphenylacetic acids and derivatives to treat or pre-
`vent neurodegenerative disorders of the retina and optic
`nerve head.
`
`BACKGROUND OF THE INVENTION
`
`3-benzoylphenylacetic acid and certain of its derivatives
`are known to possess anti-inflammatory activity. U.S. Pat.
`Nos. 4,254,146, 4,045,576, 4,126,635, and 4,503,073, and
`U.K. Patent Application Nos. 2,071,086A and 2,093,027A
`disclose various 3-benzoylphenylacetic acids, salts and
`esters, and hydrates thereof, having anti-inflammatory activ-
`ity. U.S. Pat. No. 4,568,695 discloses 2-amino-3-
`benzoylphenylethyl alcohols having anti-inflammatory
`activity. U.S. Pat. No. 4,313,949 discloses 2-amino-3-
`benzoyl-phenylacetamides having anti-inflammatory activ-
`ity.
`Certain derivatives of 2-amino-3-benzoylbenzeneacetic
`acid (amfenac) and 2-amino-3-(4-chloro-benzoyl)
`benzeneacetic acid have also been evaluated by Walsh et al.,
`J. Med Chem., 33:2296—2304 (1990),
`in an attempt
`to
`discover nonsteroidal anti-inflammatory prodrugs with
`minimal or no gastrointestinal side effects upon oral admin-
`istration.
`
`U.S. Pat. No. 4,683,242 teaches the transdermal admin-
`istration of 2-amino-3-benzoylphenylacetic acids, salts, and
`esters, and hydrates and alcoholates thereof to control
`inflammation and alleviate pain.
`U.S. Pat. No. 4,910,225 teaches certain benzoylpheny-
`lacetic acids for local administration to control ophthalmic,
`nasal or otic inflammation. Only acetic acids are disclosed in
`the ’225 patent; no esters or amides are mentioned or taught
`as anti-inflammatory agents for local administration to the
`eyes, nose and ears.
`U.S. Pat. No. 5,475,034 discloses topically administrable
`compositions containing certain amide and ester derivatives
`of 3-benzyolphenylacetic acid, including nepafenac, useful
`for treating ophthalmic inflammatory disorders and ocular
`pain. According to the ’035 patent at Col. 15, lines 35-39,
`“[s]uch disorders include, but are not limited to uveitis,
`scleritis, episcleritis, keratitis, surgically-induced inflamma-
`tion and endophthalmitis.”
`U.S. Pat. No. 6,066,671 discloses the topical use of
`certain amide and ester derivatives of 3-benzoylphenylacetic
`acid, including nepafenac, for treating GLC1A glaucoma.
`SUMMARY OF THE INVENTION
`
`It has now been found that certain 3-benzoylphenylacetic
`acids and derivatives,
`including nepafenac (2-amino,3-
`benzoyl-phenylacetamide), are useful in treating neurode-
`generative disorders of the retina and optic nerve head.
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`The 3-benzoylphenylacetic acids and derivatives useful in
`the methods of the present invention are those of formula (I)
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Page 2 of 7
`
`(1)
`
`
`
`R=H, C1_4 (un)branched alkyl, CF3, SR4
`Y=OR‘, NR"R';
`
`R'=H, C140 (un)branched alkyl, (un)substituted aryl
`(substitution as defined by X below), (un)substituted
`heterocycle (substitution as defined by X below),
`—(CH2)nZ(CH2)n'A§
`n=2—6;
`n'=1—6;
`
`Z=nothing, O, C=O, OC(=O), C(=O)O, C(=O)NR3,
`NR3C(=O), S(O)n2, CHOR3, NR3;
`n2=0—2;
`R3=H, C1_6 (un)branched alkyl, (un)substituted aryl
`(substitution as defined by X below), (un)substituted
`heterocycle (substitution as defined by X below)
`A=H, OH, optionally (un)substituted aryl (substitution as
`defined by X below),
`(un)substituted heterocycle
`(substitution as defined by X below), —(CH2)nOR3;
`R“=H, OH, OR‘
`X and X‘ independently=H, F, Cl, Br, I, OR‘, CN, OH,
`S(O)n2R4, CF3, R4, N02;
`R4=C1_6 (un)branched alkyl;
`m=0—3;
`m'=0—5;
`W=O, H.
`As used herein, the acid (Y=OH) includes pharmaceuti-
`cally acceptable salts as well.
`Preferred compounds for use in the methods of the present
`invention are those of Formula I wherein:
`
`R=H, C1_2 alkyl;
`Y=NR‘R“;
`
`R'=H, C1_6 (un)branched alkyl, —(CH2)nZ(CH2)n.A;
`Z=nothing, O, CHOR3, NR3;
`R3=H;
`A=H, OH, (un)substituted aryl (substitution as defined by
`X below);
`X and X‘ independently=H, F, Cl, Br, CN, CF3, OR‘, SR4,
`R ;
`R“=H;
`
`R4=C1_4 (un)branched alkyl;
`m=0—2;
`m'=0—2;
`W=H;
`n=2—4;
`n‘=0—3.
