DETAILED ACTION
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 .
Election/Restrictions
Applicant’s election with traverse of Group I, and election without traverse the species of water in the reply filed on September 1, 2026 are acknowledged.
The traversal is on the ground that Groups I-IV share a special technical feature because Schneider fails to disclose the “calibrated” fluorocarbon cross-linked vesicles. This is not found persuasive because Schneider discloses a nanopeptisome comprising a perfluorocarbon and amphiphilic peptides as discussed in the Office Action mailed July 2, 20206. Schneider discloses that the compound can be cross-linked and its particle size can be precisely controlled. A z-average diameter and a polydispersity are result-effective parameters that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the optimal ratio for achieving the desired droplet characteristics. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See MPEP § 2144. Accordingly, the technical feature fails to distinguish the claimed subject matter over the prior art and does not constitute a special technical feature.
The requirement is still deemed proper and is therefore made FINAL.
Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they do not include the following reference sign mentioned in the description: core portion 100 (¶ 111 of PGPub of instant application). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
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 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 1-14 are rejected under 35 U.S.C. 103 as being unpatentable over Melich et al. (International Journal of Pharmaceutics, 2020; cited on IDS filed May 9, 2024) in view of Schneider et al. (WO 2019 023706; cited on IDS files May 9, 2024) and Riché et al. (American laboratory, 2006, cited on PTO-892).
Regarding claims 1, 3, 5, and 6, Melich discloses a method for the preparation of perfluorocarbon nanodroplets (PFC-NDs) using a microfluidic platform (page 2, column 2, ¶ 5). Melich discloses that the method can comprise preparing an aqueous phase comprising water; preparing an organic phase comprising PFC and coating agent such as fluorinated surfactant or lipid; injecting the aqueous phase into the first inlet of the microfluidic cartridge; injecting the organic phase into the second inlet of the microfluidic cartridge; performing laminar mixing; and collecting the PFC NDs suspension from the exit channel (page 2, column 2, ¶ 5 - page 3, column 1, ¶ 1; Fig. 1). Melich discloses that the NDs can have a mean diameter of about 287 nm with a very good uniformity (polydispersity index of 0.078), as determined by dynamic light scattering analysis (page 3, column 1, ¶ 2; page 5, column 2, ¶ 3; Table2), indicating “calibrated” fluorocarbon vesicles (¶ 51 of PGPUb of instant application). Regarding claims 1, 7, and 8, Melich discloses that the microfluidic process can be carried out at room temperature (page 4, column 1, ¶ 1). Regarding claim 4, Melich discloses that ultrapure water obtained via Millipore® unit can be used for the aqueous phase (page 2, column 2, ¶ 4; Table 1). Riché discloses that the pH of ultrapure water is practically 5.8 though it is theoretically 6.998 (page 1, column 2, ¶ 1 – page 2, column 1, ¶ 1). Regarding claim 13, Melich discloses that the collected NDs can be diluted with ultrapure water (page 3, column 1, ¶ 1).
Melich does not disclose a cross-linkable amphiphilic peptide and a corresponding cross-linking step e) (instant claims 1, 2, and 9). Melich does not disclose an oxidizing source (instant claims 9 and 11), a time sufficient to induce a degree of cross-linking of the amphiphilic peptides of 90% or greater (instant claim 10), a dialysis procedure (instant claim 12), and a washing step f) (instant claim 14).
Schneider discloses a nanopeptisome comprising a perfluorocarbon liquid core and amphiphilic peptides surrounding the core (abstract). Schneider discloses that the amphiphilic peptides can comprise cross-linking motif (claim 2) and that cross-linking can be conducted in an aqueous solution including dimethyl sulfoxide (DMSO) or any other organic solvent capable of oxidizing and cross-linking thiol groups of cysteine amino acids (¶ 129). Schneider discloses that additional bubbling air can be employed to further promote oxidation, which reads on utilizing an oxidizing gas (¶ 145; ¶ 152). Schneider discloses a graph tracking cross-linking formation versus time in the presence of a 5% DMSO oxidizing agent (FIG. 6). Schneider discloses that the cross-linking can be performed during dialysis (¶ 129). Schneider discloses that the resulting product can be subsequently dialyzed with water (washing) and then collected (¶ 145; ¶ 192).
