IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Art Unit: 1654
`
`Examiner: Roy R. Teller
`
`Confirmation No.: 2620
`
`First Named Inventor: Desai
`
`Application No.: 10/616,709
`
`Filed: 10 Jul 2003
`
`Title: Propofol Formulations With Non(cid:173)
`Reactive Container Closures
`
`Attorney Docket No.: APP01 005 US
`
`Mail Stop Amendment
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`RESPONSE UNDER 37 CFR 1.111
`
`Dear Sir:
`
`This communication responds to the Office Action mailed on January 28, 2011.
`
`Applicants respectfully request that the Examiner reconsider the rejections in view of the
`
`following amendments and remarks.
`
`Amendments to the Claims are reflected in the listing of claims which begins on
`
`page 2.
`
`Remarks begin on page 1 6.
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`Fresenius Ex. 2031
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
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`

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`Serial No. 10/616,709
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`IN THE CLAIMS:
`
`PATENT
`Docket No. APP01 005 US
`
`In accord with Rule § 1.121, a complete claim listing is presented below, including
`
`appropriate status identifiers. The changes in amended claims are shown by strikethrough
`
`or double brackets for deleted material, and by underlining for added material.
`
`1.
`
`(Currently Amended) A sterile pharmaceutical composition of propofol in a
`
`container, comprising:
`
`a container which includes a closure and a composition in the container, and
`
`the composition in the container comprising from 0.5% to 10% by weight propofol
`
`and less than 10% by weight solvent for propofol, aR6
`
`where when the composition in the container sealed with the closure is agitated at a
`
`frequency of 300-400 cycles/minute for 16 hours at room temperature, the composition
`
`maintains a propofol concentration (w/v) measured by HPLC that is at least 93 % of the
`
`starting concentration (w/v) of the propofol.
`
`2.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 1, the composition further comprising an aqueous phase and protein.
`
`3.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 2, wherein the protein is albumin.
`
`4.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 3, wherein the albumin is present in an amount of from about 0.01 % to
`
`about 5% by weight of the composition.
`
`5.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 2, wherein the aqueous phase comprises water for injection and a pH
`
`modifier.
`
`6.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 2, wherein the composition comprises a tonicity agent.
`2
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`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
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`Serial No. 10/616,709
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`PATENT
`Docket No. APP01 005 US
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`7.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 3, wherein the pH modifier is sodium hydroxide.
`
`8.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 6, wherein the tonicity agent is glycerin.
`
`9.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 2, wherein the composition further comprises a surfactant.
`
`10.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 1, wherein the composition further comprises a solvent for propofol.
`
`11.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 10 wherein the solvent is a water-immiscible solvent.
`
`12.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 11, wherein the water-immiscible solvent is selected from the group
`
`consisting of soybean, safflower, cottonseed, corn, coconut, sunflower, arachis, castor
`
`sesame, orange, limonene or olive oil, an ester of a medium or long-chain fatty acid, a
`
`chemically modified or manufactured palmitate, glyceral ester or polyoxyl, hydrogenated
`
`castor oil, a marine oil, fractionated oils, and mixtures thereof.
`
`13.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 12, wherein the water-immiscible solvent is soybean oil.
`
`14.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 10, wherein the solvent is selected from the group consisting of
`
`chloroform, methylene chloride, ethyl acetate, ethanol, tetrahydrofuran, dioxane,
`
`acetonitrile, acetone, dimethyl sulfoxide, dimethyl formamide, methyl pyrrolidinone,
`
`C1-C20 alcohols, C2-C20 esters, C3-C20 ketones, polyethylene glycols, aliphatic
`
`3
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`Serial No. 10/616,709
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`PATENT
`Docket No. APP01 005 US
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`hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons and combinations
`
`thereof.
`
`15.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 9, wherein the surfactant is selected from the group consisting of
`
`phosphatides, synthetic phospholipids, natural phospholipids, lecithins, ethoxylated ethers
`
`and esters, tocopherol polyethylene glycol stearate, polypropylene-polyethylene block co(cid:173)
`
`polymers, polyvinyl pyrrolidone, and polyvinylalcohol and combinations thereof.
`
`16.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 15, wherein the surfactant is selected from the group consisting of egg
`
`phosphatides, soya phosphatides, egg lecithins, soya lecithins, and combinations thereof.
`
`17.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 16, wherein the surfactant is egg lecithin.
