Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of claims
Claims 1 is original. Claims 2, 6-10, 14, 16-17, 19-20, 22, 26-28, and 30-31 are currently amended. Claims 3-5, 11-13, 15, 18, 21, 23-25, 29, and 32 are cancelled. Claims 1-2, 6-10, 14, 16-17, 19-20, 22, 26-28, and 30-31 are pending and under examination.
Priority
This application is a 371 of PCT/IB2022/055385, filed on 06/09/2022. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. PT117283, filed on 06/11/2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/01/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claim 2 is objected to because of the following informalities: Claim 2 recites " wherein the active agent selected from a list consisting of”. This is not grammatically correct. The suggested amendment is to "wherein the active agent is selected from a list consisting of”.
Claims 2 and 19 use the conjunction “and/or” or “or” in a group with Markush language “selected from a list consisting of” which is similar to “selected from the group consisting of….and…”. The “and/or” or “or” needs to be changed to “and”, if applicant means to allow “combinations thereof” in claim 2, then applicant may word this part of the claim with “...a steroid compound, an antiepileptic, and combinations thereof.”
Claim 10 is objected to because of the following informalities: Claim 10 recites “self-emulsifying composition according claim 1”. “according claim 1” is grammatically incorrect. The suggested amendment is to change this phrase to “according to claim 1”. Additionally, claim 10 recites “after cooling at 2-8° C. is less than or equal to 0.2”. The “.” currently included in “at 2-8° C. is less than” is grammatically incorrect. The suggested change is to amend this statement to “after cooling at 2-8° C is less than or equal to 0.2”.
Appropriate corrections are required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-2, 6-10, 14, 16-17, 19-20, 22, 26-28, and 30-31 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 contains the trademark/trade name “miglyol”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a medium chain triglyceride derived from coconut or palm kernel oil, and, accordingly, the identification/description is indefinite.
Claims 2, 6-10, 14, 16-17, 19-20, 22, 26-28, and 30-31 are rejected as being dependent on an indefinite claim.
Regarding claim 2, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 6 is indefinite for use of the phrase “selected from the list comprising” which is similar to “selected from the group comprising…”. See MPEP 2173.05(h) “If a Markush grouping requires a material selected from an open list of alternatives (e.g., selected from the group "comprising" or "consisting essentially of" the recited alternatives), the claim should generally be rejected under 35 U.S.C. 112(b) as indefinite because it is unclear what other alternatives are intended to be encompassed by the claim. See In re Kiely, 2022 USPQ2d 532 at 2* (Fed. Cir. 2022) (each independent claim recites "a selection from the group comprising a person, an animal, an animated character, a creature, an alien, a toy, a structure, a vegetable, and a fruit." … (emphasis added). "Given the breadth of variation among the specified alternatives and the use of the open-ended word ’comprising’ to define the scope of the list, we affirm the Board's conclusion that the pending claims recite improper Markush language and are indefinite under § 112(b).").”
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 8 recites the broad recitation cationic lipid, and the claim also recites “preferably wherein the cationic lipid is selected from a list consisting of….”, which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 8 recites a “cationic lipid… selected from a list consisting of cetalkonium chloride and dioleoyl-3-trimethylammonium propane”. Cetalkonium chloride is a quaternary ammonium surfactant, and is not a lipid. The claim therefore recites a genus of “cationic lipids” while including species that does not fall within that genus, rendering the claim indefinite.
Claim 9 recites the limitation "the cationic lipid" in the claim with dependence to claim 1, where “a cationic lipid” has not been introduced. There is insufficient antecedent basis for this limitation in the claim. A suggestion would be to make claim 9 dependent on claim 8 where “a cationic lipid” is introduced.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 9 recites the broad recitation the concentration of “the cationic lipid ranges from 0.01% to 1% (w/w)”, and the claim also recites “preferably 0.05 to 0.5% (w/w)” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 10 recites the limitation "the aqueous self-emulsifying composition" in the claim where “aqueous” is only mentioned for the emulsion while the “self-emulsifying composition” comes from claim 1 where no water/aqueous is introduced for that composition. Note the self-emulsifying composition in claim 10 is being used as one of the ingredients to make the aqueous emulsion. There is insufficient antecedent basis for this limitation in the claim. Applicant may provide this portion of the limitation as “concentration of the self-emulsifying composition…”
Claims 14, 16, 17, 19, 20, 22, and 26-27 are rejected as being dependent on indefinite claims that fail to correct the issue.