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 method of Melich by using amphiphilic peptide comprising cross-linking motif as the coating agent of Melich, alongside the cross-linking, dialysis, and washing steps taught by Scheider in order to prepare more effective fluorocarbon cross-linked vesicles. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Schneider teaches a cross-linkable amphiphilic peptide surfactant along with the necessary processing steps for cross-linking, dialysis, and washing. Further, a person of ordinary skill in the art would have been motivated to utilize a cross-linkable amphiphilic peptide instead of standard surfactants to produce more stable and biocompatible vesicles tailored for pharmaceutical applications. A person of ordinary skill in the art would have been motivated to optimize the cross-linking condition such as reaction time according to the specific requirements of the intended applications. The cross-linking condition is a clearly result-effective parameters that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the cross-linking condition such as a reaction time sufficient to induce a degree of cross-linking of the amphiphilic peptides of 90% or greater in order to best achieve the desired cross-linked vesicle property. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See MPEP § 2144. Similarly, the temperature and pH of the aqueous phase are matter of routine optimization well within the purview of a person of ordinary skill in the art in order to best achieve the desired calibrated fluorocarbon vehicles as such conditions determine the properties of the vehicles. Selecting whether to incorporate the cross-linkable amphiphilic peptide into the aqueous or organic phase as well as executing specific dialysis and washing steps, represents a matter of design choice that a person of ordinary skill in the art could appropriately adjust depending on the experimental conditions and desired results.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims of copending Application No. 18/036,018 in view of Melich et al. (International Journal of Pharmaceutics, 2020; cited on IDS filed May 9, 2024), Schneider et al. (WO 2019 023706; cited on IDS files May 9, 2024), and Riché et al. (American laboratory, 2006, cited on PTO-892).
Regarding claims 1 and 2, claim 9 of the ‘018 recites a method for the preparation of an aqueous suspension of calibrated fluorocarbon nanodroplets, said nanodroplets comprising an outer layer and an inner core, said outer layer comprising a biocompatible fluorinated surfactant and said inner core comprising a fluorocarbon, said method comprising the steps of: a) Preparing an aqueous phase; b) Preparing an organic phase, wherein i) said aqueous phase comprises said biocompatible fluorinated surfactant and the organic phase comprises said fluorocarbon or ii) said organic phase comprises said biocompatible fluorinated surfactant and said fluorocarbon; c) Injecting said aqueous phase into a first inlet and said organic phase into a second inlet of a microfluidic cartridge, thereby mixing said aqueous phase and said organic phase in a mixing device of the microfluidic cartridge to obtain an aqueous suspension of calibrated fluorocarbon nanodroplets, and d) Collecting the aqueous suspension of calibrated fluorocarbon nanodroplets from the exit channel of the microfluidic cartridge. Claim 19 of the ‘018 recites that the nanodroplets can have a z-average diameter comprised between 100 nm and 1000 nm and a polydispersity lower than 0.25, indicating “calibrated” fluorocarbon vesicles. Regarding claim 3, claim 11 of the ‘018 recites that the fluorocarbon can be a perfluorocarbon. Regarding claims 4-6, claim 15 of the ‘018 recites that the aqueous liquid can be water. Riché discloses that the pH of ultrapure water is practically 5.8 though it is theoretically 6.998 (page 1, column 2, ¶ 1 – page 2, column 1, ¶ 1). Regarding claim 13, claim 14 of the ‘018 recites that the collected suspension of calibrated fluorocarbon nanodroplets can be diluted.