`
`18.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 1, wherein the closure is coated with a material inert to propofol.
`
`19.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 1, wherein the closure consists essentially of a material that is itself
`
`inert to propofol.
`
`20.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 19, wherein the closure material is selected from the group consisting
`
`of a fluoropolymer, silicone, and mixtures thereof.
`
`21.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 19, wherein the closure material is a non-rubber selected from the
`
`group consisting of metal, plastics, and mixtures thereof.
`
`4
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`Serial No. 10/616,709
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`PATENT
`Docket No. APP01 005 US
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`22.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 1, wherein the closure comprises a material selected from the group
`
`consisting of bromobutyl rubber, chlorobutyl rubber, a fluoropolymer, silicone, and
`
`mixtures thereof.
`
`23.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 1, wherein the closure comprises bromobutyl rubber coated with a
`
`fluoropolymer.
`
`24.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 1, wherein the closure comprises siliconized bromobutyl rubber.
`
`25.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 1, wherein the closure comprises a non-rubber selected from the group
`
`consisting of metal, plastics, and mixtures thereof.
`
`26.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 1, wherein the closure comprises chlorobutyl rubber coated with a
`
`fluoropolymer.
`
`27.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 1, wherein the closure comprises siliconized chlorobutyl rubber.
`
`28.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 1, wherein the composition comprises soybean oil in an amount of
`
`from about 0.5% to about 6% by weight of the composition, egg lecithin in an amount of
`
`from about 0.1 % to about 5% by weight of the composition and human serum albumin in
`
`an amount of from about 0.1 % to about 5% of the composition.
`
`5
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`

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`Serial No. 10/616,709
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`PATENT
`Docket No. APP01 005 US
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`29.
`
`(Previously presented) A sterile pharmaceutical composition of propofol in a
`
`container, comprising:
`
`a container which includes a closure and an oil-in-water emulsion for parenteral
`
`administration of propofol in the container,
`
`the emulsion comprising an oil phase comprising propofol and a solvent for
`
`propofol, and an aqueous phase comprising water for injection,
`
`the emulsion comprising less than 10% by weight of the solvent,
`
`the emulsion further comprising a stabilizing layer for the oil phase, the stabilizing
`
`layer comprising a surfactant and a protein;
`
`where when the emulsion in the container sealed with the closure is agitated at a
`
`frequency of 300-400 cycles/minute for 16 hours at room temperature, the emulsion
`
`maintains a propofol concentration (w/v) measured by HPLC that is at least 93 % of the
`
`starting concentration (w/v) of the propofol.
`
`30.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 29, wherein the protein is selected from the group consisting of
`
`albumins, globulins, immunoglobulins, lipoproteins, caseins, insulins, hemoglobins,
`
`lysozymes, al pha-2-macroglobu Ii n, fi bronecti ns, vitronecti ns, fi bri nogens, Ii pases, peptides,
`
`enzymes, antibodies and combinations thereof.
`
`31.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 29, wherein the surfactant is selected from the group consisting of
`
`phosphatides, synthetic phospholipids, natural phospholipids, lecithins, ethoxylated ethers
`
`and esters, tocopherol polyethylene glycol stearate, polypropylene-polyethylene block co(cid:173)
`
`polymers, polyvinyl pyrrolidone, and polyvinylalcohol.
`
`32.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 29, wherein the oil phase is propofol neat.
`
`33.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 29, wherein the surfactant is lecithin and the protein is albumin.
`
`6
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`Serial No. 10/616,709
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`PATENT
`Docket No. APP01 005 US
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`34.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 29, wherein the oil phase includes a solvent, and wherein the solvent is
`
`selected from the group consisting of soybean, safflower, cottonseed, corn, coconut,
`
`sunflower, arachis, castor sesame, orange, limonene or olive oil, an ester of a medium or
`
`long-chain fatty acid, a chemically modified or manufactured palmitate, glyceral ester or
`
`polyoxyl, hydrogenated castor oil, a marine oil, fractionated oils, and mixtures thereof,
`
`chloroform, methylene chloride, ethyl acetate, ethanol, tetrahydrofuran, dioxane,
`
`acetonitrile, acetone, dimethyl sulfoxide, dimethyl formamide, methyl pyrrolidinone,
`
`C1-C20 alcohols, C2-C20 esters, C3-C20 ketones, polyethylene glycols, aliphatic
`
`hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons and combinations
`
`thereof.
