-56-
`
`WHATIS CLAIMEDIS:
`
`1.
`
`An ophthalmic formulation comprising from about 2 wt % to about 4 wt % carbachol,
`
`or a pharmaceutically acceptable salt thereof, from about 0.05 wt % to about 0.2 wt % brimonidine,
`
`or a pharmaceutically acceptable salt thereof, from about 0.05 wt % to about 1 wt % of one or more
`
`viscosity agents, and from about 0.05 wt % to about 1 wt % of one or more buffers, wherein the pH
`
`of the formulation is from about 7 to about 7.6, and wherein the formulation comprises less than 5 wt
`
`% impurity A after storage for about 5 months, wherein impurity A hasthe structure:
`
`
`
`or a tautomerthereof, wherein the concentration of impurity A is measured by high-
`
`performanceliquid chromatography (HPLC) in pH 3.5 potassium octane sulfonate buffer:acetonitrile
`
`(64:36 v/v) and impurity A has a relative retention time (RRT) of about 0.9 relative to brimonidine.
`
`2.
`
`The ophthalmic formulation of claim 1, wherein the formulation is stored at 40 °C and
`
`not more than (NMT) 25% relative humidity for about 5 months.
`
`3.
`
`The ophthalmic formulation of claim 1, wherein the formulation comprises less than
`
`3 wt % impurity A after storage at 40 °C and NMT 25% relative humidity for about 3 months.
`
`4,
`
`The ophthalmic formulation of claim 1, wherein the formulation comprises less than
`
`0.5 wt % impurity A after storage at 40 °C and NMT 25% relative humidity for about 1 month.
`
`5.
`
`The ophthalmic formulation of claim 1, wherein the formulation comprises less than
`
`0.25 wt % impurity A.
`
`6.
`
`The ophthalmic formulation of claim 5, wherein the formulation comprises less than
`
`0.1 wt % impurity A.
`
`Atty. Dkt. No. 4902.0120001
`
`
`
`WHATIS CLAIMEDIS:
`
`1.
`
`An ophthalmic formulation comprising from about 2 wt % to about 4 wt % carbachol,
`
`or a pharmaceutically acceptable salt thereof, from about 0.05 wt % to about 0.2 wt % brimonidine,
`
`or a pharmaceutically acceptable salt thereof, from about 0.05 wt % to about 1 wt % of one or more
`
`viscosity agents, and from about 0.05 wt % to about 1 wt % of one or more buffers, wherein the pH
`
`of the formulation is from about 7 to about 7.6, and wherein the formulation comprises less than 5 wt
`
`% impurity A after storage for about 5 months, wherein impurity A hasthe structure:
`
`
`
`or a tautomerthereof, wherein the concentration of impurity A is measured by high-
`
`performanceliquid chromatography (HPLC) in pH 3.5 potassium octane sulfonate buffer:acetonitrile
`
`(64:36 v/v) and impurity A has a relative retention time (RRT) of about 0.9 relative to brimonidine.
`
`2.
`
`The ophthalmic formulation of claim 1, wherein the formulation is stored at 40 °C and
`
`not more than (NMT) 25% relative humidity for about 5 months.
`
`3.
`
`The ophthalmic formulation of claim 1, wherein the formulation comprises less than
`
`3 wt % impurity A after storage at 40 °C and NMT 25% relative humidity for about 3 months.
`
`4,
`
`The ophthalmic formulation of claim 1, wherein the formulation comprises less than
`
`0.5 wt % impurity A after storage at 40 °C and NMT 25% relative humidity for about 1 month.
`
`5.
`
`The ophthalmic formulation of claim 1, wherein the formulation comprises less than
`
`0.25 wt % impurity A.
`
`6.
`
`The ophthalmic formulation of claim 5, wherein the formulation comprises less than
`
`0.1 wt % impurity A.
`
`Atty. Dkt. No. 4902.0120001
`
`
`
`-57-
`
`7.
`
`The ophthalmic formulation of claim 6, wherein the formulation comprises less than
`
`0.05 wt % impurity A.
`
`8.
`
`The ophthalmic formulation of claim 1, wherein the formulation comprises less than
`
`1 wt % impurity A after storage at 25 °C and 40% relative humidity for about 5 months.
`
`9.
`
`The ophthalmic formulation of claim 1, wherein the formulation comprises less than
`
`0.5 wt % impurity A after storage at 25 °C and 40% relative humidity for about 3 months.
`
`10.
`
`The ophthalmic formulation of claim 1, wherein the formulation comprises less than
`
`0.25 wt % impurity A after storage at 25 °C and 40% relative humidity for about 1 month.
`
`11.
`
`The ophthalmic formulation of any one of claims 1-10, wherein the one or more
`
`buffers are selected from the group consisting of acetate buffer, borate buffer, borate citrate buffer,
`
`carbonate buffer, citrate buffer, lactate buffer, and phosphate buffer.
`
`12.
`
`The ophthalmic formulation of claim 11, wherein the one or more buffers is a
`
`phosphate buffer.
`
`13.
