DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after September 14, 2023, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
Receipt is acknowledged of Applicants’ claimed invention filed on 09/14/2023 in the matter of Application N° 18/368,373. Said documents are entered on the record. The Examiner further acknowledges the following:
The present application, filed on or after September 14, 2023, is being examined under the first inventor to file provisions of the AIA .
Thus, claims 21 and 22 have been cancelled, 16-20 and 23-34 represent all claims currently under consideration.
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 at the time any inventions covered therein were effectively filed 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 at the time a later invention was effectively filed 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 16-20 and 23-34 are rejected under 35 U.S.C. 103 as being unpatentable over Hashimoto et al. (WO1996040279A2) in view of Lingwood et al. (Division of Polymer Chemistry (POLY) Graphical Abstracts Submitted for the 255th ACS National Meeting & Exposition New Orleans, LA | March 18‐22, 2018), POLY 194: Probe molecules for pulsed-field-gradient diffusion NMR experiments on micelles), Ding et al. (Facile preparation of a cationic poly (amino acid) vesicle for potential drug and gene co-delivery) 2011 Nanotechnology 22 494012), and Wang et al. (In situ preparation of glycoconjugate hollow microspheres mimics the extracellular matrix via interfacial polymerization), and Breslow et al. L-amino acids catalyze the formation of an excess of D-glyceraldehyde, and thus of other D sugars, under credible prebiotic conditions (2010), and Lv et al. Charge-Conversional PEG-Polypeptide Polyionic Complex Nanoparticles from Simple Blending of a Pair of Oppositely Charged Block Copolymers as an Intelligent Vehicle for Efficient Antitumor Drug Delivery (2014), and Pliska et al. PARTITION COEFFICIENTS OF AMINO ACIDS AND HYDROPHOBIC PARAMETERS x OF THEIR SIDE-CHAINS AS MEASURED BY THIN LAYER CHROMATOGRAPHY (1981).
Hashimoto et al. teach a microsphere that is pharmacologically acceptable and has an exterior membrane made of an amphiphilic amino acid block co-polymer (See claim 1). The co-polymer is PSLGlu-block-PLLeu (See claim 13; fig.1). The PSLGlu-block-PLLeu comprises, in polymerized form, the monomer pf present claim 1 with n=0, R3 =H and R1 =CH2CH2COOCH3 (top left corner of fig.1). The gas is perfluoropropane (See pg. 4, lines 12-13). The PSLGlu-block-PLLeu comprises a CH2CH2COONa group (See bottom left of fig. 1). The microsphere is thought of as a “capsule” as specified in current claim 1. The is PSLGlu-block-PLLeu is considered to represent a “poly (amino acid)” as specified in present claim 1. The perfluoropropane is considered to represent an “organic compound” as specified in claim 1. Hashimoto et al. also teach a method of preparing the microspheres, comprising cavitation of the co-polymer in a solution in the presence of the gas (See pg. 11, lines 28-30).
Regarding claim 17, Lingwood et al. teach an octagon/water partition coefficient with low Pow > 5.5m (See pg. 196, paragraph 3).
Therefore, it would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the instant application, to incorporate the teachings of Hashimoto et al. which disclose a microsphere containing a pharmacologically acceptable water-insoluble gas encapsulated within an exterior membrane composed of an amphiphilic amino acid block copolymer, which provides structural stability and compatibility with both hydrophilic and hydrophobic environments, into the teachings of Lingwood et al. which describe micelle diffusion as best reflected by probes exhibiting an octanol/water partition coefficient (Pow) greater than 5.5. thereby emphasizing the role of partitioning behavior in predicting diffusion efficiency in biological or aqueous systems, the combination of these teachings would have motivated one of ordinary skill in the art to employ amphiphilic block copolymer membranes as delivery vehicles for hydrophobic probes and gases, since both references emphasize partitioning behavior and compatibility with hydrophobic environments, thereby reasonably expecting to achieve improved diffusion and stability in aqueous systems. Hashimoto et al. demonstrates a structural delivery platform, while Lingwood et al. emphasizes the importance of hydrophobic partitioning properties for effective diffusion. Because amphiphilic block copolymers are well recognized in the art for encapsulating and transporting hydrophobic molecules or gases, and Lingwood’s disclosure identifies the physicochemical characteristics (Pow>5.5) necessary for diffusion, one of ordinary skill would reasonably expect that combining these teachings would predictably yield microspheres capable of improving diffusion of hydrophobic agents in aqueous or biological systems. Additionally, as stated in the MPEP 2112.01"Products of identical chemical composition cannot have mutually exclusive properties." A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658(Fed. Cir. 1990),“Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identicalprocesses, a prima facie case of either anticipation or obviousness has been established.In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTOshows a sound basis for believing that the products of the applicant and the prior art arethe same, the applicant has the burden of showing that they are not."