`
`35.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 34, wherein the solvent is soybean oil.
`
`36.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 35, wherein the soybean oil is present in an amount of from about
`
`0.5% to about 6% by weight of the emulsion.
`
`37.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 33, wherein the egg lecithin is present in the emulsion in an amount of
`
`from about 0.1 % to about 5% by weight of the emulsion and the albumin is present in the
`
`emulsion in an amount of from about 0.01 % to about 5% by weight of the emulsion.
`
`38.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 37, wherein the oil phase includes soybean oil.
`
`39.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 38, wherein the soybean oil is present in an amount of from about
`
`0.5% to about 6% by weight of the emulsion.
`
`7
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`Serial No. 10/616,709
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`PATENT
`Docket No. APP01 005 US
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`40.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 38, wherein the soybean oil is present in the emulsion in an amount of
`
`from about 0.5% to about 3 % by weight of the emulsion.
`
`41.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 31, comprising:
`
`a) about 1 % to 2% by weight of propofol,
`
`b) 3-6% by weight of soybean oil,
`
`c) 0.2-1.0% by weight of egg lecithin,
`
`d) about 2.25% by weight of glycerin,
`
`e) sodium hydroxide,
`
`f) water to 100%, and
`
`g) pH between 5.0-8.5.
`
`42.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 29, wherein the closure is treated with a material inert to propofol.
`
`43.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 29, wherein the closure consists essentially of a material that is itself
`
`inert to propofol.
`
`44.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 43, wherein the closure material is selected from the group consisting
`
`of a fluoropolymer, silicone, and mixtures thereof.
`
`45.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 43, wherein the closure material is a non-rubber selected from the
`
`group consisting of metal, plastics, and mixtures thereof.
`
`46.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 29, wherein the closure comprises a material selected from the group
`
`8
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`

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`Serial No. 10/616,709
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`PATENT
`Docket No. APP01 005 US
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`consisting of bromobutyl rubber, chlorobutyl rubber, a fluoropolymer, silicone, and
`
`mixtures thereof.
`
`47.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 29, wherein the closure comprises bromobutyl rubber coated with a
`
`fluoropolymer.
`
`48.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 29, wherein the closure comprises siliconized bromobutyl rubber.
`
`49.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 29, wherein the closure comprises a non-rubber selected from the
`
`group consisting of metal, plastics, and mixtures thereof.
`
`50.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 29, wherein the closure comprises chlorobutyl rubber coated with a
`
`fluoropolymer.
`
`51.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 29, wherein the closure comprises siliconized chlorobutyl rubber.
`
`52.
`
`(Previously presented) A sterile, injectable pharmaceutical composition in a
`
`container, comprising:
`
`a container which includes a closure and a composition in the container, the
`
`composition comprising
`
`a) microdroplets having a mean size of from about 20 nanometers to about
`
`1000 nanometers, the microdroplets comprising a sphere of propofol surrounded by a
`
`stabilizing layer comprising a phospholipid and devoid of oils capable of supporting
`
`bacterial growth; and
`
`b) a pharmaceutically acceptable injectable carrier;
`
`9
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`Serial No. 10/616,709
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`PATENT
`Docket No. APP01 005 US
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`where when the composition in the container sealed with the closure is agitated at a
`
`frequency of 300-400 cycles/minute for 16 hours at room temperature, the composition
`
`maintains a propofol concentration (w/v) measured by HPLC that is at least 93 % of the
`
`starting concentration (w/v) of the propofol.
`
`53.
`
`(Previously presented) The sterile, injectable pharmaceutical composition in a
`
`container according to claim 52, wherein the composition further comprises albumin.
`
`54.
`
`(Previously presented) The sterile, injectable pharmaceutical composition in a
`
`container according to claim 52, wherein the stabilizing layer includes albumin.
`
`55.
`
`(Previously presented) The sterile, injectable pharmaceutical composition in a
`
`container according to claim 52, wherein the closure is coated with a material inert to
`
`propofol.
`
`56.
`
`(Previously presented) The sterile, injectable pharmaceutical composition in a
`
`container according to claim 52, wherein the closure consists essentially of a material that
`
`is itself inert to propofol.
`
`57.
`
`(Previously presented) The sterile, injectable pharmaceutical composition in a
`
`container according to claim 56, wherein the closure material is selected from the group
`
`consisting of a fluoropolymer, silicone, and mixtures thereof.
