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 .
DETAILED ACTION
Applicant’s Request for Reconsideration dated June 29, 2026 is acknowledged.
Claims 1-9, 11-13 and 15-43 are pending.
Claims 10 and 14 are cancelled.
Claims 1, 3, 11, 13, 15 and 20-23 are currently amended.
Claims 38-43 are new.
Claims 27-37 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions, there being no allowable generic or linking claim.
Claims 1-9, 11-13, 15-26 and 38-43 as filed on June 29, 2026 are under consideration.
This action is made FINAL.
Withdrawn Objections / Rejections
In view of the substitute specification, all previous objections to the specification are withdrawn.
In view of the amendment of the claims, all previous claim objections are withdrawn and all previous claim rejections under 35 USC 112(b) are withdrawn.
Applicant’s arguments have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on June 29, 2026 was considered.
Maintained Grounds of Rejection / New Grounds of Rejection Necessitated by Amendment
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 1-6, 9, 11, 13 and 15-19 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. “Synthesis of self-assembled porphyrin nanoparticle photosensitizers,” ACS Nano 12:3796-3803, 2018, of record in view of Ramírez-Jiménez et al. “Surfactant-free synthesis and scalable purification of triangular gold nanoprisms with low non-specific cellular uptake,” Nanomaterials 10:539, 2020, of record; Paulsen et al. “Cysteine-mediated redox signaling: chemistry, biology, and tools for discovery,” Chemical Reviews 113:4633-4679, 2013, of record; and Handa et al. (US 2019/0039910, published February 7, 2019, of record).
Wang teaches porphyrin nanoparticles comprising nitric oxide coordinated to zinc (transition metal) ions (title; abstract; Scheme 1):
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(structure I, wherein R1 is a substituted or unsubstituted aryl), as required by instant claims 4, 5, 16, 17. The porphyrin is tetra(4-pyridyl)-porphyrin (abstract), as required by instant claims 6, 18.
The nanoparticles were prepared from a solution containing cetyltrimethylammonium bromide (CTAB), NaOH (base, alkali metal hydroxide) and the zinc porphyrin (page 3798, paragraph bridging columns), as required by instant claims 2, 3. The nanoparticles were collected by centrifugation (page 3798, paragraph bridging columns), as required by instant claim 9.
The nanoparticles absorb nitric oxide (page 3798, rhc, 1st full paragraph). The nanoparticles define a photosensitizer system in the field of photodynamic therapy (title; abstract). Under light irradiation the nanoparticles release peroxynitrite molecules that exhibit antibacterial activity (abstract). The nanoparticles are biocompatible (page 3739, rhc), as required by instant claim 19.
Wang does not teach nanoparticles produced by the method of claim 1, however, product-by process claims are not limited to the manipulations of the recites steps, only the structure implied by the steps. See MPEP 2113. Wang does not teach a first compound comprising porphyrin and glutathione, wherein the glutathione is covalently bonded to a nitric oxide / S-nitrosothiol compound as required by claim 1.
Wang does not teach a nanoparticle comprising a porphyrin and a nitric oxide / S-nitrosothiol compound covalently bonded to glutathione as required by claim 13.
Wang does not teach the S-nitrosothiol compound is inter alia S-nitroso-S-acetyl-penicillamine or/and nitrosated cysteine as required by claims 11, 15.
These deficiencies are made up for in the teachings of Ramírez-Jiménez, Paulsen and Handa.
Ramírez-Jiménez teaches cetyltrimethylammonium bromide (CTAB) is a cytotoxic surfactant which can be replaced with a non-toxic glutathione (GSH) thiol-containing ligand (abstract; page 2, 1st full paragraph; paragraph bridging pages 2 and 3; Figure 1).
Paulsen teaches nitric oxide is a reactive nitrogen species (paragraph bridging pages 4655-4656). Nitric oxide covalently modifies protein cysteines, a modification termed S-nitrosylation (page 4658, rhc, 1st full paragraph). An S-nitrosothiol can react with a neighboring cysteine or with GSH to undergo transnitrosylation (paragraph bridging pages 4658 and 4659; Figure 15). GSH reduces S-nitrosothiol to give the free thiol and GSNO (S-nitrosoglutathione) (page 4659, rhc, 2nd full paragraph).
Handa teaches nitric oxide releasing silica particles with an outer surface having a plurality of S-nitroso-N-acetyl-penicillamine groups covalently attached thereto (title; abstract; claims), as required by instant claims 11, 15. The particles have a nitric oxide content of about 0.025 to 0.05 micromole per mg of material and a half-life for nitric oxide release of about 20 to 40 hours (claims 2, 3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the process of porphyrin nanoparticle formation of Wang to comprise glutathione as taught by Ramírez-Jiménez instead of CTAB because CTAB is cytotoxic. It would have been obvious to modify the process of porphyrin nanoparticle formation of Wang and Ramírez-Jiménez to further comprise a step of exposing the nanoparticles to an S-nitrosothiol (nitric oxide compound) as taught by Paulsen in order to transnitrosylate the glutathione within the nanoparticle thereby maximizing / optimizing the nitric oxide content of the nanoparticles or/and to modify the glutathione within the nanoparticle to further comprise a plurality of S-nitroso-N-acetyl-penicillamine groups covalently attached thereto (e.g., attached to the glutathione) as taught by Handa in order to maximize / optimize the nitric oxide content of the nanoparticles. It is prima facie obvious to optimize such result-effective variables within prior art conditions or through routine experimentation. "[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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05.