Claims of the ‘018 do not recite aqueous phase in specific temperature such as room temperature. Claims of the ‘018 do not recite a cross-linkable amphiphilic peptide, and cross-linking step and conditions using an oxidizing source such as a mixture of an oxidizing solution and an oxidizing gas. Claims of the ‘018 do not recite that dialysis and washing steps.
As discussed above, Melich discloses a method for the preparation of PFC-NDs using a microfluidic platform (page 2, column 2, ¶ 5). Melich discloses that the microfluidic process can be carried out at room temperature (page 4, column 1, ¶ 1).
As discussed above, Schneider discloses a nanopeptisome comprising a perfluorocarbon liquid core and amphiphilic peptides surrounding the core (abstract). Schneider discloses that the amphiphilic peptides can comprise cross-linking motif (claim 2) and that cross-linking can be conducted in an aqueous solution including dimethyl sulfoxide (DMSO) or any other organic solvent capable of oxidizing and cross- linking thiol groups of cysteine amino acids (¶ 129). Schneider discloses that additional bubbling air can be employed to further promote oxidation, which reads on utilizing an oxidizing gas (¶ 145; ¶ 152). Schneider discloses a graph tracking cross-linking formation versus time in the presence of a 5% DMSO oxidizing agent (FIG. 6). Schneider discloses that the cross-linking can be performed during dialysis (¶ 129). Schneider discloses that the resulting product can be subsequently dialyzed with water (washing) and then collected (¶ 145; ¶ 192).
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 method of the ‘018 by using an amphiphilic peptide comprising cross-linking motif as a biocompatible surfactant, alongside the cross-linking, dialysis, and washing steps taught by Scheider in order to prepare more effective fluorocarbon cross-linked vesicles. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Schneider teaches a cross-linkable peptide surfactant along with the necessary processing steps for cross-linking, dialysis, and washing. Further, a person of ordinary skill in the art would have been motivated to utilize a cross-linkable amphiphilic peptide instead of standard surfactants to produce more stable and biocompatible vesicles tailored for pharmaceutical applications. A person of ordinary skill in the art would have been motivated to optimize the cross-linking condition such as reaction time according to the specific requirements of the intended applications. The cross-linking condition is a clearly result-effective parameters that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the cross-linking condition such as a reaction time sufficient to induce a degree of cross-linking of the amphiphilic peptides of 90% or greater in order to best achieve the desired cross-linked vesicle property. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See MPEP § 2144. Similarly, the temperature and pH of the aqueous phase are matter of routine optimization well within the purview of a person of ordinary skill in the art in order to best achieve the desired calibrated fluorocarbon vehicles as such conditions determine the properties of the vehicles. Selecting whether to incorporate the cross-linkable amphiphilic peptide into the aqueous or organic phase as well as executing specific dialysis and washing steps, represents a matter of design choice that a person of ordinary skill in the art could appropriately adjust depending on the experimental conditions and desired results.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims of copending Application No. 18/722,126 in view of Melich et al. (International Journal of Pharmaceutics, 2020; cited on IDS filed May 9, 2024), Schneider et al. (WO 2019 023706; cited on IDS files May 9, 2024), and Riché et al. (American laboratory, 2006, cited on PTO-892).
Regarding claims 1 and 2, claim 1 of the ‘126 recites a method for the preparation of an aqueous suspension of calibrated nanodroplets said nanodroplets comprising an outer shell and an inner core, wherein said outer shell comprises an amphiphilic component and said inner core comprises a low boiling fluorinated compound, said method comprising: a) Preparing an aqueous phase; b) Preparing an organic phase; wherein - said aqueous phase comprises an amphiphilic component and the organic phase comprises a low boiling fluorinated compound or - said organic phase comprises an amphiphilic component and a low boiling fluorinated compound; c) Injecting said aqueous phase into a first inlet and said organic phase into a second inlet of a microfluidic cartridge thereby mixing said aqueous phase and said organic phase in a mixing device of the microfluidic cartridge to obtain an aqueous suspension of calibrated nanodroplets; and d) Collecting the aqueous suspension of calibrated nanodroplets from the exit channel of the microfluidic cartridge. Claim 15 of the ‘126 recites that the vesicles can have a z-average diameter comprised between 100 nm and 1000 nm and a polydispersity lower than 0.20, indicating “calibrated” fluorocarbon vesicles. Regarding claims 1 and 3, claim 4 of the ‘126 recites that the fluorinated compound can be a perfluorocarbon.