`
`The ophthalmic formulation of claim 12, wherein the phosphate buffer comprises
`
`sodium phosphate monobasic monohydrate and sodium phosphate dibasic heptahydrate.
`
`14.
`
`The ophthalmic formulation of any one of claims 1-13, wherein the one or more
`
`viscosity agents are selected from the group consisting of hydroxypropylmethyl] cellulose (HPMC),
`
`hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose, and polyvinyl alcohol, and
`
`polyvinylpyrrolidone.
`
`15.
`
`The ophthalmic formulation of claim 14, wherein the one or more viscosity agents is
`
`HPMC.
`
`16.
`
`The ophthalmic formulation of any one of claims 1-15, wherein the formulation
`
`further comprises from about 0.0025 wt % to about 0.02 wt % benzalkonium chloride.
`
`Atty. Dkt. No. 4902.0120001
`
`
`
`- 58 -
`
`17.
`
`The ophthalmic formulation of claim 16, wherein the formulation comprises from
`
`about 0.0075 wt % to about 0.0125 wt % benzalkonium chloride.
`
`18.
`
`The ophthalmic formulation of claim 17, wherein the formulation comprises about
`
`0.01 wt % benzalkonium chloride.
`
`19.
`
`The ophthalmic formulation of any one of claims 1-18, wherein the formulation does
`
`not contain EDTA.
`
`20.
`
`Anophthalmic formulation comprising about 2.75 wt % carbachol, about 0.1 wt %
`
`brimonidine, about 0.2 wt % HPMC,and from about 0.05 wt % to about 1 wt % of one or more
`
`buffers, wherein the pH is about 7.4, and wherein the formulation comprises less than about 5 wt %
`
`impurity A after storage for about 5 months, wherein impurity A hasthe structure:
`
`
`
`or a tautomerthereof, wherein the concentration of impurity A is measured by high-
`
`performanceliquid chromatography (HPLC)in pH 3.5 potassium octane sulfonate buffer:acetonitrile
`
`(64:36 v/v) and impurity A has a relative retention time (RRT) of about 0.9 relative to brimonidine.
`
`21.
`
`The ophthalmic formulation of claim 20, further comprising from about 0.0025 wt %
`
`to about 0.02 wt % benzalkonium chloride.
`
`22.
`
`The ophthalmic formulation of claim 21, wherein the formulation comprises from
`
`about 0.0075 wt % to about 0.0125 wt % benzalkonium chloride.
`
`Atty. Dkt. No. 4902.0120001
`
`
`
`-59-
`
`23.
`
`The ophthalmic formulation of claim 21 or 22, wherein the formulation comprises
`
`about 2.75 wt % carbachol, about 0.1 wt % brimonidine, about 0.01 wt % benzalkonium chloride,
`
`and about 0.2 wt % HPMC,and wherein the pH is about 7.4.
`
`24.
`
`The ophthalmic formulation of any one of claims 1-23, further comprising impurity
`
`B, wherein the formulation comprises less than 2 wt % impurity B after storage for about 5 months,
`
`wherein impurity B hasthe structure:
`
`NH,
`
`or a tautomerthereof, wherein the concentration of impurity B is measured by high-
`
`performanceliquid chromatography (HPLC) in pH 3.5 potassium octane sulfonate buffer:acetonitrile
`
`(64:36 v/v) and impurity B hasa relative retention time (RRT) of about 0.67 relative to brimonidine.
`
`25.
`
`The ophthalmic formulation of claim 24, wherein the formulation comprises less than
`
`0.1 wt % impurity B after storage for about 5 months.
`
`26.
`
`The ophthalmic formulation of claim 24, wherein the formulation comprises less than
`
`0.05 wt % impurity B after storage for about 5 months.
`
`27.
`
`The ophthalmic formulation of claim 24, wherein the formulation comprises less than
`
`2 wt % impurity B after storage at 40 °C and NMT 25% relative humidity for about 5 months.
`
`28.
`
`The ophthalmic formulation of claim 24, wherein the formulation comprises less than
`
`0.25 wt % impurity B after storage at 25 °C and 40% relative humidity for about 3 months.
`
`29.
`
`The ophthalmic formulation of any one of claims 20-28, wherein the formulation
`
`does not contain EDTA.
`
`Atty. Dkt. No. 4902.0120001
`
`
`
`- 60 -
`
`30.|Anophthalmic formulation comprising from about 2 wt % to about 4 wt % carbachol,
`
`or a pharmaceutically acceptable salt thereof, from about 0.05 wt % to about 0.2 wt % brimonidine,
`
`or a pharmaceutically acceptable salt thereof, from about 0.05 wt % to about 1 wt % of one or more
`
`viscosity agents, and from about 0.05 wt % to about 0.1 wt % of one or more buffers, wherein the
`
`pHof the formulation is from about 7 to about 7.6, and wherein the formulation comprisesless than
`
`5 wt % impurity B after storage for about 5 months, wherein impurity B hasthe structure:
`
`Br
`
`O
`
`N
`N
`JL
`( WTS Yr Sy NH,
`
`N
`
`N
`
`N
`
`yn a
`
`"
`
`or a tautomer thereof, wherein the concentration of impurity B is measured by high-
`
`performanceliquid chromatography (HPLC) in pH 3.5 potassium octane sulfonate buffer:acetonitrile
`
`(64:36 v/v) and impurity B hasa relative retention time (RRT)of about 0.67 relative to brimonidine.