Claims 7, 8 and 20-26 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. “Synthesis of self-assembled porphyrin nanoparticle photosensitizers,” ACS Nano 12:3796-3803, 2018, of record in view of Ramírez-Jiménez et al. “Surfactant-free synthesis and scalable purification of triangular gold nanoprisms with low non-specific cellular uptake,” Nanomaterials 10:539, 2020, of record; Paulsen et al. “Cysteine-mediated redox signaling: chemistry, biology, and tools for discovery,” Chemical Reviews 113:4633-4679, 2013, of record; and Handa et al. (US 2019/0039910, published February 7, 2019, of record) as applied to claims 1-6, 9, 11, 13 and 15-19 above, and further in view of Wang et al. 2016 “Morphology-controlled synthesis and metalation of porphyrin nanoparticles with enhanced photocatalytic performance,” Nano Letters 16:6523-6528, 2016, of record and Hwan et al. (KR 2018-0086754 A, published August 1, 2018, as evidenced by the Google translation, of record) as evidenced by Zenkevich et al. “Self-assembly of semiconductor quantum dots with porphyrin chromophores: energy relaxation processes and biomedical applications,” Journal of Molecular Structure 1244:131239, 2021, of record.
The teachings of Wang, Ramírez-Jiménez, Paulsen and Handa have been described supra.
Wang teaches the nanoparticles were prepared from 9.1 mL of an aqueous solution containing cetyltrimethylammonium bromide (CTAB) (0.011 M) and 0.45 mL of zinc porphyrin (0.01 M) (page 3798, paragraph bridging columns). Wang further teaches well-defined cubic morphologies having an average size of about 40 nm with a narrow size distribution (page 3798, paragraph bridging columns). The self-assembly process was driven by non-covalent interactions between molecules or surfactants (page 3798, paragraph bridging columns).
They do not teach a molar ratio of porphyrin to glutathione of about 0.5:1 to 2:1 as required by claim 7.
They do not teach a molar ratio of porphyrin to glutathione of about 1:1 as required by claim 8.
They do not teach an octahedron as required by claim 20.
They do not teach an edge length of about 100 to 120 nm as required by claim 21.
They do not teach an average size of about 100 to 200 nm as required by claim 22.
They do not teach a polydispersity index of about 0.1 to 0.3 as required by claim 23.
They do not teach a zeta potential of about -20 to -40 mV as required by claim 24.
They do not teach about 100 to 300 mol/(min mg) nitric oxide release under the conditions of claim 25.
They do not teach about 200 to 400 mol/(min mg) nitric oxide release under the conditions of claim 26.
These deficiencies are made up for in the teachings of Wang 2016 and Hwan.
Wang 2016 teaches the type of surfactant and kinetic conditions control the structure of self-assembled porphyrin nanoparticles; structures include nanooctahedra (title; abstract), as required by instant claim 20. Exemplary nanooctahedra self-assembled in CTAB are uniform in size, with edge lengths of 200 nm with 3.2% standard deviation (Figure 1; page 6524, paragraph bridging columns), as required by instant claim 22.
Hwan teaches manufacture of gold nanoclusters in the presence of a ligand comprising a thiol group such as glutathione; the ligand is bound to the periphery of the nanoparticles (title; abstract; claims; Figures 1 & 2; page 4, middle). The mole ratio of the gold precursor to the glutathione is 1:1.5 (about 1:1 because the qualifier about permits some tolerance) to 1:2 (claims), as required by instant claims 7, 8. The carboxyl group of glutathione is negatively charged (page 4, middle). As evidenced by Figure 8 of Zenkevich, glutathione electrostatically interacts with porphyrin:
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Regarding claims 7, 8, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the process of porphyrin nanoparticle formation of Wang in view of Ramírez-Jiménez, Paulsen and Handa to adjust the concentrations / relative amounts of the porphyrin and the glutathione within the mole ratio as taught by Hwan and to optimize therein in order to adjust the amount of residual surfactant / glutathione non-covalently / electrostatically associated with the nanoparticles. See MPEP 2144.05. One would have been motivated to do so in order to optimize / maximize the nitric oxide content of the nanoparticles. There would have been a reasonable expectation of success because it is known from Wang 2016 that the type of surfactant and process conditions control the structure of porphyrin nanoparticles.
Regarding claim 20, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize the surfactant / glutathione and kinetic conditions of porphyrin nanoparticle formation of Wang in view of Ramírez-Jiménez, Paulsen and Handa in order to control the structure of the self-assembled particles as taught by Wang 2016 such as to produce nanooctahedra.