Claims of the ‘126 do not recite aqueous phase comprising specific component such as water in specific temperature such as room temperature and pH lower than 7.0. Claims of the ‘126 do not recite a cross-linkable amphiphilic peptide and cross-linking step and conditions. Claims of the ‘126 do not recite that dialysis, diluting, and washing steps.
As discussed above, Melich discloses a method for the preparation of PFC-NDs using a microfluidic platform (page 2, column 2, ¶ 5). Melich discloses that the method can comprise injecting an aqueous phase such as water into the first inlet of the microfluidic cartridge (page 2, column 2, ¶ 5-page 3, column 1, ¶ 1; Fig. 1). Melich discloses that the microfluidic process can be carried out at room temperature (page 4, column 1, ¶ 1). Melich discloses that ultrapure water obtained via Millipore® unit can be used for the aqueous phase (page 2, column 2, ¶ 4; Table 1). Riché discloses that the pH of ultrapure water is practically 5.8 though it is theoretically 6.998 (page 1, column 2, ¶ 1 – page 2, column 1, ¶ 1). Melich discloses that the collected NDs can be diluted with ultrapure water (page 3, column 1, ¶ 1).
As discussed above, Schneider discloses a nanopeptisome comprising a perfluorocarbon liquid core and amphiphilic peptides surrounding the core (abstract). Schneider discloses that the amphiphilic peptides can comprise cross-linking motif (claim 2) and that cross-linking can be conducted in an aqueous solution including dimethyl sulfoxide (DMSO) or any other organic solvent capable of oxidizing and cross- linking thiol groups of cysteine amino acids (¶ 129). Schneider discloses that additional bubbling air can be employed to further promote oxidation, which reads on utilizing an oxidizing gas (¶ 145; ¶ 152). Schneider discloses a graph tracking cross-linking formation versus time in the presence of a 5% DMSO oxidizing agent (FIG. 6). Schneider discloses that the cross-linking can be performed during dialysis (¶ 129). Schneider discloses that the resulting product can be subsequently dialyzed with water (washing) and then collected (¶ 145; ¶ 192).
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 method of the ‘126 by using an aqueous phase comprising water and amphiphilic peptide comprising cross-linking motif as an amphiphilic component, alongside cross-linking, dialysis, dilution, and washing steps taught by Melich and Scheider in order to prepare more effective fluorocarbon cross-linked vesicles. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Melich teaches an aqueous phase comprising water and a dilution step; and Schneider teaches a cross-linkable peptide surfactant and steps for cross-linking, dialysis, and washing. Further, a person of ordinary skill in the art would have been motivated to utilize a cross-linkable amphiphilic peptide instead of standard surfactants to produce more stable and biocompatible vesicles tailored for pharmaceutical applications. A person of ordinary skill in the art would have been motivated to optimize the cross-linking condition such as reaction time according to the specific requirements of the intended applications. The cross-linking condition is a clearly result-effective parameters that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the cross-linking condition such as a reaction time sufficient to induce a degree of cross-linking of the amphiphilic peptides of 90% or greater in order to best achieve the desired cross-linked vesicle property. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See MPEP § 2144. Similarly, the temperature and pH of the aqueous phase are matter of routine optimization well within the purview of a person of ordinary skill in the art in order to best achieve the desired calibrated fluorocarbon vehicles as such conditions determine the properties of the vehicles. Selecting whether to incorporate the cross-linkable amphiphilic peptide into the aqueous or organic phase as well as executing specific dialysis and washing steps, represents a matter of design choice that a person of ordinary skill in the art could appropriately adjust depending on the experimental conditions and desired results.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims of copending Application No. 18/864,464 in view of Melich et al. (International Journal of Pharmaceutics, 2020; cited on IDS filed May 9, 2024), Schneider et al. (WO 2019 023706; cited on IDS files May 9, 2024), and Riché et al. (American laboratory, 2006, cited on PTO-892).
