IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Patent Application No. 10/616,709
`
`Applicant: Desai et al.
`
`Filed: July 10, 2003
`
`TC/AU: 1654
`
`Examiner: Roy R. Teller
`
`Docket No.: 223416
`
`Customer No.: 23460
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Sir:
`
`REPLY TO OFFICE ACTION
`
`In reply to the Office Action dated July 6, 2009, please enter the following
`
`amendments and consider the following remarks.
`
`The claims pending in this application are reflected in the listing of claims which
`
`begins on page 2 of this paper.
`
`Remarks begin on page 12 of this paper.
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`Application No. 10/616,709
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`Reply to Office Action
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`AMENDMENTS TO THE CLAIMS
`
`1.
`
`(Previously Presented) A sterile pharmaceutical composition of propofol in a
`
`container, comprising a container which includes a closure inert to propofol and a
`
`composition in the container, the composition in the container comprising propofol and less
`
`than about 10% by weight solvent for 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.
`
`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.
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`Application No. 10/616, 709
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`Reply to Office Action
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`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, com, 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, C 1-C20 alcohols,
`
`C2-C20 esters, C3-C20 ketones, polyethylene glycols, aliphatic 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 compositions thereof.
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`Reply to Office Action
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`17.
`
`(Previously Presented) The sterile pharmaceutical composition in a container
`
`according to claim 16, wh~rein 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 is comprised of a material that is itself inert to
`
`pro po fol.
`
`20.
`
`(Previously Presented) The sterile pharmaceutical composition in a container
`
`according to claim 19, wherein the material inert to propofol 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 material is selected from the group consisting of
`
`bromobutyl rubber, chlorobutyl rubber, a fluoropolymer, silicone, non-rubber, metal, and
`
`mixtures thereof.
`
`22.
`
`(Previously Presented) The sterile pharmaceutical composition in a container
`
`according to claim 19, wherein the material is 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.
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`Reply to Office Action
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`25.
`
`(Previously Presented) The sterile phannaceutical composition in a container
`
`according to claim 1, wherein the closure comprises a non-rubber, or metal.
`
`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 propofol in an amount of from
`
`about 0.1 % to about 10% by weight of the composition, 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.
`
`29.
`
`(Previously Presented) A sterile pharmaceutical composition of propofol in a
`
`container comprising a container which includes a closure inert to propofol and an oil-in(cid:173)
`
`water emulsion for parenteral administration of propofol in the container,
`
`the composition comprising an oil phase comprising propofol and less than about 10%
`
`by weight solvent for propofol and an aqueous phase comprising water for injection, and
`
`the composition further comprising a stabilizing layer for the oil phase, the stabilizing
`
`layer comprising a surfactant and a protein.
`
`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, alpha-
`
`2-macroglobulin, fibronectins, vitronectins, fibrinogens, lipases, peptides, enzymes,
`
`antibodies and combinations thereof.
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`Application No. 10/616,709
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`Reply to Office Action
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`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.
`
`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, com, 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, C l-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 composition.
`
`3 7.
`
`(Previously Presented) The sterile pharmaceutical composition in a container
`
`according to claim 33, wherein the egg lecithin is present in the composition in an amount of
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`Application No. 10/616,709
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`Reply to Office Action
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`from about 0.1 % to about 5% by weight of the composition and the albumin is present in the
`
`composition in an amount of from about 0.01 % to about 5% by weight of the composition.
`
`3 8.
`
`(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 composition.
`
`40.
`
`(Previously Presented) The sterile pharmaceutical composition in a container
`
`according to claim 38, wherein the soybean oil is present in the composition in an amount of
`
`from about 0.5% to about 3% by weight of the composition.
`
`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 comprises a material that is itself inert to propofol.
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`Application No. 10/616,709
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`Reply to Office Action
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`44.
`
`(Previously Presented) The sterile pharmaceutical composition in a container
`
`according to claim 42, wherein the material inert to propofol 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 material is selected from the group consisting of
`
`bromobutyl rubber, chlorobutyl rubber, a fluoropolymer, silicone, non-rubber, metal, and
`
`mixtures thereof.
`
`46.
`
`(Previously Presented) The sterile pharmaceutical composition in a container
`
`according to claim 46, wherein the material is selected from the group 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 non-rubber, or metal.
`
`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.
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`Application No. 10/616,709
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`Reply to Office Action
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`52.
`
`(Previously Presented) A sterile, injectable pharmaceutical composition in a
`
`container comprising a container which includes a closure inert to propofol 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.