Claim 10 recites that “90% of the droplets comprise a dimension less than 200 nm”. Claim 14 recites “droplets comprise a dimension ranging from 90 to 120 nm”. However, neither the claims nor the specifications specify what “dimension” refers to (e.g., droplet radius, diameter, hydrodynamic diameter, Feret diameter, or other characteristic dimensions). No measurement basis is provided, and accordingly, claim 10 and 14 are indefinite.
Claims 16, 17, 19, 20, 22, and 26-27 are rejected as being dependent on indefinite claims that fail to correct the issue.
Claim 20 recites “further comprising a salt; preferably the salt is sodium chloride”. It is unclear whether sodium chloride is a required species of the salt or merely an optional, non-limiting embodiment. The use of the term “preferably” introduces ambiguity to the scope of the claim and fails to clearly define whether salts other than sodium chloride are within the scope of the claim. Accordingly, claim 20 is therefore indefinite.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 27 recites the broad recitation “stored at 2 to 25° C. for long periods of time” and the claim also recites “preferably periods longer than 6 months; more preferably for periods longer than 1 year” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 2, 28, and 30-31 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bezerra-Souza et al. (Bezerra-Souza A, Fernandez-Garcia R, Rodrigues GF, et al. Repurposing Butenafine as An Oral Nanomedicine for Visceral Leishmaniasis. Pharmaceutics. 2019;11(7):353. Published 2019 Jul 20. doi:10.3390/pharmaceutics11070353).
Bezerra-Souza et al. discloses the butenafine (active agent, self-nanoemulsifying drug delivery systems (BSNEDDS) against Leishmania infantum, said system comprising a non-ionic (neutral) hydrophilic surfactant Labrasol, Capryol 90 (propylene glycol monocaprylate) and Peceol (glyceryl monooleate). Bezerra-Souza et al. discloses a number of formulations, with Butenafine (30 mg/g) being solubilized within the excipients (page 3, section 2.4). Bezerra-Souza et al. teaches that these formulations are for oral (or enteral) administration (page 2, paragraph 4). In one embodiment (page 7, table 2, experiment 7), Bezerra-Souza et al. teaches such formulation comprising 9% (w/w) of labrasol, 61 % of Capryol 90 and 29% of Peceol, and thus having 90% w/w of a combination of two hydrophobic excipients in a mass ratio of 2.1 :1, which falls within the claimed range, in addition to having a particle size of 244 nm. In another embodiment (page 7, table 2, experiment 12), Bezerra-Souza et al. teaches the composition comprising 12% (w/w) of labrasol, 52% of Peceol and 35% of Capryol 90, and thus having 87% w/w of a combination of two hydrophobic excipients in a mass ratio of 1.5:1, which falls within the claimed range, and has a particle size of 167 nm. In another embodiment (page 7, section 3.2, combination A), Bezerra-Souza et al. teaches the composition comprising 15% (w/w) of labrasol, 58% of Capryol 90 and 27% of Peceol, thus having 85% w/w of a combination of two hydrophobic excipients in a mass ratio of 2:1 falling within the claimed range and have a particles size of 159.7 nm (page 8, paragraph 1, section 3.2).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 6 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Bezerra-Souza et al. (Bezerra-Souza A, Fernandez-Garcia R, Rodrigues GF, et al. Repurposing Butenafine as An Oral Nanomedicine for Visceral Leishmaniasis. Pharmaceutics. 2019;11(7):353. Published 2019 Jul 20. doi:10.3390/pharmaceutics11070353) in view of Hsu et al. et al. (US20100273730A1).
Bezerra-Souza et al. teaches all of the limitations previously stated, including a self-emulsifying composition comprising: a neutral hydrophilic surfactant with concentrations overlapping with 9-19% w/w; a combination of at least two hydrophobic excipients with concentrations overlapping with 81-91% w/w, at a mass ratio overlapping with 4:1 to 1.2:1, with propylene glycol monocaprylate being the first excipient, and the second excipient selected from the following list: glycerol monooleate, miglyol 812; glycerol monocaprylocaprate, soybean oil, type I glycerol monocaprylate, sorbitan monooleate, decyl oleate, glycerol monolinoleate, vitamin E, or mixtures thereof.