`
`31.
`
`The ophthalmic formulation of claim 30, wherein the formulation comprises less than
`
`2 wt % impurity B after storage at 40 °C and NMT 25% relative humidity for about 5 months.
`
`32.
`
`The ophthalmic formulation of claim 30, wherein the formulation comprises less than
`
`0.25 wt % impurity B after storage at 25 °C and 40% relative humidity for about 3 months.
`
`33.
`
`The ophthalmic formulation of any one of claims 30-32, wherein the one or more
`
`buffers are selected from the group consisting of acetate buffer, borate buffer, borate citrate buffer,
`
`citrate buffer, lactate buffer, and phosphate buffer.
`
`34.
`
`The ophthalmic formulation of claim 33, wherein the one or more buffers is a
`
`phosphate buffer.
`
`35.
`
`The ophthalmic formulation of claim 34, wherein the phosphate buffer comprises
`
`sodium phosphate monobasic monohydrate and sodium phosphate dibasic heptahydrate.
`
`Atty. Dkt. No. 4902.0120001
`
`
`
`-61 -
`
`36.
`
`The ophthalmic formulation of any one of claims 30-35, wherein the one or more
`
`viscosity agents are selected from the group consisting of hydroxypropylmethyl] cellulose (HPMC),
`
`hydroxyethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, and
`
`polyvinylpyrrolidine.
`
`37.
`
`The ophthalmic formulation of claim 36, wherein the one or more viscosity agents is
`
`HPMC.
`
`38.
`
`The ophthalmic formulation of claim 37, wherein the formulation comprises about
`
`2.75 wt % carbachol, about 0.1 wt % brimonidine, and about 0.2 wt % HPMC,and wherein the pH
`
`is about 7.4.
`
`39.
`
`The ophthalmic formulation of any one of claims 30-38, further comprising from
`
`about 0.0025 wt % to about 0.02 wt % benzalkonium chloride.
`
`40.
`
`The ophthalmic formulation of claim 39, wherein the formulation comprises from
`
`about 0.0075 wt % to about 0.0125 wt % benzalkonium chloride.
`
`41.
`
`The ophthalmic formulation of claim 40, wherein the formulation comprises about
`
`0.01 wt % benzalkonium chloride.
`
`42.
`
`The ophthalmic formulation of any one of claims 30-41, wherein the formulation
`
`does not contain EDTA.
`
`43.|Anophthalmic formulation comprising about 2.75 wt % carbachol, about 0.1 wt %
`
`brimonidine, about 0.2 wt % HPMC,and from about 0.05 wt % to about 1 wt % of one or more
`
`buffers, wherein the pH is about 7.4, and wherein the formulation comprises less than about 2 wt %
`
`impurity B after storage for about 5 months, wherein impurity B hasthe structure:
`
`Atty. Dkt. No. 4902.0120001
`
`
`
`-62-
`
`Br
`
`N
`
`H
`N
`
`H
`N
`
`‘a a
`
`O
`
`AAn
`
`or a tautomerthereof, wherein the concentration of impurity B is measured by high-
`
`performanceliquid chromatography (HPLC) in pH 3.5 potassium octane sulfonate buffer:acetonitrile
`
`(64:36 v/v) and impurity B hasa relative retention time (RRT) of about 0.67 relative to brimonidine.
`
`44.
`
`The ophthalmic formulation of claim 43, further comprising from about 0.0025 wt %
`
`to about 0.02 wt % benzalkonium chloride.
`
`45.
`
`The ophthalmic formulation of claim 44, wherein the formulation comprises from
`
`about 0.0075 wt % to about 0.0125 wt % benzalkonium chloride.
`
`46.
`
`The ophthalmic formulation of claim 45, wherein the formulation comprises about
`
`0.01 wt % benzalkonium chloride.
`
`47.
`
`The ophthalmic formulation of any one of claims 43-46, wherein the formulation
`
`comprises about 2.75 wt % carbachol, about 0.1 wt % brimonidine, about 0.01 wt % benzalkonium
`
`chloride, and about 0.2 wt % HPMC,and wherein the pH is about 7.4.
`
`48.
`
`The ophthalmic formulation of any one of claims 30-47, wherein the formulation
`
`does not contain impurity A, wherein impurity A hasthe structure:
`
`NH,
`
`Atty. Dkt. No. 4902.0120001
`
`
`
`- 63 -
`
`or a tautomerthereof, wherein the concentration of impurity A is measured by high-
`
`performanceliquid chromatography (HPLC) in pH 3.5 potassium octane sulfonate buffer:acetonitrile
`
`(64:36 v/v) and impurity A has a relative retention time (RRT) of about 0.9 relative to brimonidine.
`
`49.