Regarding claims 1 and 2, claim 6 of the ‘464 recites a method for the preparation of an aqueous suspension comprising a plurality of nanodroplets, said nanodroplets comprising an outer layer and an inner core, said outer layer comprising a biocompatible fluorinated surfactant, and said inner core comprising a fluorinated compound, said method comprising the steps of: a) preparing an aqueous phase; b) preparing an organic phase, wherein i) said aqueous phase comprises a biocompatible fluorinated surfactant or a mixture thereof and the organic phase comprises a fluorinated compound or ii) said organic phase comprises a biocompatible fluorinated surfactant or a mixture thereof, a fluorinated compound; c) injecting said aqueous phase into a first inlet and said organic phase into a second inlet of a microfluidic cartridge, thereby mixing said aqueous phase and said organic phase in a mixing device of the microfluidic cartridge to obtain said aqueous suspension; and d) collecting said aqueous suspension from the exit channel of the microfluidic cartridge. Claim 5 of the ‘464 recites that the vesicles can have a z-average diameter comprised between 100 nm and 1000 nm and a polydispersity lower than 0.25, indicating “calibrated” vesicles. Regarding claims 1 and 3, claim 8 of the ‘464 recites that the fluorinated compound can be a perfluorocarbon. Regarding claim 13, claim 13 of the ‘464 recites that the collected aqueous suspension can be diluted.
Claims of the ‘464 do not recite aqueous phase comprising specific component such as water in specific temperature such as room temperature and pH lower than 7.0. Claims of the ‘464 do not recite a cross-linkable amphiphilic peptide and cross-linking step and conditions. Claims of the ‘464 do not recite that dialysis and washing steps.
As discussed above, Melich discloses a method for the preparation of PFC-NDs using a microfluidic platform (page 2, column 2, ¶ 5). Melich discloses that the method can comprise injecting an aqueous phase such as water into the first inlet of the microfluidic cartridge (page 2, column 2, ¶ 5-page 3, column 1, ¶ 1; Fig. 1). Melich discloses that the microfluidic process can be carried out at room temperature (page 4, column 1, ¶ 1). Melich discloses that ultrapure water obtained via Millipore® unit can be used for the aqueous phase (page 2, column 2, ¶ 4; Table 1). Riché discloses that the pH of ultrapure water is practically 5.8 though it is theoretically 6.998 (page 1, column 2, ¶ 1 – page 2, column 1, ¶ 1).
As discussed above, Schneider discloses a nanopeptisome comprising a perfluorocarbon liquid core and amphiphilic peptides surrounding the core (abstract). Schneider discloses that the amphiphilic peptides can comprise cross-linking motif (claim 2) and that cross-linking can be conducted in an aqueous solution including dimethyl sulfoxide (DMSO) or any other organic solvent capable of oxidizing and cross- linking thiol groups of cysteine amino acids (¶ 129). Schneider discloses that additional bubbling air can be employed to further promote oxidation, which reads on utilizing an oxidizing gas (¶ 145; ¶ 152). Schneider discloses a graph tracking cross-linking formation versus time in the presence of a 5% DMSO oxidizing agent (FIG. 6). Schneider discloses that the cross-linking can be performed during dialysis (¶ 129). Schneider discloses that the resulting product can be subsequently dialyzed with water (washing) and then collected (¶ 145; ¶ 192).