`
`58.
`
`(Previously presented) The sterile, injectable pharmaceutical composition in a
`
`container according to claim 56, wherein the closure material is a non-rubber selected
`
`from the group consisting of metal, plastics, and mixtures thereof.
`
`59.
`
`(Previously presented) The sterile, injectable pharmaceutical composition in a
`
`container according to claim 52, wherein the closure comprises a material selected from
`
`the group consisting of bromobutyl rubber, chlorobutyl rubber, a fluoropolymer, silicone,
`
`and mixtures thereof.
`
`10
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`Serial No. 10/616,709
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`PATENT
`Docket No. APP01 005 US
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`60.
`
`(Previously presented) The sterile, injectable pharmaceutical composition in a
`
`container according to claim 52, wherein the closure comprises bromobutyl rubber coated
`
`with a fluoropolymer.
`
`61.
`
`(Previously presented) The sterile, injectable pharmaceutical composition in a
`
`container according to claim 52, wherein the closure comprises siliconized bromobutyl
`
`rubber.
`
`62.
`
`(Previously presented) The sterile, injectable pharmaceutical composition in a
`
`container according to claim 52, wherein the closure comprises a non-rubber selected from
`
`the group consisting of metal, plastics and mixtures thereof.
`
`63.
`
`(Previously presented) The sterile, injectable pharmaceutical composition in a
`
`container according to claim 52, wherein the closure comprises chlorobutyl rubber coated
`
`with a fluoropolymer.
`
`64.
`
`(Previously presented) The sterile, injectable pharmaceutical composition in a
`
`container according to claim 52, wherein the closure comprises siliconized chlorobutyl
`
`rubber.
`
`65-67. (Cancelled)
`
`68.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 1, wherein when the composition is stored in the container sealed with
`
`the closure for at least two months, the composition maintains a propofol concentration
`
`(w/v) measured by HPLC that is at least about 95% of the starting concentration (w/v) of the
`
`propofol.
`
`69.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 68, wherein the composition is stored in the container sealed with the
`
`11
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`Docket No. APP01 005 US
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`closure in a controlled environment of about 40°C and about 75% relative humidity for at
`
`least two months.
`
`70.
`
`(Cancel led)
`
`71.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 1, where when the composition in the container sealed with the closure
`
`is agitated at a frequency of 300-400 cycles/minute for 16 hours at room temperature, the
`
`composition maintains a propofol concentration (w/v) measured by HPLC that is at least
`
`95% of the starting concentration (w/v) of the propofol.
`
`72.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 1, where when the composition in the container sealed with the closure
`
`is agitated at a frequency of 300-400 cycles/minute for 16 hours at room temperature, the
`
`composition maintains a propofol concentration (w/v) measured by HPLC that is at least
`
`97% of the starting concentration (w/v) of the propofol.
`
`73.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 1, where when the composition in the container sealed with the closure
`
`is agitated at a frequency of 300-400 cycles/minute for 16 hours at room temperature, the
`
`composition maintains a propofol concentration (w/v) measured by HPLC that is at least
`
`99% of the starting concentration (w/v) of the propofol.
`
`74.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 29, where when the emulsion in the container sealed with the closure
`
`is agitated at a frequency of 300-400 cycles/minute for 16 hours at room temperature, the
`
`emulsion maintains a propofol concentration (w/v) measured by HPLC that is at least 95%
`
`of the starting concentration (w/v) of the propofol.
`
`75.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 29, where when the emulsion in the container sealed with the closure
`
`12
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`

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`Serial No. 10/616,709
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`PATENT
`Docket No. APP01 005 US
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`is agitated at a frequency of 300-400 cycles/minute for 16 hours at room temperature, the
`
`emulsion maintains a propofol concentration (w/v) measured by HPLC that is at least 97%
`
`of the starting concentration (w/v) of the propofol.
`
`76.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 29, where when the emulsion in the container sealed with the closure
`
`is agitated at a frequency of 300-400 cycles/minute for 16 hours at room temperature, the
`
`emulsion maintains a propofol concentration (w/v) measured by HPLC that is at least 99%
`
`of the starting concentration (w/v) of the propofol.
`
`77.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 29, where when the emulsion is stored in the container sealed with the
`
`closure for at least two months, the emulsion maintains a propofol concentration (w/v)
`
`measured by HPLC that is at least 95% of the starting concentration (w/v) of the propofol.