`
`The most preferred compounds for use in the composi-
`tions or method of the present invention are 2-Amino-3-(4-
`fluorobenzoyl)-phenylacetamide; 2-Amino-3-benzoyl-
`
`Page 2 of 7
`
`

`
`3
`
`US 6,638,976 B2
`
`phenylacetamide (nepafenac); and 2-Amino-3-(4-
`chlorobenzoyl)-phenylacetamide.
`According to the present
`invention, a therapeutically
`effective amount of a compound of formula (I) is adminis-
`tered topically, locally or systemically to treat or prevent
`neurodegenerative disorders of the retina and optic nerve
`head. Such disorders include, but are not limited to atrophic
`macular degeneration; retinitis pigmentosa; iatrogenic ret-
`inopathy; retinal tears and holes; diabetic retinopathy; sickle
`cell retinopathy; retinal vein and artery occlusion; and optic
`neuropathy. Certain ophthalmic disorders, such as sickle cell
`retinopathy and retinal vein or artery occlusion, can be
`characterized by both angiogenesis and neurodegenerative
`components. According to the present invention, a com-
`pound of formula (I) is administered to treat or prevent
`disorders characterized, at least in part, by neurodegenera-
`tion.
`The compounds of formula (I) can be administered in a
`variety of ways, including all forms of local delivery to the
`eye, such as subconjunctival injections or implants, intrav-
`itreal
`injections or
`implants, sub-Tenon’s injections or
`implants, incorporation in surgical irrigating solutions, etc.
`Additionally, the compounds of formula (I) can be admin-
`istered systemically, such as orally or intravenously. Suitable
`pharmaceutical vehicles or dosage forms for
`injectable
`compositions,
`implants, and systemic administration are
`known. The compounds of formula (I) and especially those
`wherein Y=NR‘R“, however, are preferably administered
`topically to the eye and can be formulated into a variety of
`topically administrable ophthalmic compositions, such as
`solutions, suspensions, gels or ointments.
`Pharmaceutical compositions comprising a compound of
`formula (I) in aqueous solution or suspension, optionally
`containing a preservative for multidose use and other con-
`ventionally employed ophthalmic adjuvants, can be topi-
`cally administered to the eye. The most preferred form of
`delivery is by aqueous eye drops, but gels or ointments can
`also be used. Aqueous eye drops, gels and ointments can be
`formulated according to conventional technology and would
`include one or more excipients. For example,
`topically
`administrable compositions may contain tonicity-adjusting
`agents, such as mannitol or sodium chloride; preservatives
`such as chlorobutanol, benzalkonium chloride,
`polyquaternium-1, or chlorhexidine; buffering agents, such
`as phosphates, borates, carbonates and citrates; and thick-
`ening agents, such as high molecular weight carboxy vinyl
`polymers,
`including those known as carbomers,
`hydroxyethylcellulose, or polyvinyl alcohol.
`The doses of the compounds of formula (I) used in the
`treatment or prevention of neurodegenerative disorders of
`the retina and optic nerve head will depend on the type of
`disorder to be prevented or treated, the age and body weight
`of the patient, and the form of preparation/route of admin-
`istration. Compositions intended for
`topical ophthalmic
`administration will typically contain a compound of formula
`(I) in an amount of from about 0.001 to about 4.0% (w/v),
`preferably from about 0.01 to about 0.5% (w/v), with 1-2
`drops once to several times a day. Likewise, representative
`doses for other forms of preparations are approximately
`1-100 mg/day/adult for injections and approximately
`10-1000 mg/adult for oral preparations, each administered
`once to several times a day.
`Additional therapeutic agents may be added to supple-
`ment the compounds of formula
`The following examples are presented to illustrate various
`aspects of the present invention, but are not intended to limit
`the scope of the invention in any respect. The percentages
`are expressed on a weight/volume basis.