However, Bezerra-Souza et al. fails to teach the limitations of claim 2, where the composition has an active agent, wherein the active agent is selected from a list consisting of: a hydrophilic agent, and whose permeation of biological barriers such as mucous membranes and consequently absorption and bioavailability are improved by the formulation, a statin, a steroid compound and/or an antiepileptic. Bezerra-Souza et al. also fails to teach the limitations of claim 6, wherein the active agent from claim 2 is selected from a list comprising: atorvastatin, rosuvastatin, pravastatin, lovastatin, fluvastatin, pitavastatin, simvastatin, phenytoin, fosphenytoin, progesterone, nestorone or mixtures thereof. Bezerra-Souza et al. also fails to teach the limitations of claim 7, wherein the neutral hydrophilic surfactant from claim 1 is macrogolglycerol hydroxystearate (known as PEG 40 hydrogenated castor oil).
Hsu et al. discloses an oral self-emulsifying pharmaceutical composition of hydrophilic drugs and preparation thereof, further one or more solvents for solving the hydrophilic drug to form a drug-solvent solution and a surfactant system, further comprises one or more hydrophilic carrier which are compatible with said drug-solvent solution and the surfactant system (abstract). Hsu et al. teaches that one or more surfactants––such as propylene glycol monocaprylate and glyceryl monooleate (paragraph 33 and claim 7), PEG 40 hydrogenated castor oil (known as macrogolglycerol hydroxystearate, which is a neutral hydrophilic surfactant)---––can be included in the surfactant system of the composition. Hsu et al. teaches that the surfactant system is present in the composition an amount ranging from 20.0% to 75% (w/w) based on the weight of the pharmaceutical composition (paragraph 33). Hsu et al. teaches that the composition may contain water as the solvent, with its concentration ranging from 2.5% to 60% (w/w) based on the weight of the pharmaceutical composition (paragraph 32). Hsu et al. teaches that the composition may contain one or more hydrophilic carriers such as polyethylene glycol (PEG) (paragraph 32). Hsu et al. teaches that steroid drugs including progesterone can be included in the composition (paragraph 31).
It would have been obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to modify the self-emulsifying composition of Bezerra-Souza et al. with another active ingredient such as progesterone (a steroid) taught by Hsu et al., with the motivation being to provide an alternative therapeutic formulation for oral delivery of the drug using the same self-emulsifying carrier platform. Additionally, it would have been obvious to substitute the neutral hydrophilic surfactant (labrasol) taught by Bezerra-Souza et al. with an alternative neutral hydrophilic surfactant, namely PEG-40 hydrogenated castor oil, as taught by Hsu et al. for use in in self-emulsifying compositions–– as these conventional surfactants are widely known to be interchangeable based on formulation needs such as optimizing drug-solvent compatibility and enhancing self-emulsifying performance––rendering such variations a matter of routine and predictable optimization using well-established result-effective variables. A person of ordinary skill in the art would have had a reasonable expectation of success in making these substitutions because both references teach self-emulsifying oral-delivery systems employing similar classes of excipients and surfactants for solubilizing and delivering active agents, and Hsu et al. expressly demonstrates that steroid drugs such as progesterone and neutral hydrophilic surfactants such as PEG-40 hydrogenated castor oil are compatible with and function effectively in such self-emulsifying formulations, thereby indicating that the modified composition would be expected to form a stable and effective self-emulsifying system for oral delivery.
Claims 8 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Bezerra-Souza et al. (Bezerra-Souza A, Fernandez-Garcia R, Rodrigues GF, et al. Repurposing Butenafine as An Oral Nanomedicine for Visceral Leishmaniasis. Pharmaceutics. 2019;11(7):353. Published 2019 Jul 20. doi:10.3390/pharmaceutics11070353) in view of Aquilue et al. (US20190298737A1).
Bezerra-Souza et al. teaches all of the limitations previously stated, including a self-emulsifying composition comprising: a neutral hydrophilic surfactant with concentrations overlapping with 9-19% w/w; a combination of at least two hydrophobic excipients with concentrations overlapping with 81-91% w/w, at a mass ratio overlapping with 4:1 to 1.2:1, with propylene glycol monocaprylate being the first excipient, and the second excipient selected from the following list: glycerol monooleate, miglyol 812; glycerol monocaprylocaprate, soybean oil, type I glycerol monocaprylate, sorbitan monooleate, decyl oleate, glycerol monolinoleate, vitamin E, or mixtures thereof.