`
`78.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 29, where when the emulsion is stored in the container sealed with the
`
`closure in a controlled environment of about 40°C and about 75% relative humidity for at
`
`least two months, the emulsion maintains a propofol concentration (w/v) measured by
`
`HPLC that is at least 95% of the starting concentration (w/v) of the propofol.
`
`79.
`
`(Previously presented) The sterile, injectable pharmaceutical composition in a
`
`container according to claim 52, where when the composition in the container sealed with
`
`the closure is agitated at a frequency of 300-400 cycles/minute for 16 hours at room
`
`temperature, the composition maintains a propofol concentration (w/v) measured by HPLC
`
`that is at least 95% of the starting concentration (w/v) of the propofol.
`
`80.
`
`(Previously presented) The sterile, injectable pharmaceutical composition in a
`
`container according to claim 52, where when the composition in the container sealed with
`
`the closure is agitated at a frequency of 300-400 cycles/minute for 16 hours at room
`
`13
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`Serial No. 10/616,709
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`Docket No. APP01 005 US
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`temperature, the composition maintains a propofol concentration (w/v) measured by HPLC
`
`that is at least 97% of the starting concentration (w/v) of the propofol.
`
`81.
`
`(Previously presented) The sterile, injectable pharmaceutical composition in a
`
`container according to claim 52, where when the composition in the container sealed with
`
`the closure is agitated at a frequency of 300-400 cycles/minute for 16 hours at room
`
`temperature, the composition maintains a propofol concentration (w/v) measured by HPLC
`
`that is at least 99% of the starting concentration (w/v) of the propofol.
`
`82.
`
`(Previously presented) The sterile, injectable pharmaceutical composition in a
`
`container according to claim 52, where when the composition is stored in the container
`
`sealed with the closure for at least two months, the composition maintains a propofol
`
`concentration (w/v) measured by HPLC that is at least 95% of the starting concentration
`
`(w/v) of the propofol.
`
`83.
`
`(Previously presented) The sterile, injectable pharmaceutical composition in a
`
`container according to claim 52, where when the composition is stored in the container
`
`sealed with the closure in a controlled environment of about 40°C and about 75% relative
`
`humidity for at least two months, the composition maintains a propofol concentration (w/v)
`
`measured by HPLC that is at least 95% of the starting concentration (w/v) of the propofol.
`
`84.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 1, the composition comprising less than about 0.5% by weight solvent
`
`for propofol, and the closure comprises a material selected from the group consisting of a
`
`fluoropolymer, a metal, and butyl rubber coated with a fluoropolymer.
`
`85.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 1, the composition comprising from about 0.5% to about 6% by weight
`
`solvent for propofol, and the closure comprises a material selected from the group
`
`consisting of a fluoropolymer, a metal, butyl rubber coated with a fluoropolymer,
`
`bromobutyl rubber and chlorobutyl rubber.
`
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`

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`Serial No. 10/616,709
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`PATENT
`Docket No. APP01 005 US
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`86.
`
`(Currently Amended) The sterile pharmaceutical composition in a container
`
`according to claim ge 85, the composition comprising from about 3% to about 6% by
`
`weight solvent for propofol.
`
`87.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 86, the solvent comprising soybean oil.
`
`88.
`
`(Previously presented) The sterile pharmaceutical composition in a container
`
`according to claim 28, wherein the closure comprises a material selected from the group
`
`consisting of bromobutyl rubber, chlorobutyl rubber, a fluoropolymer, metal, and
`
`combinations thereof.
`
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`

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`Serial No. 10/616,709
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`PATENT
`Docket No. APP01 005 US
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`Claims 1 and 86 have been amended to correct inadvertent typographical errors.
`
`No new matter has been added. Claims 1-64, 68, 69 and 71-88 are pending.
`
`REMARKS
`
`REQUEST FOR RECONSIDERATION
`
`Independent claims 1, 29 and 52 are directed to sterile pharmaceutical
`
`compositions that include a propofol composition in a container having a closure, where
`
`the propofol is protected from degradation while in the closed container. Each
`
`independent claim recites different aspects of the propofol composition. Claim 1 recites
`
`that the composition includes from 0.5% to 10% by weight propofol and less than 10% by
`
`weight solvent for propofol. Claim 29 recites an emulsion including an oil phase that
`
`includes propofol, an aqueous phase, and a stabilizing layer for the oil phase that includes
`
`a surfactant and a protein. Claim 52 recites microdroplets and an injectable carrier, where
`
`the microdroplets contain propofol spheres surrounded by a layer that includes a
`
`phospholipid but that does not include an oil that can support bacterial growth. Thus,
`
`while the independent claims share a common performance feature, they recite distinct
`
`features of the propofol compositions that are protected from degradation.