`EXAMPLE 1
`
`The following formulations are representative of the
`topical compositions useful in the present invention.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Formulation 1
`
`Compound of formula (I)
`Polysorbate 80
`Benzalkonium Chloride
`Disodium EDTA
`Monobasic Sodium Phosphate
`Dibasic Sodium Phosphate
`Sodium Chloride
`pH adjustment with NaOH and/or HCl
`Water
`
`0.01-0.5%
`0.01%
`0.01% + 10% excess
`0.1%
`0.03%
`0.1%
`q.s. 290-300 mOsm/Kg
`pH 4.2-7.4
`q.s. 100%
`
`Formulation 2
`
`Compound of formula (I)
`Hydroxypropyl Methylcellulose
`Polysorbate 80
`Benzalkonium Chloride
`Disodium EDTA
`Dibasic Sodium Phosphate
`Sodium Chloride
`pH adjustment with NaOH and/or HCl
`Water
`
`0.01-0.5%
`0.5%
`0.01%
`0.01% + 5% excess
`0.01%
`0.2%
`q.s. 290-300 mOsm/Kg
`pH 4.2-7.4
`q.s. 100%
`
`Formulation 3
`
`Nepafenac
`Carbopol 974P
`Tyloxapol
`Glycerin
`Disodium EDTA
`Benzalkonium Chloride
`pH adjustment with NaOH and/or HCl
`Water
`
`0.1 + 6% excess
`0.08%
`0.01%
`2.4%
`0.01%
`0.01%
`pH 7.5 1 0.2
`q.s. 100%
`
`This invention has been described by reference to certain
`preferred embodiments; however, it should be understood
`that it may be embodied in other specific forms or variations
`thereof without departing from its special or essential char-
`acteristics. The embodiments described above are therefore
`considered to be illustrative in all respects and not
`restrictive, the scope of the invention being indicated by the
`appended claims rather than by the foregoing description.
`We claim:
`
`1. Amethod of treating or preventing a neurodegenerative
`disorder of the retina or optic nerve head in a patient
`suffering from or predisposed to such a disorder which
`comprises administering to the patient a therapeutically
`effective amount of 3-benzoylphenylacetic acid or deriva-
`tive of the formula:
`
`
`
`Page 3 of 7
`
`Page 3 of 7
`
`

`
`US 6,638,976 B2
`
`wherein
`
`5
`
`R=H, C1_4 (un)branched alkyl, CF3, SR4;
`Y=OR‘, NR“R‘;
`R'=H, CH0 (un)branched alkyl, aryl, aryl substituted
`by X, heterocycle, heterocycle substituted by X,
`—(CH2)nZ(CH2)n~A;
`n=2—6;
`n'=1—6;
`Z=nothing, 0, C-0, OC(—O), C(—O)O, C(—O)
`NR3, NR3C(=O), S(O)2, CHOR3, NR3;
`n2=0—2;
`R3=H, C1_6 (un)branched alkyl, aryl, aryl substituted by
`X, heterocycle, heterocycle substituted by X;
`A=H, OH, aryl, aryl substituted by X, heterocycle,
`heterocycle substituted by X, —(CH2)nOR3;
`R“=H, OH, OR‘;
`X and X‘ independently=H, F, Cl, Br, I, OR‘, CN, OH,
`S(O)n2R4, CF3, R4, N02;
`R4=C1_6 (un)branched alkyl;
`m=0—3;
`m‘=0—5; and
`W=O, H.
`2. The method of claim 1 wherein
`
`R=H, C1_2 alkyl;
`Y=NR‘R“;
`
`R‘=H, C1_6 (un)branched alkyl, —(CH2)nZ(CH2)n,A;
`Z=nothing, O, CHOR3, NR3;
`R3=H;
`A=H, OH, aryl, aryl substituted by X;
`
`X and X‘ independently=H, F, Cl, Br, CN, CF3, OR‘, SR4,
`R4;
`Ru=H;
`
`R4=C1_4 (un)branched alkyl;
`m=0—2;
`m‘=0—2;
`W=H;
`n=2—4; and
`n‘=0—3.
`3. The method of claim 2 wherein the
`
`3-benzoylphenylacetic acid or derivative is selected from the
`group consisting of 2-Amino-3-(4-fluorobenzoyl)-
`phenylacetamide; 2-Amino-3-benzoyl-phenylacetamide;
`and 2-Amino-3-(4-chlorobenzoyl)-phenylacetamide.
`4. The method of claim 1 wherein the
`
`3-benzoylphenylacetic acid or derivative is topically admin-
`istered to the eye.
`5. The method of claim 4 wherein the therapeutically
`effective amount of 3-benzoylphenylacetic acid or deriva-
`tive is from about 0.001 to about 4.0% (w/v).
`6. The method of claim 1 wherein the
`
`3-benzoylphenylacetic acid or derivative is administered
`orally,
`intravenously,
`in a subconjunctival
`injection or
`implant, in a sub-Tenon’s injection or implant, in an intra-
`vitreal injection or implant, or in a surgical irrigating solu-
`tion.