However, Bezerra-Souza et al. fails to teach the limitations of claim 8 and 9, which includes the composition according to claim 1 further comprising a cationic lipid; preferably wherein the cationic lipid is selected from a list consisting of cetalkonium chloride and dioleoyl-3-trimethylammonium propane; at concentrations overlapping with 0.01% to 1% (w/w), preferably 0.05 to 0.5% (w/w).
Aquilue et al. discloses an oil-in-water nanoemulsion composition having a continuous aqueous phase and dispersed oil droplets, wherein the nanoemulsion comprises: (a) clobetasol; (b) one or more oil components; and (c) one or more surfactants; together with one or more pharmaceutically acceptable excipients or carriers (abstract). Aquilue et al. teaches that the composition can be administered as an oral spray (paragraph 69). Aquilue et al. teaches that stabilizers such as polyvinylpyrrolidone, and hydroxypropyl methylcellulose can be included in the composition (paragraph 59). Aquilue et al. teaches that the composition can include polyoxyl 40 hydrogenated castor oil as a hydrophilic surfactant (paragraph 46). Aquilue et al. teaches that the composition can include hydrophobic excipients including glyceryl monooleate (paragraph 46). Aquilue et al. teaches that the composition can include a penetration enhancer such as cetalkonium chloride at concentrations ranging from 0.01% to 10% w/w (paragraph 64).
It would have been obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to incorporate the cetalkonium chloride taught by Aquilue et al. into the self-emulsifying composition taught by Bezerra-Souza et al. This is because Bezerra-Souza et al. teaches nano-emulsions containing an active agent, hydrophobic excipients, and a neutral hydrophilic surfactant. Concurrently, Aquilue et al. teaches that cetalkonium chloride is a pharmaceutically acceptable cationic excipient suitable to use in nano-emulsion compositions comprising an active agent, hydrophobic excipients, and neutral hydrophilic surfactants––at concentrations overlapping with those in the present claims. Therefore, a person of ordinary skill in the art would have been motivated to incorporate the cetalkonium chloride taught by Aquilue et al. into the self-emulsifying nano-emulsion taught by Bezerra-Souza et al. to enhance its penetration. Additionally, since Aquilue et al. teaches cetalkonium chloride and its concentration range to be compatible and conventional for such nano-emulsions, a person of ordinary skill in the art would have had a reasonable expectation of success in combining the above teachings to arrive at the claimed invention.
Claims 10, 14, 16-17, 19-20, 22, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Bezerra-Souza et al. (Bezerra-Souza A, Fernandez-Garcia R, Rodrigues GF, et al. Repurposing Butenafine as An Oral Nanomedicine for Visceral Leishmaniasis. Pharmaceutics. 2019;11(7):353. Published 2019 Jul 20. doi:10.3390/pharmaceutics11070353) in view of Hsu et al. (US20100273730A1) in further view of Wooster et al. (US20190085034A1).
Bezerra-Souza et al. teaches all of the limitations previously stated, including a self-emulsifying composition comprising: a neutral hydrophilic surfactant with concentrations overlapping with 9-19% w/w; a combination of at least two hydrophobic excipients with concentrations overlapping with 81-91% w/w, at a mass ratio overlapping with 4:1 to 1.2:1, with propylene glycol monocaprylate being the first excipient, and the second excipient selected from the following list: glycerol monooleate, miglyol 812; glycerol monocaprylocaprate, soybean oil, type I glycerol monocaprylate, sorbitan monooleate, decyl oleate, glycerol monolinoleate, vitamin E, or mixtures thereof.
However, Bezerra-Souza et al. fails to teach the limitations of claims 10, 14, 16-17, 19-20, 22, and 26.