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 method of the ‘464 by using an aqueous phase comprising water and amphiphilic peptide comprising cross-linking motif as an amphiphilic component, alongside cross-linking, dialysis, and washing steps taught by Scheider in order to prepare more effective fluorocarbon cross-linked vesicles. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Melich teaches an aqueous phase comprising water; and Schneider teaches a cross-linkable peptide surfactant and steps for cross-linking, dialysis, and washing. Further, a person of ordinary skill in the art would have been motivated to utilize a cross-linkable amphiphilic peptide instead of standard surfactants to produce more stable and biocompatible vesicles tailored for pharmaceutical applications. A person of ordinary skill in the art would have been motivated to optimize the cross-linking condition such as reaction time according to the specific requirements of the intended applications. The cross-linking condition is a clearly result-effective parameters that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the cross-linking condition such as a reaction time sufficient to induce a degree of cross-linking of the amphiphilic peptides of 90% or greater in order to best achieve the desired cross-linked vesicle property. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See MPEP § 2144. Similarly, the temperature and pH of the aqueous phase are matter of routine optimization well within the purview of a person of ordinary skill in the art in order to best achieve the desired calibrated fluorocarbon vehicles as such conditions determine the properties of the vehicles. Selecting whether to incorporate the cross-linkable amphiphilic peptide into the aqueous or organic phase as well as executing specific dialysis and washing steps, represents a matter of design choice that a person of ordinary skill in the art could appropriately adjust depending on the experimental conditions and desired results.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims of copending Application No. 19/139,565 in view of Melich et al. (International Journal of Pharmaceutics, 2020; cited on IDS filed May 9, 2024), Schneider et al. (WO 2019 023706; cited on IDS files May 9, 2024), and Riché et al. (American laboratory, 2006, cited on PTO-892).
Regarding claims 1, 2, and 13, claims 1 and 20 of the ‘565 recites a method for the preparation of an aqueous suspension comprising a plurality of cross-linked vesicles comprising an outer layer and an inner core, said outer layer comprising a cationic amphiphilic peptide and said inner core comprising a fluorinated compound in liquid form, comprising the steps of: a) Preparing an aqueous phase comprising a cationic amphiphilic peptide, wherein the pH of said aqueous phase is 4 or lower; b) Preparing an organic phase, comprising a fluorinated compound; c) Injecting said aqueous phase in a first inlet and said organic phase in a second inlet of a microfluidic cartridge, thereby mixing said aqueous phase and said organic phase in a mixing portion of the microfluidic cartridge to obtain an aqueous suspension of vesicles; d) Collecting the aqueous suspension of cross-linkable vesicles from an exit channel of the microfluidic cartridge; f) Diluting the aqueous suspension of cross-linkable vesicles; and e) Cross-linking the cationic amphiphilic peptides to obtain an aqueous suspension of cross-linked vesicles. Claim 19 of the ‘565 recites that the vesicles can have a z-average diameter comprised between 100 nm and 1000 nm and a polydispersity lower than 0.2, indicating “calibrated” vesicles. Regarding claims 1 and 3, claim 5 of the ‘565 recites that the fluorinated compound can be a perfluorocarbon.
Claims of the ‘565 do not recite aqueous phase comprising specific component such as water in specific temperature such as room temperature and pH lower than 7.0. Claims of the ‘565 do not recite an oxidizing source and cross-linking conditions. Claims of the ‘565 do not recite that dialysis and washing steps.
As discussed above, Melich discloses a method for the preparation of PFC-NDs using a microfluidic platform (page 2, column 2, ¶ 5). Melich discloses that the method can comprise injecting an aqueous phase such as water into the first inlet of the microfluidic cartridge (page 2, column 2, ¶ 5-page 3, column 1, ¶ 1; Fig. 1). Melich discloses that ultrapure water obtained via Millipore® unit can be used for the aqueous phase (page 2, column 2, ¶ 4; Table 1). Riché discloses that the pH of ultrapure water is practically 5.8 though it is theoretically 6.998 (page 1, column 2, ¶ 1 – page 2, column 1, ¶ 1). Melich discloses that the microfluidic process can be carried out at room temperature (page 4, column 1, ¶ 1).