`
`Impurity A, havingthe structure:
`
`
`
`or a tautomer, salt or solvate thereof.
`
`50.
`
`Impurity B, having the structure:
`
`NH,
`
`or a tautomer, salt or solvate thereof.
`
`51.
`
`A process for manufacturing an ophthalmic formulation comprising from about 2 wt
`
`% to about 4 wt % carbachol, or a pharmaceutically acceptable salt thereof, from about 0.05 wt % to
`
`about 0.2 wt % brimonidine, or a pharmaceutically acceptable salt thereof, from about 0.05 wt % to
`
`about 1 wt % of one or more viscosity agents, and from about 0.05 wt % to about 1 wt % of one or
`
`more buffers, wherein the pH of the formulation is from about 7 to about 7.6, the process comprising
`
`adding carbachol, or a pharmaceutically acceptable salt thereof, brimonidine, or a pharmaceutically
`
`Atty. Dkt. No. 4902.0120001
`
`
`
`- 64 -
`
`acceptable salt thereof, and one or more viscosity agents to water and mixingto provide the
`
`formulation.
`
`52.
`
`The process of claim 51, wherein the one or more buffers comprises sodium
`
`phosphate monobasic monohydrate and sodium phosphate dibasic heptahydrate.
`
`53.
`
`The process of claim 51 or 52, wherein the one or more viscosity agents is
`
`hydroxypropylmethyl cellulose (HPMC).
`
`54.
`
`The process of any one of claims 51-53, wherein the process comprises
`
`addingbenzalkoniumchloride.
`
`55.
`
`The process of any one of claims 51-54, wherein the process comprises adding
`
`sodium chloride.
`
`56.
`
`The process of any one of claims 51-55, wherein the process comprises adding
`
`hydrochloric acid.
`
`57.
`
`The process of any one of claims 51-55, wherein the process comprises adding
`
`sodium hydroxide.
`
`58.
`
`The process of any one of claims 51-57, wherein the ophthalmic formulation is
`
`aseptically filled into vials.
`
`59.
`
`The process of claim 58, wherein eachvialis filled with from about 0.1 g to about 0.3
`
`g of the ophthalmic formulation.
`
`60.
`
`The process of claim 58, wherein eachvialis filled with from about 2 g to about 2.7 g
`
`of the ophthalmic formulation.
`
`61.|A method for ameliorating or reducing presbyopia in a subject comprising
`
`administering to at least one eye of the subject an ophthalmic formulation comprising from about 2
`
`wt % to about 4 wt % carbachol, or a pharmaceutically acceptable salt thereof, from about 0.05 wt %
`
`to about 0.2 wt % brimonidine, or a pharmaceutically acceptable salt thereof, from about 0.05 wt %
`
`Atty. Dkt. No. 4902.0120001
`
`
`
`-65-
`
`to about 1 wt % of one or more viscosity agents, and from about 0.05 wt % to about 1 wt % of one or
`
`more buffers, wherein the pH of the formulation is from about 7 to about 7.6, and wherein the
`
`formulation comprises less than 5 wt % impurity A after storage for about 5 months, wherein
`
`impurity A hasthe structure:
`
`
`
`or a tautomerthereof, wherein the concentration of impurity A is measured by high-
`
`performanceliquid chromatography (HPLC) in pH 3.5 potassium octane sulfonate buffer:acetonitrile
`
`(64:36 v/v) and impurity A has a relative retention time (RRT) of about 0.9 relative to brimonidine.
`
`62.
`
`The method of claim 61, wherein the one or more viscosity agents is
`
`hydroxypropylmethyl cellulose (HPMC)or carboxymethy] cellulose.
`
`63.
`
`The method of claim 61 or 62, wherein the one or more buffers is a phosphate buffer.
`
`64.
`
`The methodof any one of claims 61-63, wherein the ophthalmic formulation further
`
`comprises from about 0.0025 wt % to about 0.02 wt % benzalkonium chloride.
`
`65.
`
`The methodof claim 64, wherein the ophthalmic formulation comprises about 0.01
`
`wt % benzalkonium chloride.
`
`66.
`
`The methodof claim 64 or 65, wherein the ophthalmic formulation comprises about
`
`2.75 wt % carbachol, about 0.1 wt % brimonidine, about 0.01 wt % benzalkonium chloride, and
`
`about 0.2 wt % HPMC,and wherein the pHis about 7.4.
`
`Atty. Dkt. No. 4902.0120001
`
`
`
`- 66 -
`
`67.
`
`The methodof any one of claims 61-66, wherein the ophthalmic formulation further
`
`comprises impurity B, wherein the formulation comprises less than 2 wt % impurity B after storage
`
`for about 5 months, wherein impurity B hasthe structure:
`
`Br
`
`
`
`H
`
`H
`
`N NNO JkN
`TT
`N
`
`oO
`
`NH
`
`;
`
`or a tautomer thereof, wherein the concentration of impurity B is measured by high-
`
`performanceliquid chromatography (HPLC) in pH 3.5 potassium octane sulfonate buffer:acetonitrile
`
`(64:36 v/v) and impurity B hasa relative retention time (RRT)of about 0.67 relative to brimonidine.