`
`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.
`
`(Currently Amended) The sterile pharmaeeutieal eomposition sterile,
`
`injectable pharmaceutical composition in a container according to claim 52, wherein the
`
`closure is coated with a material inert to propofol.
`
`56.
`
`(Currently Amended) The sterile pharmaeeutieal eomposition sterile,
`
`injectable pharmaceutical composition in a container according to claim 52, wherein the
`
`closure comprises a material that is itself inert to propofol.
`
`57.
`
`(Currently Amended) The sterile pharmaeeutieal eomposition sterile,
`
`injectable pharmaceutical composition in a container according to claim 55, wherein the
`
`material inert to propofol is selected from the group consisting of a fluoropolymer, silicone,
`
`and mixtures thereof.
`
`58.
`
`(Currently Amended) The sterile pharrnaeeutieal eomposition sterile,
`
`injectable pharmaceutical composition in a container according to claim 56, wherein the
`
`material is selected from the group consisting ofbromobutyl rubber, chlorobutyl rubber, a
`
`fluoropolymer, silicone, non-rubber, metal, and mixtures thereof.
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`Application No. 10/616,709
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`Reply to Office Action
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`59.
`
`(Currently Amended) The sterile pharmaceutical sterile, injectable
`
`pharmaceutical composition in a container according to claim 55, wherein the material is
`
`selected from the group consisting ofbromobutyl rubber, chlorobutyl rubber, a
`
`fluoropolymer, silicone, and mixtures thereof.
`
`60.
`
`(Currently Amended) The sterile pharmaceutical composition sterile,
`
`injectable pharmaceutical composition in a container according to claim 52, wherein the
`
`closure comprises bromobutyl rubber coated with a fluoropolymer.
`
`61.
`
`(Currently Amended) The sterile, injectable pharmaceutical composition in a
`
`container according to claim 52, wherein the closure comprises siliconized bromobutyl
`
`rubber.
`
`62.
`
`(Currently Amended) The sterile pharmaceutical composition sterile,
`
`injectable pharmaceutical composition in a container according to claim 52, wherein the
`
`closure comprises a non-rubber, or metal.
`
`63.
`
`(Currently Amended) The sterile pharmaceutical composition 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.
`
`Claims 65-67. (Canceled)
`
`68.
`
`(Previously Presented) The sterile pharmaceutical composition in a container
`
`according to claim 1, wherein the concentration of propofol in the composition in the
`
`container is at least about 95% of the starting concentration of propofol for at least about two
`
`months.
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`Reply to Office Action
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`69.
`
`(Previously Presented) The sterile pharmaceutical composition in a container
`
`according to claim 68, wherein the composition is stored in the container in a controlled
`
`environment of about 40°C and about 75% relative humidity for at least about two months.
`
`70.
`
`(Previously Presented) The sterile pharmaceutical composition in a container
`
`according to claim 1, wherein the concentration of propofol in the composition in the
`
`container is at least about 95% of the starting concentration of propofol after the composition
`
`in the container is agitated at a frequency of about 300-400 cycles/minute for about 16 hours
`
`at room temperature.
`
`This listing of claims replaces all prior versions, and listings, of claims in the
`application.
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`Application No. 10/616,709
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`Reply to Office Action
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`Reconsideration of the pending application is respectfully requested in view of the
`
`REMARKS
`
`following remarks.
`
`Status of the Application
`
`Claims 1-54, 64, and 68-70 were previously submitted and are currently under
`
`examination. Claims 55-63 are amended to sharpen the claim language and provide a
`
`description of the subject matter which Applicants consider to be their invention. As
`
`amended, the claims are fully supported by the application as filed and no new matter has
`
`been added to the application by way of these amendments. Claims 65-67 were previously
`
`cancelled without prejudice.
`
`Summary of the Office Action
`
`Claims 1-64 and 68-70 are rejected under 35 U.S.C. § 103(a) as allegedly
`
`unpatentable over U.S. Patent 6,399,087 ("Zhang et. al.") in view of U.S. Patent 6,576,245
`
`("Lundgren et al.").
`
`Discussion of the Claim Rejections
`
`Claims 1-64 and 68-70 are rejected under 35 U.S.C. § 103(a). Applicants respectfully
`
`traverse the obviousness rejection.
`
`Zhang discloses and teaches compositions containing propofol-without more.