Regarding claim 20, Hashimoto et al. teach the microspheres range in size from 2 to 7 microns (See pg. 15, lines 17-18). The value of 2 microns falls within the range of from 0.07 to 5 microns. Additionally, regarding claim 20, Hashimoto et al. teach the microspheres range in size from 2 to 7 microns (See pg. 15, lines 17-18). The value of 2 microns falls within the range of from 0.07 to 5 microns.
However, Himoshoto fails to teach instant claims 18 and 27.
Ding et al. teach with regards to instant claims 18 and 27, doxorubicin hydrochloride, or DOX HCL, is considered as a pharmaceutical ingredient. According to present claim 8, doxorubicin hydrochloride is also considered as a “anti-cancer drug. Specifically, cationic poly (amino acid) vesicles have drawn a lot of interest due to their capacity to co-deliver traditional chemotherapeutic medications, such as Paclitaxel (PTX) and Doxorubicin (DOX). Combining two or more chemotherapeutic active ingredients with distinct processes can prevent the growth of cancer together and is a viable method for treating cancers that work well together (See pg. 3, paragraph 2).
Therefore, it would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the instant application, to substitute the teachings of Ding et al. which teach an organic compound for the gas of Hashimoto et al.
Regarding claims 21, 30, 32, and 33, Wang et al. teach crosslinking of polymeric capsule shells.
It would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the instant application, to apply the crosslinking methods of Wang et al. to the polymeric capsule shells of Hashimoto et al., since both references are directed to polymeric encapsulating structures used to contain or protect internal contents. A person of ordinary skill would have reasonably expected that crosslinking the amphiphilic amino acid block copolymer membrane of Hashimoto et al. would further improve structural stability, reduce premature rupture or leakage of the encapsulated gas, and enhance compatibility under varied physiological environments.
Regarding claim 24, Hashimoto et al. teach the CH2CH2COONa group is considered as a “dispersing group being a salt of a carboxylic acid”. The second block, a poly amino acid, can be referred to as a “hydrophilic block” since the side chains of the amino acids are hydrophilic. Hydrophilic functional groups, like carboxylic acid or amino groups, are frequently found on hydrophilic side chains. The block co-polymer made of L-leucine and sodium L-glutamate (i.e., with hydrophilic side-chain CH2CH2COONa), which can be represented as PLLeu-block-PSLGlu, is one poly amino acid that is helpful in the current invention (See pg. 9, lines 23-33).
Regarding claim 25, Ding et al. teach polymeric vesicles have been created using synthetic poly (amino acids). L-glutamic acid and L-lysine are examples of synthetic poly (amino acids) that are biocompatible, biodegradable, adjustable, and possess distinct secondary structures (See pg. 2, paragraph 3).
However, Ding et al. fail to teach D-amino acids.
Breslow et al. teach if the L-amino acids had caused the L-glyceraldehyde to develop preferentially, we would have to come up with a brand-new explanation for why D sugars predominate in our biology. Although the enantiomeric excesses with L-alanine and L-serine were negligible. Table 1 demonstrates that all of the L-amino acids we looked at) except from L-proline) promoted the preferential production of D-glyceraldehyde. Simply holding a solution of different L-amino acids made the reaction conditions believable prebiotic. The D/L ratio was then calculated using liquid chromatography with chiral high pressure (See pg. 2, results and discussion).
Therefore, it would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the instant application, to incorporate the stereochemical findings of Breslow et al. into the poly (amino acid) teachings of Ding et al., since both references concern the consequences of using L-amino acids on stereochemical outcomes. A person of ordinary skill would have recognized that employing L-amino acids in Ding et al. polymers, in light of Breslow et al. teaching that L-amino acids bias the information of the D-isomer, would predictably influence downstream stereochemical properties of the polymer system.