`
`68.
`
`The methodof any one of claims 61-67, wherein the ophthalmic formulation does not
`
`contain EDTA.
`
`69.
`
`The methodof any one of claims 61-68, wherein the ophthalmic formulation is
`
`administered to one eye of the subject.
`
`70.
`
`The methodof any one of claims 61-68, wherein the ophthalmic formulation is
`
`administered to both eyes of the subject.
`
`71.
`
`The methodof any one of claims 61-70, wherein the amelioration or reduction of
`
`presbyopiais effective for at least 8 hours.
`
`72.
`
`The methodof any one of claims 61-71, wherein administration of the ophthalmic
`
`formulation reducesperiorbital pain in the subject.
`
`73.
`
`A method for ameliorating or reducing presbyopia in a subject comprising
`
`administering to at least one eye of the subject an ophthalmic formulation comprising from about 2
`
`wt % to about 4 wt % carbachol, or a pharmaceutically acceptable salt thereof, from about 0.05 wt %
`
`to about 0.2 wt % brimonidine, or a pharmaceutically acceptable salt thereof, from about 0.05 wt %
`
`Atty. Dkt. No. 4902.0120001
`
`
`
`-67-
`
`to about 1 wt % of one or more viscosity agents, and from about 0.05 wt % to about 1 wt % of one or
`
`more buffers, wherein the pH of the formulation is from about 7 to about 7.6, and wherein the
`
`formulation comprises less than 2 wt % impurity B after storage for about 5 months, wherein
`
`impurity B hasthe structure:
`
`Br
`
`oO
`
`S
`
`LA
`
`N
`
`TT Sy NH,
`
`O
`
`>
`
`or a tautomer thereof, wherein the concentration of impurity B is measured by high-
`
`performanceliquid chromatography (HPLC) in pH 3.5 potassium octane sulfonate buffer:acetonitrile
`
`(64:36 v/v) and impurity B hasa relative retention time (RRT)of about 0.67 relative to brimonidine.
`
`74.
`
`The method of claim 73, wherein the one or more viscosity agents is
`
`hydroxypropylmethyl cellulose (HPMC)or carboxymethy] cellulose.
`
`75.
`
`The method of claim 73 or 74, wherein the one or more buffers is a phosphate buffer.
`
`76.
`
`The methodof any one of claims 73-75, wherein the ophthalmic formulation further
`
`comprises from about 0.0025 wt % to about 0.02 wt % benzalkonium chloride.
`
`77.
`
`The methodof claim 76, wherein the ophthalmic formulation comprises about 0.01
`
`wt % benzalkonium chloride.
`
`78.
`
`The methodof claim 76 or 77, wherein the ophthalmic formulation comprises about
`
`2.75 wt % carbachol, about 0.1 wt % brimonidine, about 0.01 wt % benzalkonium chloride, and
`
`about 0.2 wt % HPMC,and wherein the pHis about 7.4.
`
`79.
`
`The methodof any one of claims 73-78, wherein the ophthalmic formulation does not
`
`contain EDTA.
`
`Atty. Dkt. No. 4902.0120001
`
`
`
`- 68 -
`
`80.
`
`The methodof any one of claims 73-79, wherein the ophthalmic formulation is
`
`administered to one eye of the subject.
`
`81.
`
`The methodof any one of claims 73-79, wherein the ophthalmic formulation is
`
`administered to both eyes of the subject.
`
`82.
`
`The methodof any one of claims 73-81, wherein the amelioration or reduction of
`
`presbyopiais effective for at least 8 hours.
`
`83.
`
`The methodof any one of claims 73-82, wherein administration of the ophthalmic
`
`formulation reducesperiorbital pain in the subject.
`
`84.|A method for ameliorating or reducing at least one refractive error in a subject with
`
`hyperopia comprising administering to at least one eye of the subject an ophthalmic formulation
`
`comprising from about 2 wt % to about 4 wt % carbachol, or a pharmaceutically acceptable salt
`
`thereof, from about 0.05 wt % to about 0.2 wt % brimonidine, or a pharmaceutically acceptable salt
`
`thereof, from about 0.05 wt % to about 1 wt % of one or more viscosity agents, and from about 0.05
`
`wt % to about 1 wt % of one or more buffers, wherein the pH of the formulation is from about 7 to
`
`about 7.6, and wherein the formulation comprises less than 5 wt % impurity A after storage for about
`
`5 months, wherein impurity A has the structure:
`
`NH,
`
`or a tautomerthereof, wherein the concentration of impurity A is measured by high-
`
`performanceliquid chromatography (HPLC) in pH 3.5 potassium octane sulfonate buffer:acetonitrile
`
`(64:36 v/v) and impurity A has a relative retention time (RRT) of about 0.9 relative to brimonidine.
`
`Atty. Dkt. No. 4902.0120001
`
`
`
`- 69 -
`
`85.
`
`The methodof claim 84, wherein the one or more viscosity agents is
`
`hydroxypropylmethyl cellulose (HPMC)or carboxymethy] cellulose.