`
`Indeed, the sole focus of Zhang is teaching the preparation of an optimized propofol
`
`formulation that is bacteriostatic or fungistatic. Zhang purportedly solves this problem by
`
`providing a formulation containing relatively low amounts of lecithin and soybean oil.
`
`In contrast to the claimed invention, Zhang does not teach or suggest a container for
`
`its propofol compositions. Zhang, in fact, does not even mention a container or its
`
`equivalent. Because of this deficiency, Zhang, alone, cannot render any of the instant claims
`
`obvious.
`
`The Office Action acknowledges this deficiency, but purports to cure it by the
`
`combination of Zhang and Lundgren. Office Action contends that Lundgren discloses low
`
`molecular weight peptide-based thrombin inhibitors in a primary package sealed with a
`
`rubber stopper or plunger containing bromobutyl rubber. The Office Action states that the
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`combination of the references is proper because "bromobutyl rubber would inherently work
`
`for a low molecular weight (1,000 M.W.) composition such as propofol (M.W. 178.28)." See
`
`Office Action, p. 4.
`
`Applicants respectfully submit that Lundgren is not analogous art to Zhang.
`
`Lundgren it is directed to solving the problem of degradation of certain peptide-based
`
`thrombin inhibitors, purportedly by using a rubber stopper or plunger containing bromobutyl
`
`rubber (as opposed to chlorobutyl rubber). This is in marked contrast to Zhang which is
`
`directed not to solving the problem of peptide degradation, but to reducing microbial growth
`
`in propofol compositions. As the components (peptide-based thrombin inhibitors versus
`
`propofol compositions) and problems (degradation of specific peptide-based thrombin
`
`inhibitors versus microbial growth in propofol composition) facing Lundgren are not the
`
`same as that those facing Zhang, the ordinarily skilled artisan would not combine Zhang and
`
`Lundgren.
`
`In addition, Applicants submit that the teaching attributable to Lundgren in the Office
`
`Action is not fairly based on the actual language of the reference. A fair reading of the
`
`reference by one skilled in the art is that Lundgren solves a problem associated with only
`
`those peptide-based thrombin inhibitors disclosed therein. Indeed, there is nothing in
`
`Lundgren that suggests that its solution is universally applicable to actives other than those
`
`specifically disclosed therein, let alone to the specific propofol compositions disclosed in
`
`Zhang. Indeed, there is no mention of propofol compositions in Lundgren at all.
`
`Moreover, propofol is a very different compound from the peptides disclosed in
`
`Lundgren. While both propofol and Lundgren's peptides are smaller than 1,000 D, the
`
`peptides disclosed in Lundgren are much larger than propofol. Chemically, peptides are
`
`compounds containing two or more amino acids linked by the amide bond, while propofol is
`
`a small phenol derivative. Lundgren's peptides are water soluble, propofol is not water
`
`soluble. Peptides degrade by hydrolosis, while propofol degrades by oxidation. These
`
`features suggest that different containers may be optimal for the compounds disclosed by
`
`Zhang relative to those disclosed in Lundgren. Accordingly, those of ordinary skill would
`
`not look to containers appropriate for peptides as a means of storing propofol. The only basis
`
`for the combination is improper hindsight.
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`Even if one were to assume arguendo the asserted combination was proper, the
`
`combination would not provide the invention as claimed.
`
`Lundgren teaches that bromobutyl rubber closures prevent degradation of peptide(cid:173)
`
`based thrombin inhibitors, whereas chlorobutyl rubber closures do not. The Office Action
`
`inferred from Lundgren that "bromobutyl rubber would inherently work for a low molecular
`
`weight composition such as propofol" (emphasis added). In contrast, Example 33 of the
`
`instant application demonstrates a discovery by Applicants that not all bromobutyl rubber
`
`closures prevented degradation of propofol compositions. In fact, different types of
`
`bromobutyl rubbers (i.e., Rubbers 1, 2, and 3) had varying effects (52.9%, 93.4%, and 99.9%
`
`propofol percentage of control, respectively,) on propofol compositions containing 3% by
`
`weight soybean oil. In addition, whereas Lundgren discloses that chlorobutyl rubber
`
`closures did not prevent degradation ofthrombin inhibitors, Example 33 shows that
`
`chlorobutyl rubber closures (Rubber 4) resulted in a 95.8% propofol concentration, that is,
`
`only a 4.2% loss ofpropofol compared to control. Thus, not only are the teachings of
`
`Lundgren inapplicable to propofol compositions (for the reasons set forth above), the asserted
`
`combination would not yield the invention as claimed.