As discussed above, Schneider discloses a nanopeptisome comprising a perfluorocarbon liquid core and amphiphilic peptides surrounding the core (abstract). Schneider discloses that the amphiphilic peptides can comprise cross-linking motif (claim 2) and that cross-linking can be conducted in an aqueous solution including dimethyl sulfoxide (DMSO) or any other organic solvent capable of oxidizing and cross- linking thiol groups of cysteine amino acids (¶ 129). Schneider discloses that additional bubbling air can be employed to further promote oxidation, which reads on utilizing an oxidizing gas (¶ 145; ¶ 152). Schneider discloses a graph tracking cross-linking formation versus time in the presence of a 5% DMSO oxidizing agent (FIG. 6). Schneider discloses that the cross-linking can be performed during dialysis (¶ 129). Schneider discloses that the resulting product can be subsequently dialyzed with water (washing) and then collected (¶ 145; ¶ 192).
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 method of the ‘565 by using an aqueous phase comprising water, alongside cross-linking, dialysis, and washing steps taught by Scheider in order to prepare more effective fluorocarbon cross-linked vesicles. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Melich teaches an aqueous phase comprising water; and Schneider teaches a cross-linkable peptide surfactant and steps for cross-linking, dialysis, and washing. Further, a person of ordinary skill in the art would have been motivated to utilize a cross-linkable amphiphilic peptide instead of standard surfactants to produce more stable and biocompatible vesicles tailored for pharmaceutical applications. A person of ordinary skill in the art would have been motivated to optimize the cross-linking condition such as reaction time according to the specific requirements of the intended applications. The cross-linking condition is a clearly result-effective parameters that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the cross-linking condition such as a reaction time sufficient to induce a degree of cross-linking of the amphiphilic peptides of 90% or greater in order to best achieve the desired cross-linked vesicle property. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See MPEP § 2144. Similarly, the temperature and pH of the aqueous phase are matter of routine optimization well within the purview of a person of ordinary skill in the art in order to best achieve the desired calibrated fluorocarbon vehicles as such conditions determine the properties of the vehicles. Selecting whether to incorporate the cross-linkable amphiphilic peptide into the aqueous or organic phase as well as executing specific dialysis and washing steps, represents a matter of design choice that a person of ordinary skill in the art could appropriately adjust depending on the experimental conditions and desired results.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims of copending Application No. 19/492,768 in view of Melich et al. (International Journal of Pharmaceutics, 2020; cited on IDS filed May 9, 2024), Schneider et al. (WO 2019 023706; cited on IDS files May 9, 2024), and Riché et al. (American laboratory, 2006, cited on PTO-892).
Regarding claims 1, 2, 9, and 13, claims 1 and 22 of the ‘768 recites a method for the preparation of an aqueous suspension comprising a plurality of cross-linked vesicles comprising an outer layer and an inner core, said outer layer comprising a cationic amphiphilic peptide and said inner core comprising a liquid fluorinated compound, comprising the steps of: a) Preparing an aqueous phase comprising an amphiphilic peptide, wherein the pH of said aqueous phase is of 4 or lower; b) Preparing an organic phase, comprising a fluorinated compound having a boiling point lower than 25°C; c) Injecting said aqueous phase in a first inlet and said organic phase in a second inlet of a microfluidic cartridge, thereby mixing said aqueous phase and said organic phase in a mixing portion of the microfluidic cartridge to obtain an aqueous suspension of cross-linkable vesicles; d) Collecting the aqueous suspension of cross-linkable vesicles from an exit channel of the microfluidic cartridge; e) Diluting the aqueous suspension of cross-linkable vesicles, and f) Contacting said aqueous suspension of cross-linkable vesicles with an oxidizing source able to induce the cross-linking of the amphiphilic peptides to obtain an aqueous suspension of cross-linked vesicles. Claim 21 of the ‘768 recites that the vesicles can have a z-average diameter comprised between 100 nm and 1000 nm and a polydispersity lower than 0.3. A z-average diameter and a polydispersity are result-effective parameters that a person of ordinary skill in the art would routinely optimize. Regarding claims 1 and 3, claim 3 of the ‘768 recites that the fluorinated compound can be perfluorobutane (perfluorocarbon). Claim 23 of the ‘768 recites that the oxidizing source can be an oxidizing solution comprising disulfiram.