`
`86.
`
`87.
`
`The method of claim 84 or 85, wherein the one or more buffers is a phosphate buffer.
`
`The methodof any one of claims 84-86, wherein the ophthalmic formulation further
`
`comprises from about 0.0025 wt % to about 0.02 wt % benzalkonium chloride.
`
`88.
`
`The methodof claim 87, wherein the ophthalmic formulation comprises about 0.01
`
`wt % benzalkonium chloride.
`
`89.
`
`The methodof claim 87 or 88, wherein the ophthalmic formulation comprises about
`
`2.75 wt % carbachol, about 0.1 wt % brimonidine, about 0.01 wt % benzalkonium chloride, and
`
`about 0.2 wt % HPMC, and wherein the pHis about 7.4.
`
`90.
`
`The methodof any one of claims 84-89, wherein the ophthalmic formulation further
`
`comprises impurity B, wherein the formulation comprises less than 2 wt % impurity B after storage
`
`for about 5 months, wherein impurity B hasthe structure:
`
`Br
`
`O
`
`( QW aa SS NH,
`
`ny a
`
`©
`
`>
`
`or a tautomer thereof, wherein the concentration of impurity B is measured by high-
`
`performanceliquid chromatography (HPLC) in pH 3.5 potassium octane sulfonate buffer:acetonitrile
`
`(64:36 v/v) and impurity B hasa relative retention time (RRT)of about 0.67 relative to brimonidine.
`
`91.
`
`The methodof any one of claims 84-90, wherein the ophthalmic formulation does not
`
`contain EDTA.
`
`Atty. Dkt. No. 4902.0120001
`
`
`
`-70-
`
`92.
`
`The methodof any one of claims 84-91, wherein the ophthalmic formulation is
`
`administered to one eye of the subject.
`
`93.
`
`The methodof any one of claims 84-91, wherein the ophthalmic formulation is
`
`administered to both eyes of the subject.
`
`94.
`
`The methodof any one of claims 84-93, wherein the vision of the subject with
`
`hyperopia is improvedbyat least 20% relative to no treatment.
`
`95.|A method for ameliorating or reducing at least one refractive error in a subject with
`
`hyperopia comprising administering to at least one eye of the subject an ophthalmic formulation
`
`comprising from about 2 wt % to about 4 wt % carbachol, or a pharmaceutically acceptable salt
`
`thereof, from about 0.05 wt % to about 0.2 wt % brimonidine, or a pharmaceutically acceptable salt
`
`thereof, from about 0.05 wt % to about 1 wt % of one or more viscosity agents, and from about 0.05
`
`wt % to about 1 wt % of one or more buffers, wherein the pH of the formulation is from about7 to
`
`about 7.6, and wherein the formulation comprises less than 2 wt % impurity B after storage for about
`
`5 months, wherein impurity B hasthe structure:
`
`Br
`
`oO
`
`Zz x=
`
`2i
`
`2i
`
`riz
`
`or a tautomer thereof, wherein the concentration of impurity B is measured by high-
`
`performanceliquid chromatography (HPLC) in pH 3.5 potassium octane sulfonate buffer:acetonitrile
`
`(64:36 v/v) and impurity B hasa relative retention time (RRT)of about 0.67 relative to brimonidine.
`
`96.
`
`The method of claim 95, wherein the one or more viscosity agents is
`
`hydroxypropylmethyl cellulose (HPMC)or carboxymethy] cellulose.
`
`97.
`
`The method of claim 95 or 96, wherein the one or more buffers is a phosphate buffer.
`
`Atty. Dkt. No. 4902.0120001
`
`
`
`-7l-
`
`98.
`
`The methodof any one of claims 95-97, wherein the ophthalmic formulation further
`
`comprises from about 0.0025 wt % to about 0.02 wt % benzalkonium chloride.
`
`99.
`
`The methodof claim 98, wherein the ophthalmic formulation comprises about 0.01
`
`wt % benzalkonium chloride.
`
`100.
`
`The method of claim 98 or 99, wherein the ophthalmic formulation comprises about
`
`2.75 wt % carbachol, about 0.1 wt % brimonidine, about 0.01 wt % benzalkonium chloride, and
`
`about 0.2 wt % HPMC, and wherein the pHis about 7.4.
`
`101.
`
`The method of any one of claims 95-100, wherein the ophthalmic formulation does
`
`not contain EDTA.
`
`102.
`
`The method of any one of claims 95-101, wherein the ophthalmic formulation is
`
`administered to one eye of the subject.
`
`103.
`
`The method of any one of claims 95-101, wherein the ophthalmic formulation is
`
`administered to both eyes of the subject.
`
`104.
`
`The method of any one of claims 95-103, wherein the vision of the subject with
`
`hyperopia is improvedbyat least 20% relative to no treatment.