`
`Further, there is absolutely no recognition in either of the cited references that
`
`degradation or potency loss of a pro po fol composition could occur even if the weight percent
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`of solvent used in such a composition was relatively low, or that the type of closure material
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`would have an effect on the degradation or potency loss of such propofol compositions. For
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`example, and as shown in Examples 32-37 of the instant application, propofol compositions
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`containing relatively low amounts of solvent, e.g., less than 10% by weight of solvent (e.g.,
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`soybean oil), degraded to a greater extent when contacted with certain closure materials,
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`whereas propofol compositions containing at least 10% by weight of solvent did not. As
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`neither Zhang nor Lundgren recognizes the foregoing, neither motivates one skilled in the art
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`to provide the invention as claimed, e.g., a sterile pharmaceutical composition of propofol in
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`a container, comprising a container which includes a closure inert to propofol and a
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`composition in the container, the composition in the container comprising propofol and less
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`than about 10% by weight solvent for propofol (claim 1 ).
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`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
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`

`
`Application No. 10/616,709
`
`Reply to Office Action
`
`Additionally, claims 20, 23-27, 44, 47-51, 57, and 60-64 cannot be obvious over
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`Zhang in view of Lundgren. Zhang does not disclose any containers for propofol
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`compositions, nor does it teach any materials which are inert to propofol. Lundgren only
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`discloses the benefit of stoppers containing bromobutyl instead of chlorobutyl in preventing
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`degradation of low molecular weight thrombin inhibitors. Claims 25, 49, and 62 are directed
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`to propofol compositions wherein the closure comprises a non-rubber or metal. Neither
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`Zhang nor Lundgren disclose or even suggest the use of a non-rubber or metal closure for
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`propofol compositions. Claims 26, 27, 50, 51, 63, and 64 are directed to propofol
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`compositions wherein the closure is comprised of either chlorobutyl rubber coated with a
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`flurorpolymer or a siliconized chlorobutyl. Lundgren actually teaches away from using a
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`closure containing chlorobutyl by showing that chlorobutyl increases degradation oflow
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`molecular weight thrombin inhibitors over bromobutyl. Claims 23, 47 and 60 are directed to
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`propofol compositions wherein the closure comprises bromobutyl coated with a
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`fluoropolymer. Lundgren fails to disclose or suggest the use of a fluoropolymer in
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`combination with bromobutyl. Finally, claims 20, 44, and 57 are directed to propofol
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`compositions wherein the closure is comprised of material that is inert to propofol selected
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`from a fluoropolymer, silicone, and mixtures thereof, and claims 24, 48, and 61 are directed
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`to propofol compositions wherein the closure is comprised of siliconized bromobutyl. The
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`sole discussion of siliconized bromobutyl in Lundgren occurs in Example 2 which is a
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`comparison of low molecular weight thrombin inhibitors in a water solution of HP~CD
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`versus a water solution of NaCl. Given the differences between low molecular weight
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`thrombin inhibitors and propofol described above, there would have been no motivation or
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`suggestion to utilize siliconized bromobutyl to prevent the degradation of pharmaceutical
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`propofol compositions.
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`In summary, it would not have been prima facie obvious to one of ordinary skill in the
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`art at the time the invention was made to have combined the composition of Zhang with the
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`teachings of Lundgren. Given the differences between peptides and propofols, one of
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`ordinary skill in the art could not expect them to behave in similar fashions and would have
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`no reasonable expectation of success even if one had combined references from non(cid:173)
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`analogous arts.
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`Page 15of16
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`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
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`

`
`Application No. 10/616,709
`
`Reply to Office Action
`
`In view of the foregoing, Applicants respectfully request that the obviousness
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`rejection be withdrawn.
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`Conclusion
`
`Applicants respectfully submit that the patent application is in condition for
`allowance. If in the opinion of the Examiner a telephone conference would expedite the
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`prosecution of the subject application, the Examiner is invited to call the undersigned
`
`attorney.
`
`Respectfully submitted,
`
`Peter H. Domer, Registration No. 60,072
`LEYDIG, VOIT & MAYER, LTD.
`Two Prudential Plaza, Suite 4900
`180 North Stetson A venue
`Chicago, Illinois 60601-6731
`(312) 616-5600 (telephone)
`(312) 616-5700 (facsimile)
`
`Date: November 5, 2009
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`Page 16of16
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`Fresenius Ex. 2030
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254