`
`7. A method of providing neuroprotection to the retina or
`optic nerve head in a patient suffering from or predisposed
`to a neurodegenerative disorder of the retina or optic nerve
`head said method comprising administering to the patient a
`therapeutically effective amount of 3-benzoylphenylacetic
`acid or derivative of the formula:
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`
`
`wherein
`
`R =H, C1_4 (un)branched alkyl, CF3, SR4
`Y=OR', NR"R‘;
`R'=H, CH0 (un)branched alkyl, alkyl substituted by X,
`heterocycle, heterocycle substituted by X,
`—(CH2)nZ(CH2)n~A;
`n=2—6;
`n‘=1—6;
`Z=nothing, O, C=O, OC(=O), C(=O)O, C(=O)
`NR3, NR3C(=O), S(O)n2, CHOR3, NR3;
`n2=0—2;
`R3=H, C1_6 (un)branched alkyl, aryl, aryl substituted by
`X, heterocycle, heterocycle substituted by X;
`A=H, OH, aryl, aryl substituted by X, heterocycle,
`heterocycle substituted by X, —(CH2)nOR3,
`R“=H, OH, OR‘;
`X and X‘ independently=H, F, Cl, Br, I, OR‘, CN, OH,
`S(O)n2R4, CF3, R4, N02;
`R4=C1_6 (un)branched alkyl;
`m=0—3;
`m‘=0—5; and
`W=O, H;
`wherein the disorder is selected from the group consisting
`of atrophic macular degeneration;
`retinitis pigmentosa;
`iatrogenic retinopathy;
`retinal tears and holes;
`diabetic retinopathy;
`sickle cell retinopathy;
`retinal vein and artery occlusion; and
`optic neuropathy.
`8. The method of claim 7 wherein
`
`R=H, C1_2 alkyl;
`Y=NR‘R“;
`R'=H, C1_6 (un)branched all<yl,—(CH2)nZ(CH2)n.A;
`Z=nothing, O, CHOR3, NR3;
`R3=H;
`A=H, OH, aryl, aryl substituted by X;
`X and X‘ independently=H, F, Cl, Br, CN, CF3, OR‘, SR4,
`R ;
`R“=H;
`
`R4=C1_4 (un)branched alkyl;
`m=0—2;
`m'=0—2;
`W=H;
`n=2—4; and
`n‘=0—3.
`9. The method of claim 8 wherein the
`
`3-benzoylphenylacetic acid or derivative is selected from the
`group consisting of 2-Amino-3-(4-fluorobenzoyl)-
`phenylacetamide;
`
`Page 4 of 7
`
`Page 4 of 7
`
`

`
`US 6,638,976 B2
`
`7
`2-Amino-3-benzoyl-phenylacetamide; and
`2_Amin0-3_(4_Chlorobenzoy1)_pheny1aCetamide.
`10, The method of claim 7 wherein the
`3-benzoylphenylacetic acid or derivative is topically admin-
`istered to the eye.
`11. The method of claim 10 wherein the therapeutically
`effective amount of 3-benzoylphenylacetic acid or deriva-
`tive is from about 0.001 to about 4.0% (W/v).
`
`8
`o f claim 7 Wh e r e in th e
`1 2 . Th e m e t h o d
`3-benzoylphenylacetic acid or derivative is administered
`orally,
`intravenously,
`in a subconjunctival
`injection or
`implant, in a sub-Tenon’s injection or implant, in an intra-
`5 vitreal injection or implant, or in a surgical irrigating solu-
`t1on.
`
`*
`
`*
`
`*
`
`*
`
`*
`
`Page 5 of 7
`
`Page 5 of 7
`
`

`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`CERTIFICATE OF CORRECTION
`
`PATENT NO.
`DATED
`INVENTOR(S)
`
`: 6,638,976 B2
`: October 28, 2003
`: Gamache et a1.
`
`Page 1 of 1
`
`It is certified that error appears in the above—identified patent and that said Letters Patent is
`hereby corrected as shown below:
`
`
`Column 5
`
`Line 2, delete “SR4” and add —— SR4
`
`Signed and Sealed this
`
`Second Day of March, 2004
`
`WW4)»
`
`JON W. DUDAS
`Acting Director ofthe United States Patent and Trademark O}j"ice
`
`Page 6 of 7
`
`Page 6 of 7
`
`

`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`CERTIFICATE OF CORRECTION
`
`PATENT NO.
`DATED
`INVENTOR(S)
`
`: 6,638,976 B2
`: October 28, 2003
`: Gamache et a1.
`
`Page 1 of 1
`
`It is certified that error appears in the above—identified patent and that said Letters Patent is
`hereby corrected as shown below:
`
`Title page,
`Item [57], ABSTRACT, change “3—benz01pheny1acetic” to —— 3—benz0y1pheny1acetic
`
`Signed and Sealed this
`
`Thi1rty—first Day of May, 2005
`
`A WQIJW
`
`JON W. DUDAS
`Director ofthe United States Patent and Trademark O}j"ice
`
`Page 7 of 7
`
`Page 7 of 7