`
`105. A method ofrelaxing a ciliary muscle of a subject stimulated by sympathetic
`
`innervation to reduce at least one of headache, browache andperiorbital pain comprising
`
`administering to at least one eye of the subject an ophthalmic formulation comprising from about 2
`
`wt % to about 4 wt % carbachol, or a pharmaceutically acceptable salt thereof, from about 0.05 wt %
`
`to about 0.2 wt % brimonidine, or a pharmaceutically acceptable salt thereof, from about 0.05 wt %
`
`to about 1 wt % of one or more viscosity agents, and from about 0.05 wt % to about 1 wt % of one or
`
`more buffers, wherein the pH of the formulation is from about 7 to about 7.6, and wherein the
`
`formulation comprises less than 5 wt % impurity A after storage for about 5 months, wherein
`
`impurity A hasthe structure:
`
`Atty. Dkt. No. 4902.0120001
`
`
`
`-72-
`
`
`
`or a tautomerthereof, wherein the concentration of impurity A is measured by high-
`
`performanceliquid chromatography (HPLC) in pH 3.5 potassium octane sulfonate buffer:acetonitrile
`
`(64:36 v/v) and impurity A has a relative retention time (RRT) of about 0.9 relative to brimonidine.
`
`106.
`
`The method of claim 105, wherein the one or more viscosity agents is
`
`hydroxypropylmethyl cellulose (HPMC)or carboxymethy] cellulose.
`
`107.
`
`The method of claim 105 or 106, wherein the one or more buffers is a phosphate
`
`buffer.
`
`108.
`
`The method of any one of claims 105-107, wherein the ophthalmic formulation
`
`further comprises from about 0.0025 wt % to about 0.02 wt % benzalkonium chloride.
`
`109.
`
`The method of claim 108, wherein the ophthalmic formulation comprises about 0.01
`
`wt % benzalkonium chloride.
`
`110.
`
`The method of claim 108 or 109, wherein the ophthalmic formulation comprises
`
`about 2.75 wt % carbachol, about 0.1 wt % brimonidine, about 0.01 wt % benzalkonium chloride,
`
`and about 0.2 wt % HPMC, and wherein the pH is about 7.4.
`
`111.
`
`The method of any one of claims 105-110, wherein the ophthalmic formulation
`
`further comprises impurity B, wherein the formulation comprises less than 2 wt % impurity B after
`
`storage for about 5 months, wherein impurity B hasthe structure:
`
`Atty. Dkt. No. 4902.0120001
`
`
`
`-73-
`
`Br
`
`oO
`
`( WTS th SS NH,
`
`nw a
`
`°
`
`>
`
`or a tautomer thereof, wherein the concentration of impurity B is measured by high-
`
`performanceliquid chromatography (HPLC) in pH 3.5 potassium octane sulfonate buffer:acetonitrile
`
`(64:36 v/v) and impurity B hasa relative retention time (RRT)of about 0.67 relative to brimonidine.
`
`112.
`
`The method of any one of claims 105-111, wherein the ophthalmic formulation does
`
`not contain EDTA.
`
`113.
`
`The method of any one of claims 105-112, wherein the ophthalmic formulation is
`
`administered to one eye of the subject.
`
`114.
`
`The method of any one of claims 105-112, wherein the ophthalmic formulation is
`
`administered to both eyes of the subject.
`
`115. A method ofrelaxing a ciliary muscle of a subject stimulated by sympathetic
`
`innervation to reduce at least one of headache, browache andperiorbital pain comprising
`
`administering to at least one eye of the subject an ophthalmic formulation comprising from about 2
`
`wt % to about 4 wt % carbachol, or a pharmaceutically acceptable salt thereof, from about 0.05 wt %
`
`to about 0.2 wt % brimonidine, or a pharmaceutically acceptable salt thereof, from about 0.05 wt %
`
`to about 1 wt % of one or more viscosity agents, and from about 0.05 wt % to about 1 wt % of one or
`
`more buffers, wherein the pH of the formulation is from about 7 to about 7.6, and wherein the
`
`formulation comprises less than 2 wt % impurity B after storage for about 5 months, wherein
`
`impurity B hasthe structure:
`
`Atty. Dkt. No. 4902.0120001
`
`
`
`-74 -
`
`Br
`
`N
`
`H
`N
`
`H
`N
`
`‘a a
`
`O
`
`AAn
`
`or a tautomerthereof, wherein the concentration of impurity B is measured by high-
`
`performanceliquid chromatography (HPLC) in pH 3.5 potassium octane sulfonate buffer:acetonitrile
`
`(64:36 v/v) and impurity B hasa relative retention time (RRT)of about 0.67 relative to brimonidine.
`
`116.
`
`The method of claim 115, wherein the one or more viscosity agents is
`
`hydroxypropylmethyl cellulose (HPMC)or carboxymethy] cellulose.
`
`117.
`
`The method of claim 115 or 116, wherein the one or more buffers is a phosphate
`
`buffer.
`
`118.
`
`The method of any one of claims 115-117, wherein the ophthalmic formulation
`
`further comprises from about 0.0025 wt % to about 0.02 wt % benzalkonium chloride.
`
`119.
`
`The method of claim 118, wherein the ophthalmic formulation comprises about 0.01
`
`wt % benzalkonium chloride.
`
`120.