Lv et al. teach instant claim 28 using a dialysis technique at 37 degrees Celsius in phosphate buffered saline (PBS) at several pH values, the drug release behavior of DOX-NPs was examined. The strong interaction between the carriers and DOX may be the cause of the comparatively delayed release at pH 7.4. The total carrier/DOX interaction is influenced by pi-pi stacking between DOX molecules and phenylalanine units in addition to hydrophobic contact with DOX (See pg. 7, Release behavior of charge-conversional DOX-NPS). Lv also teaches regarding claim 34, cyclic and highly reactive alpha-amino acid N-carboxyanhydride (NCAs) were synthesized and polymerized, a large variety of poly (amino acid) polymers have been created by carefully polymerizing alpha-amino acid NCAs with a primary amine initiator (See pg. 5, Results and Discussion).
Pliska et al. with regards to claim 31, teach thin-layered chromatography in various solvent systems has been used to estimate the partition coefficients in n-octanol water for both naturally occurring and certain synthesized alpha-amino acids. (See pg. 1, Summary). Since the product is the same and as stated supra, "Products of identical chemical composition cannot have mutually exclusive properties." A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.
As stated in the MPEP 2112.01 "Products of identical chemical composition cannot have mutually exclusive properties." A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658(Fed. Cir. 1990),“Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identicalprocesses, a prima facie case of either anticipation or obviousness has been established.In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTOshows a sound basis for believing that the products of the applicant and the prior art arethe same, the applicant has the burden of showing that they are not."
Therefore, one of ordinary skill in the art would have been motivated to combine the cited prior art and make modification to result in the claimed invention at the time the invention was filed.
Response to Arguments
Applicant's arguments filed December 09, 2025 have been fully considered but they are not persuasive.
The nonstatutory obviousness-type double patenting rejection has been acknowledged and is hereby withdrawn.
Claims 16-20 and 23-29 are rejected. Claims 30-34 are allowable.
Claim 16, as currently amended, recites that the polymeric shell is “obtainable” by interfacial polymerization of an N-carboxyanhydride monomer. The term “obtainable” does not require that the claimed polymeric shell is actually formed by the recited process, but merely indicates that it is capable of being formed by such a process. Therefore, this language does not impose a structural limitation sufficient to distinguish the claimed capsule from those disclosed in the prior art.
In contrast, claims 30-34 recite specific process limitations directed to the formation of the polymeric shell by interfacial polymerization of an N-carboxyanhydride monomer. The prior art of record does not teach or suggest the method of making as recited in claims 30-34. Accordingly, claims 30-34 are allowable.
Applicant was advised that claim 16 may be placed in condition for allowance if amended to recite that the polymeric shell is “obtained” by interfacial polymerization, rather than “obtainable” thereby, and further to incorporate the specific process limitations recited in claim 30 into claim 16.
Accordingly, the rejection of claims 16-20 and 23-29 is maintained, and claims 30-34 are allowable.
The prior art of record, including Hashimoto et al. and Wang et al. does not teach or suggest the claimed invention.
Independent claims are directed to capsules obtainable by interfacial polymerization, specifically involving ring-opening polymerization of N-carboxy-anhydride monomers at an organic-aqueous interface, resulting in formation of a polymer shell at that interface.
Hashimoto et al. discloses capsule formation using pre-formed amphiphilic block copolymers, which are synthesized separately in a homogeneous organic phase prior to encapsulation. The encapsulation process in Hashimoto et al. relies on cavitation of these pre-synthesized block copolymers, rather than polymerization occurring at an interface. Thus, Hashimoto et al. does not disclose or suggest forming capsules via interfacial polymerization, nor does it teach initiating polymerization at a liquid-liquid interface.
In contrast, the presently claimed method involves dissolving monomers in a water-immiscible phase, dispersing this phase into an aqueous medium, and initiating polymerization at the interface between the two phases, thereby forming a shell in situ. This represents a fundamentally different reaction environment and mechanism from that of Hashimoto et al. As a result, the capsules produced by the claimed method possess structural and chemical characteristics distinct from those of Hashimoto et al.
Furthermore, Hashimoto et al. emphasizes that capsule formation is sensitive to the balance of hydrophilic and hydrophobic interactions, which varies depending on the interface involve. The interfacial conditions of the claimed method differ from those employed in Hashimoto et al. further supporting that the resulting capsule structures would not be the same.
Wang et al. does not cure these deficiencies. While Wang et al. discusses polymeric capsule systems, it does not disclose or suggest incorporating a crosslinking agent during interfacial polymerization, nor does it describe introducing such an agent prior to or during formation of the capsule shell. The reference is silent with respect to the use of crosslinkers in the manner required by the claims.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kimberly Barber whose telephone number is (703) 756-5302. The examiner can normally be reached on Monday through Friday from 6:30 AM to 3:30 PM EST.
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/KIMBERLY BARBER/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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