Claims of the ‘768 do not recite aqueous phase comprising specific component such as water in specific temperature such as room temperature and pH lower than 7.0. Claims of the ‘768 do not recite an oxidizing source comprising a mixture of an oxidizing solution and an oxidizing gas and cross-linking conditions. Claims of the ‘768 do not recite that dialysis and washing steps.
As discussed above, Melich discloses a method for the preparation of PFC-NDs using a microfluidic platform (page 2, column 2, ¶ 5). Melich discloses that the method can comprise injecting an aqueous phase such as water into the first inlet of the microfluidic cartridge (page 2, column 2, ¶ 5-page 3, column 1, ¶ 1; Fig. 1). Melich discloses that ultrapure water obtained via Millipore® unit can be used for the aqueous phase (page 2, column 2, ¶ 4; Table 1). Riché discloses that the pH of ultrapure water is practically 5.8 though it is theoretically 6.998 (page 1, column 2, ¶ 1 – page 2, column 1, ¶ 1). Melich discloses that the microfluidic process can be carried out at room temperature (page 4, column 1, ¶ 1).
As discussed above, Schneider discloses a nanopeptisome comprising a perfluorocarbon liquid core and amphiphilic peptides surrounding the core (abstract). Schneider discloses that the amphiphilic peptides can comprise cross-linking motif (claim 2) and that cross-linking can be conducted in an aqueous solution including dimethyl sulfoxide (DMSO) or any other organic solvent capable of oxidizing and cross- linking thiol groups of cysteine amino acids (¶ 129). Schneider discloses that additional bubbling air can be employed to further promote oxidation, which reads on utilizing an oxidizing gas (¶ 145; ¶ 152). Schneider discloses a graph tracking cross-linking formation versus time in the presence of a 5% DMSO oxidizing agent (FIG. 6). Schneider discloses that the cross-linking can be performed during dialysis (¶ 129). Schneider discloses that the resulting product can be subsequently dialyzed with water (washing) and then collected (¶ 145; ¶ 192).
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 method of the ‘768 by using an aqueous phase comprising water, alongside cross-linking using a mixture of an oxidizing solution and an oxidizing gas, dialysis, and washing steps taught by Scheider in order to prepare more effective fluorocarbon cross-linked vesicles. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Melich teaches an aqueous phase comprising water; and Schneider teaches a cross-linkable peptide surfactant and steps for cross-linking, dialysis, and washing. Further, a person of ordinary skill in the art would have been motivated to utilize a cross-linkable amphiphilic peptide instead of standard surfactants to produce more stable and biocompatible vesicles tailored for pharmaceutical applications. A person of ordinary skill in the art would have been motivated to optimize the cross-linking condition such as reaction time according to the specific requirements of the intended applications. The cross-linking condition is a clearly result-effective parameters that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the cross-linking condition such as a reaction time sufficient to induce a degree of cross-linking of the amphiphilic peptides of 90% or greater in order to best achieve the desired cross-linked vesicle property. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See MPEP § 2144. Similarly, the temperature and pH of the aqueous phase are matter of routine optimization well within the purview of a person of ordinary skill in the art in order to best achieve the desired calibrated fluorocarbon vehicles as such conditions determine the properties of the vehicles. Selecting whether to incorporate the cross-linkable amphiphilic peptide into the aqueous or organic phase as well as executing specific dialysis and washing steps, represents a matter of design choice that a person of ordinary skill in the art could appropriately adjust depending on the experimental conditions and desired results.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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/JONG HWAN BAEK/Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