`
`The rejection of all the pending claims as obvious over U.S. Patent No. 6,399,087
`
`to Zhang et al. (Zhang) in view of U.S. Patent No. 6,576,245 to Lundgren et al. (Lundgren)
`and/or Sautou-Miranda, Int. J. Pharm. 130, 251-255, 1996 (Sautou-Miranda) is respectfully
`
`traversed. The present office action provides neither the factual basis nor the rationale
`
`required to make a basic prima facie case of obviousness against any of the pending
`
`claims. In the response filed December 16, 2010, Applicants presented rebuttal evidence
`
`showing that the cited references do not teach or suggest the claimed protection of
`
`propofol (claim 1 ), or a propofol composition having the claimed structure of an emulsion
`
`(claim 29) or of microdroplets (claim 52).
`
`With regard to claim 1, the office action does not provide a factual basis or
`
`reasoning for predictably combining the teachings of Lundgren and/or Sautou-Miranda
`
`with the compositions of Zhang. With regard to claims 29 and 52, the office action does
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`Serial No. 10/616,709
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`PATENT
`Docket No. APP01 005 US
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`not even acknowledge the elements of the claims. In particular, the office action does not
`
`recognize the components of the emulsion that are recited in claim 29, or the
`
`microdroplets that are recited in claim 52, and as a result fails to provide the required
`
`comparisons between these claims and the cited references. Accordingly, no prima facie
`
`case of obviousness has been presented for any of claims 1, 29 or 52.
`
`CLAIMS 29 AND 52 ARE NOT PRIMA fACIE OBVIOUS OVER THE CITED REFERENCES
`
`Claim 29 is not obvious over Zhang, Lundgren and/or Sautou-Miranda.
`
`The Office has erred substantially as to the factual findings regarding the scope and
`
`content of the cited references, and regarding the differences between claim 29 and the
`
`references. Zhang, Lundgren and Sautou-Miranda, alone or in combination, do not teach
`
`or suggest the claimed propofol emulsion composition, which contains an oil phase that
`
`includes propofol and a solvent for propofol, and which contains a stabilizing layer for the
`
`oil phase that includes a protein. Zhang and Sautou-Miranda disclose propofol emulsions,
`
`but do not disclose or suggest a protein in the emulsions. Lundgren does not disclose
`
`emulsions of any sort, and thus does not disclose or suggest a stabilizing layer for an
`
`emulsion that includes a protein. Thus, the combination of the references does not provide
`
`each and every element of claim 29.
`
`The elements of claim 29 are not listed anywhere in the office action. Claim 29
`
`recites a propofol composition that includes an oil-in-water emulsion. The claimed
`
`emulsion has an oil phase, an aqueous phase, and a stabilizing layer for the oil phase. The
`
`oil phase of the claimed emulsion includes propofol and a solvent for propofol. The
`
`aqueous phase of the claimed emulsion includes water for injection. The stabilizing layer
`
`of the claimed emulsion includes a surfactant and a protein.
`
`Zhang does not disclose or suggest a protein in an emulsion. Zhang discloses
`
`propofol formulations having a reduced amount of soybean oil triglycerides, a reduced
`
`amount of lecithin surfactant, and no preservatives (col. 3, lines 17-27). Zhang compares
`
`these low oil formulations with the propofol formulation sold commercially as DIPRIVAN®,
`
`which contains 10% (w/v) soybean oil, 1.2% (w/v) egg lecithin surfactant, and EDTA
`
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`Serial No. 10/616,709
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`PATENT
`Docket No. APP01 005 US
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`preservative (col. 1, lines 57-63). There is no disclosure or suggestion in Zhang regarding
`
`the addition of a protein to the low oil propofol formulations, or to the DIPRIVAN®
`
`formulation.
`
`Sautou-Miranda does not disclose or suggest a protein in an emulsion. Sautou(cid:173)
`
`Miranda discloses DIPRIVAN® formulations that had been diluted from their original
`
`concentration of 10 mg/ml propofol (p.2