Rhett Mead SCHIFFMAN
`Application No. 18/250,921
`
`Amendments to the Claims
`
`This listing of claims will replace all prior versions, andlistings, of claims in the application.
`
`1.
`
`(Currently Amended) 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 aboutatleast 5 months,
`
`wherein impurity A has the structure:
`
`rp
`
`NH
`
`2
`
`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 hasa relative retention time (RRT) of about 0.9
`
`relative to brimonidine.
`
`2.-7.
`
`(Canceled)
`
`8.
`
`(Currently Amended) 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 abexut at least 5 months.
`
`Atty. Dkt. No. 4902.0110003
`
`
`Application No. 18/250,921
`
`Amendments to the Claims
`
`This listing of claims will replace all prior versions, andlistings, of claims in the application.
`
`1.
`
`(Currently Amended) 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 aboutatleast 5 months,
`
`wherein impurity A has the structure:
`
`rp
`
`NH
`
`2
`
`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 hasa relative retention time (RRT) of about 0.9
`
`relative to brimonidine.
`
`2.-7.
`
`(Canceled)
`
`8.
`
`(Currently Amended) 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 abexut at least 5 months.
`
`Atty. Dkt. No. 4902.0110003
`
`
`
`Rhett Mead SCHIFFMAN
`Application No. 18/250,921
`
`9.-11.
`
`(Canceled)
`
`12.
`
`(Currently Amended) The ophthalmic formulation of elatwaHt claim 1, wherein the
`
`one or more buffers is a phosphate buffer.
`
`13.
`
`(Original)
`
`The ophthalmic formulation of claim 12, wherein the phosphate
`
`buffer comprises sodium phosphate monobasic monohydrate and sodium phosphate dibasic
`
`heptahydrate.
`
`14.
`
`15.
`
`(Canceled)
`
`(Currently Amended) The ophthalmic formulation of elata44 claim 1, wherein the
`
`one or more viscosity agents is HPMC.
`
`16.-19. (Canceled)
`
`20.
`
`(Currently Amended) An ophthalmic 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 abeutatleast 5 months, wherein impurity A has
`
`the structure:
`
`Br
`
`NH2rp
`
`2
`
`Atty. Dkt. No. 4902.0110003
`
`
`
`Rhett Mead SCHIFFMAN
`Application No. 18/250,921
`
`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 hasa relative retention time (RRT) of about 0.9
`
`relative to brimonidine.
`
`21.-23. (Canceled)
`
`24.any-one-ofclaims+23claim 1(Currently Amended) The ophthalmic formulation of
`
`
`
`
`
`
`
`or 20, further comprising impurity B, wherein the formulation comprises less than 2 wt % impurity
`
`B after storage for about at least 5 months, wherein impurity B hasthe structure:
`
`Br
`
`O
`
`NN
`
`ZA
`
`N
`
`nid ao NHy
`
`O
`
`2
`
`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.-27. (Canceled)
`
`28.
`
`(Currently Amended) 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 abexut at least 3 months.
`
`29.-42. (Canceled)
`
`Atty. Dkt. No. 4902.0110003
`
`
`
`Rhett Mead SCHIFFMAN
`Application No. 18/250,921
`
`43.
`
`(Currently Amended) An ophthalmic 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 abeut at least 5 months, wherein impurity B has
`
`the structure:
`
`Br
`
`O
`
`2
`
`wouwwee
`SQ
`na ry NH
`
`ZA
`
`N
`
`O
`
`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.-47. (Canceled)
`
`48.
`
`(Currently Amended) The ophthalmic formulation of any-erne-ofelatms30—-4+7 claim
`
`43, wherein the formulation does not contain impurity A, wherein impurity A hasthe structure:
`
`Br
`
`0
`
`NH2
`
`S
`
`ZA
`
`2r
`
`ae
`
`N
`
`Atty. Dkt. No. 4902.0110003
`
`
`
`Rhett Mead SCHIFFMAN
`Application No. 18/250,921
`
`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 hasa relative retention time (RRT) of about 0.9
`
`relative to brimonidine.
`
`49.
`
`(Original)
`
`Impurity A, having the structure:
`
`NHz
`
`rp
`
`or a tautomer, salt or solvate thereof.
`
`50.
`
`(Original)
`
`Impurity B, having the structure:
`
`2
`
`O
`
`Br
`
`SQ
`
`ZA
`
`N
`
`na Sy NH
`
`O
`
`or a tautomer, salt or solvate thereof.
`
`51.-60. (Canceled)
`
`61.
`
`(Currently Amended) A method for ameliorating or reducing presbyopia in a subject
`
`comprising administering to at least one eye of the subject an ophthalmic formulation comprising
`
`Atty. Dkt. No. 4902.0110003
`
`
`
`Rhett Mead SCHIFFMAN
`Application No. 18/250,921
`
`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 abeut at
`
`least 5 months, wherein impurity A has the structure:
`
`rp
`
`NH
`
`2
`
`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 hasa relative retention time (RRT) of about 0.9
`
`relative to brimonidine.
`
`62.
`
`(Original)
`
`The method of claim 61, wherein the one or more viscosity agents is
`
`hydroxypropylmethyl cellulose (HPMC)or carboxymethyl cellulose.
`
`
`
`63. (Currently Amended) The method of elaim-6ter62claim 61, wherein the one or
`
`more buffers is a phosphate buffer.
`
`64.-66. (Canceled)
`
`Atty. Dkt. No. 4902.0110003
`
`
`
`Rhett Mead SCHIFFMAN
`Application No. 18/250,921
`
`67.
`
`(Currently Amended) The method of any-erne-ofeclaims461+66 claim 61, wherein the
`
`ophthalmic formulation further comprises impurity B, wherein the formulation comprises less than
`
`2 wt % impurity B after storage for abeut at least 5 months, wherein impurity B hasthe structure:
`
`Br
`
`—
`
`NC
`
`ZA
`
`N
`
`O
`
`OL
`oo
`aa ™ NH,
`
`O
`
`2
`
`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.
`
`68.-70. (Canceled)
`
`71.
`
`(Currently Amended) The method of ansy-ene-ofclatms4+-70 claim 61, wherein the
`
`amelioration or reduction of presbyopia is effective for at least 8-heurs 6 hours.
`
`72.
`
`73.
`
`(Canceled)
`
`(Currently Amended) 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 % 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
`
`Atty. Dkt. No. 4902.0110003
`
`
`
`Rhett Mead SCHIFFMAN
`Application No. 18/250,921
`
`7.6, and wherein the formulation comprises less than 2 wt % impurity B after storage for abeut at
`
`least 5 months, wherein impurity B hasthe structure:
`
`Br
`
`oe
`SS
`
`ZA
`
`N
`
`O
`
`L
`nid ~~ NHy
`
`O
`
`2
`
`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.
`
`74.
`
`(Original)
`
`The method of claim 73, wherein the one or more viscosity agents is
`
`hydroxypropylmethyl cellulose (HPMC)or carboxymethyl cellulose.
`
`75.
`
`(Currently Amended) The method of elaim—B-er-+4 claim 73, wherein the one or
`
`more buffers is a phosphate buffer.
`
`76.-81. (Canceled)
`
`82.
`
`(Currently Amended) The methodof aay-ene-ofclaims—B-84 claim 73, wherein the
`
`amelioration or reduction of presbyopia is effective for at least $-heurs 6 hours.
`
`83.-146.
`
`(Canceled)
`
`Atty. Dkt. No. 4902.0110003
`
`
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