Hsu et al. discloses an oral self-emulsifying pharmaceutical composition of hydrophilic drugs and preparation thereof, further comprising one or more solvents for solving the hydrophilic drug to form a drug-solvent solution and a surfactant system, further comprising one or more hydrophilic carrier which are compatible with said drug-solvent solution and the surfactant system (abstract). Hsu et al. teaches that one or more surfactants––such as propylene glycol monocaprylate, glyceryl monooleate, PEG 40 hydrogenated castor oil (known as macrogolglycerol hydroxystearate, which is a neutral hydrophilic surfactant)--––can be included in the surfactant system of the composition (paragraph 33). Hsu et al. teaches that the surfactant system may be present in the composition an amount ranging from 20.0% to 75% (w/w) based on the weight of the pharmaceutical composition (paragraph 33), which overlaps with the aqueous self-emulsifying composition being at least 0.1% (w/w) per present claim 10. Hsu et al. teaches that the composition may contain water as the solvent at concentrations ranging from 2.5% to 60% (w/w) based on the weight of the pharmaceutical composition (paragraph 32), which overlaps with the composition comprising at least 50% (w/w) of water per present claim 10. Hsu et al. teaches that the composition may contain one or more hydrophilic carriers such as polyethylene glycol (PEG) (paragraph 32), which satisfies all limitations of present claims 17 and 19. Hsu et al. teaches that hydrophilic drugs including progesterone can be included in the composition at concentrations ranging from 0.2% to about 15% (w/w) based on the weight of the pharmaceutical composition, which overlaps with the claimed active agent ranges of up to 100 mg/g, per present claim 22. Hsu et al. teaches that the composition may be administered orally (paragraph 44). Hsu et al. teaches that the composition according to the invention may also exhibit good stability during storage (paragraph 34).
Wooster et al. discloses particles, including nanoparticles and microparticles, and pharmaceutical formulations thereof, comprising conjugates of an active agent such as a therapeutic, prophylactic, or diagnostic agent attached to a targeting moiety via a linker (abstract). Wooster et al. teaches that the formulation can include self-assembling particles (paragraph 7). Wooster et al. teaches that the particles in the composition can be a lipid micelle, which can be formed as a water-in-oil emulsion with a lipid surfactant (paragraph 175). Wooster et al. teaches that active ingredients, such as lovastatin, fosphenytoin, and progesterone, can be included in the composition (paragraph 72 and 508). Wooster et al. teaches that 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) can be added to such compositions as cationic lipids (paragraph 180). Wooster et al. teaches that Cold Homogenization method can be used to prepare such emulsions (including liposomes and micelles), with the process involving using a cold surfactant system to cool the composition to below room-temperature (paragraph 443), encompassing the temperature range of 2-8° C as stated in present claims 10 and 16, and the temperature range of 2 to 37° C stated in present claim 26. Wooster et al. teaches that another method (solvent dilution) can be used to prepare such emulsions, which involves reducing the temperature of the system via cold water from about 0 to about 10° C (paragraph 404), and thus also overlaps the temperature range of 2-8° C as stated in present claims 10 and 16, in addition to the temperature range of 2 to 37° C stated in present claim 26. Wooster et al. teaches that the particles of the composition may have a Polydispersity index (PDI) of ≤0.2, or ≤ 0.1 (paragraph 135), which encompasses the PDIs stated in present claims 10 and 16, and the homogeneity limitation stated in claim 26. Wooster et al. teaches that the particles in the composition may be nanoparticles having a diameter from about 70 nm to about 130 nm (paragraph 135), which overlaps with the droplet sizes in present claims 10 and 14. Wooster et al. teaches that the composition may be suitable for nasal (or parenteral) administration, having an average particle and/or droplet size in the range from about 0.1 nm to about 200 nm (paragraph 387), which also overlaps with the droplet sizes in present claims 10 and 14, taking into account the stated option of the droplets in the composition having a PDI of ~0. Wooster et al. teaches that the composition may contain sodium chloride (paragraph 248), which satisfies the limitations of present claim 20. Wooster et al. teaches that the particles of the composition may be administered orally and intranasally (paragraph 352).