`
`The method of claim 118 or 119, wherein the ophthalmic formulation comprises
`
`about 2.75 wt % carbachol, about 0.1 wt % brimonidine, about 0.01 wt % benzalkonium chloride,
`
`and about 0.2 wt % HPMC, and wherein the pH is about 7.4.
`
`121.
`
`The method of any one of claims 115-120, wherein the ophthalmic formulation does
`
`not contain EDTA.
`
`122.
`
`The method of any one of claims 115-121, wherein the ophthalmic formulation is
`
`administered to one eye of the subject.
`
`Atty. Dkt. No. 4902.0120001
`
`
`
`-75-
`
`123.
`
`The method of any one of claims 115-121, wherein the ophthalmic formulation is
`
`administered to both eyes of the subject.
`
`124. A method for preventing a parasympathomimetic induced myopic shift in a patient
`
`with presbyopia receiving parasympathomimetic drugs or pharmaceutically acceptable salts thereof
`
`comprising administering to at least one eye of the subject an ophthalmic formulation comprising
`
`from about 2 wt % to about 4 wt % carbachol, or a pharmaceutically acceptable salt thereof, from
`
`about 0.05 wt % to about 0.2 wt % brimonidine, or a pharmaceutically acceptable salt thereof, from
`
`about 0.05 wt % to about 1 wt % of one or moreviscosity agents, and from about 0.05 wt % to about
`
`1 wt % of one or more buffers, wherein the pH of the formulation is from about 7 to about 7.6, and
`
`wherein the formulation comprises less than 5 wt % impurity A after storage for about 5 months,
`
`wherein impurity A hasthe structure:
`
`NH,
`
`or a tautomerthereof, wherein the concentration of impurity A is measured by high-
`
`performanceliquid chromatography (HPLC) in pH 3.5 potassium octane sulfonate buffer:acetonitrile
`
`(64:36 v/v) and impurity A has a relative retention time (RRT) of about 0.9 relative to brimonidine.
`
`125.
`
`The method of claim 124, wherein the one or more viscosity agents is
`
`hydroxypropylmethyl cellulose (HPMC)or carboxymethy] cellulose.
`
`126.
`
`The method of claim 124 or 125, wherein the one or more buffers is a phosphate
`
`buffer.
`
`127.
`
`The method of any one of claims 124-126, wherein the ophthalmic formulation
`
`further comprises from about 0.0025 wt % to about 0.02 wt % benzalkonium chloride.
`
`Atty. Dkt. No. 4902.0120001
`
`
`
`-76-
`
`128.
`
`The method of claim 127, wherein the ophthalmic formulation comprises about 0.01
`
`wt % benzalkonium chloride.
`
`129.
`
`The method of claim 127 or 128, wherein the ophthalmic formulation comprises
`
`about 2.75 wt % carbachol, about 0.1 wt % brimonidine, about 0.01 wt % benzalkonium chloride,
`
`and about 0.2 wt % HPMC, and wherein the pH is about 7.4.
`
`130.
`
`The method of any one of claims 124-129, wherein the ophthalmic formulation
`
`further comprises impurity B, wherein the formulation comprises less than 2 wt % impurity B after
`
`storage for about 5 months, wherein impurity B hasthe structure:
`
`O
`NSCE
`
`O
`
`eee
`ya
`
`Br
`
`N
`
`or a tautomer thereof, wherein the concentration of impurity B is measured by high-
`
`performanceliquid chromatography (HPLC) in pH 3.5 potassium octane sulfonate buffer:acetonitrile
`
`(64:36 v/v) and impurity B hasa relative retention time (RRT)of about 0.67 relative to brimonidine.
`
`131.
`
`The method of any one of claims 124-130, wherein the ophthalmic formulation does
`
`not contain EDTA.
`
`132.
`
`The method of any one of claims 124-131, wherein the ophthalmic formulation is
`
`administered to one eye of the subject.
`
`133.
`
`The method of any one of claims 124-131, wherein the ophthalmic formulation is
`
`administered to both eyes of the subject.
`
`134.
`
`The method of any one of claims 124-133, wherein administration of the ophthalmic
`
`formulation increases depth of focus in the vision of the subject.
`
`Atty. Dkt. No. 4902.0120001
`
`
`
`-77-
`
`135.
`
`The method of any one of claims 124-134, wherein administration of the ophthalmic
`
`formulation preserves visual acuity in the vision of the subject.
`
`136. A method for preventing a parasympathomimetic induced myopic shift in a patient
`
`with presbyopia receiving parasympathomimetic drugs or pharmaceutically acceptable salts thereof
`
`comprising administering to at least one eye of the subject an ophthalmic formulation comprising
`
`from about 2 wt % to about 4 wt % carbachol, or a pharmaceutically acceptable salt thereof, from
`
`about 0.05 wt % to about 0.2 wt % brimonidine, or a pharmaceutically acceptable salt thereof, from
`
`about 0.05 wt % to about 1 wt % of one or more viscosity agents, and from about 0.05 wt % to about
`
`1 wt % of one or more buffers, wherein the pH of the formulation is from about 7 to about 7.6,
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