It would have been obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to modify the self-emulsifying composition of Bezerra-Souza et al. to form an aqueous self-emulsifying emulsion comprising water, and optional hydrophilic carriers, and having controlled particle size and polydispersity characteristics, as taught by Hsu et al. and Wooster et al., in order to obtain an aqueous dispersed self-emulsifying formulation suitable for oral administration. Particularly, Hsu et al. teaches that self-emulsifying pharmaceutical compositions may comprise water, surfactant systems, and hydrophilic carriers including polyethylene glycol, in addition to containing active ingredients––all at concentrations overlapping with those in the present claims (see MPEP 2144.05). Concurrently, Wooster et al. teaches lipid and surfactant-based nanoparticle systems including emulsions having size ranges, PDI ranges, storage temperature ranges, and salts that overlap with those in the present claims, for nasal and oral administration of active agents. A person of ordinary skill in the art would have had a reasonable expectation of success combining these teachings because all three references are directed closely to lipid and surfactant-based emulsions suitable for oral delivery of active agents, in addition to the fact that both Wooster et al. and Hsu et al. collectively demonstrate that such systems can routinely be formulated to achieve stable aqueous emulsions with controlled particle size and low polydispersity using conventional techniques, thereby indicating that the modified self-emulsifying composition of Bezerra-Souza et al. may be routinely optimized by working within ranges of the prior art to predictably form a stable aqueous emulsion that meets the claimed droplet size, polydispersity, temperature handling, and excipient limitations stated in the present claims.
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Bezerra-Souza et al. (Bezerra-Souza A, Fernandez-Garcia R, Rodrigues GF, et al. Repurposing Butenafine as An Oral Nanomedicine for Visceral Leishmaniasis. Pharmaceutics. 2019;11(7):353. Published 2019 Jul 20. doi:10.3390/pharmaceutics11070353) in view of Hsu et al. (US20100273730A1) in further view of Wooster et al. (US20190085034A1) in further view of Ensign et al. (US20150297531A1).
Bezerra-Souza et al., Hsu et al., and Wooster et al. collectively teach all limitations of claim 10, including an aqueous emulsion comprising the self-emulsifying composition according claim 1, wherein the concentration of the aqueous self-emulsifying composition is at least 0.1% (w/w) and at least 50% (w/w) of water, wherein 90% of the droplets comprise a dimension less than 200 nm, wherein the polydispersity index after cooling at 2-8° C. is less than or equal to 0.2.
However, Bezerra-Souza et al., Hsu et al., and Wooster et al. fail to collectively teach the limitations of Claim 27, The aqueous emulsion according to claim 10, wherein the conditions is guaranteed that promote chemical and microbiological stability of the preparation; the emulsion maintains physical stability when stored at 2 to 25° C. for long periods of time; preferably periods longer than 6 months; more preferably for periods longer than 1 year.
Ensign et al. evaluated hypotonic formulations for delivering water-soluble drugs and for drug delivery with muco-inert (that is, non-adhesive) mucus-penetrating nanoparticles (abstract). Ensign et al. teaches that the composition may include emulsions (paragraph 80), which include self-emulsifying systems (paragraph 154). Ensign et al. teaches that the emulsifier in the composition can be positively charged, negatively charged, or neutral (paragraph 76). Ensign et al. teaches that the particles in the composition may have surface-alternating agents (paragraph 64), which include surfactants (paragraph 65). Ensign et al. teaches that examples of such surfactants is glyceryl monooleate (paragraph 66). Ensign et al. teaches that oral dosage forms of the composition may include pharmaceutically acceptable excipients including stabilizers and preservatives, and combinations thereof (paragraph 163). Ensign et al. teaches that the nanoparticles retain their article size and ζ-potential after storage for at least 1 month, more preferably at least 2 months, most preferably at least 3 months at 4° C (paragraph 78).
It would have been obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention, to combine the teachings of Bezerra-Souza et al., Hsu et al., Wooster et al., and Ensign et al. to further formulate the aqueous self-emulsifying composition of Bezerra-Souza et al. under conditions that promote chemical, microbiological, and physical stability during storage, by incorporating stabilizers and preservatives as taught by ensign et al. for emulsion-based oral dosage forms. Ensign et al. teaches that oral dosage forms comprising emulsion systems may include pharmaceutically acceptable stabilizers and preservatives, which would both inhibit microbial growth and thereby promote microbiological stability of the composition during storage. A person of ordinary skill in the art would have further had a reasonable expectation of success in achieving the claimed stability because Ensign et al. demonstrates that such formulations retain particle size and zeta-potential for preferably at least three months at storage temperatures that overlap with those in the present claims. Retention of size and charge is recognized in the art as an indicator that the dispersed system remains physically stable and the interfacial and colloidal properties of the composition are maintained, which is further indicative of chemical stability of the formulation components during storage.
Conclusions
No claim is found allowable.
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Arya A. Bazargani, Ph.D.
Patent Examiner
Art Unit 1613
/MARK V STEVENS/Primary Examiner, Art Unit 1613