Regarding claims 21, 22, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize the surfactant / glutathione and kinetic conditions of porphyrin nanoparticle formation of Wang in view of Ramírez-Jiménez, Paulsen and Handa and optionally Wang 2016 in order to adjust the structure / size of the self-assembled particles / nanooctahedra within dimensions of about 40 nm as taught by Wang to about 200 nm as taught by Wang 2016. See MPEP 2144.05.
Regarding claim 23, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize the surfactant / glutathione and kinetic conditions of porphyrin nanoparticle formation of Wang in view of Ramírez-Jiménez, Paulsen and Handa and optionally Wang 2016 in order to adjust the structure / size distribution of the self-assembled particles / nanooctahedra to be narrow (monodisperse) as taught by Wang to or to have a small standard deviation as taught by Wang 2016. See MPEP 2144.05.
Regarding claim 24, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that the glutathione ligated porphyrin nanoparticles of Wang in view of Ramírez-Jiménez, Paulsen and Handa would have an overall net charge because Hwan teaches the carboxyl groups of glutathione are negatively charged. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the process of porphyrin nanoparticle formation of Wang in view of Ramírez-Jiménez, Paulsen and Handa to adjust the concentrations / amounts of the porphyrin and the glutathione in order to optimize the net charge of the nanoparticles. See MPEP 2144.05.
Regarding claims 20-26, additionally or/and alternatively, because the combined teachings of Wang in view of Ramírez-Jiménez, Paulsen and Handa render obvious the nanoparticles of claim 1 and because the combined teachings of Wang in view of Ramírez-Jiménez, Paulsen, Handa, Wang 2016 and Hwan render obvious the relative amounts of porphyrin and glutathione therein, it necessarily follows that the nanoparticles of the prior art are also characterized by the same shape as instantly claimed, the same size as instantly claimed, the same polydispersity as instantly claimed, the same charge as instantly claimed, and the same capacity to outgas nitric oxide under the conditions as instantly claimed because a chemical composition and its properties are inseparable. See MPEP 2112 and 2145 II.
Claims 12, 25 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. “Synthesis of self-assembled porphyrin nanoparticle photosensitizers,” ACS Nano 12:3796-3803, 2018, of record in view of Ramírez-Jiménez et al. “Surfactant-free synthesis and scalable purification of triangular gold nanoprisms with low non-specific cellular uptake,” Nanomaterials 10:539, 2020, of record; Paulsen et al. “Cysteine-mediated redox signaling: chemistry, biology, and tools for discovery,” Chemical Reviews 113:4633-4679, 2013, of record; and Handa et al. (US 2019/0039910, published February 7, 2019, of record) as applied to claims 1-6, 9, 11, 13 and 15-19 above, and further in view of Brisbois et al. (US 2015/0366831, published December 24, 2015).
The teachings of Wang, Ramírez-Jiménez, Paulsen and Handa have been described supra.
Handa teaches a nitric oxide content of about 0.025 to 0.05 micromole per mg of material and a half-life for nitric oxide release of about 20 to 40 hours (claims 2, 3).
They do not teach nitrosated cysteine as required by claim 12.
They do not teach about 100 to 300 mol/(min mg) nitric oxide release under the conditions of claim 25.
They do not teach about 200 to 400 mol/(min mg) nitric oxide release under the conditions of claim 26.
These deficiencies are made up for in the teachings of Brisbois.
Brisbois teaches S- nitroso-N-acetyl-penicillamine doped nitric oxide release polymers (title; abstract; claims; Figure 2). Alternatives to S-nitroso-N-acetyl-penicillamine include S-nitrosocysteine (paragraph [0043]), as required by instant claim 12. Therapeutically relevant fluxes of nitric oxide range from about (0.2 to 20) x 10-10 mole / (cm2 min) (paragraph [0036]).
Regarding claim 12, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the glutathione ligated porphyrin nanoparticles of Wang in view of Ramírez-Jiménez, Paulsen and Handa to comprise S-nitrosocysteine as taught by Brisbois in lieu of S-nitroso-N-acetyl-penicillamine because S-nitrosocysteine is an art-recognized functional equivalent of S-nitroso-N-acetyl-penicillamine for purposes of nitric oxide release and it is prima facie obvious to substitute equivalents. See MPEP 2144.06.
Regarding claims 25, 26, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the glutathione ligated porphyrin nanoparticles of Wang in view of Ramírez-Jiménez, Paulsen, Handa and Brisbois to have a nitric oxide content as taught by Handa or/and to comprise a nitric oxide content as taught by Brisbois and to optimize therein in order to provide therapeutically or/and antibacterially relevant nitrogen oxide outgas fluxes over appropriate timeframes.
Claims 38-43 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. “Synthesis of self-assembled porphyrin nanoparticle photosensitizers,” ACS Nano 12:3796-3803, 2018, of record in view of Ramírez-Jiménez et al. “Surfactant-free synthesis and scalable purification of triangular gold nanoprisms with low non-specific cellular uptake,” Nanomaterials 10:539, 2020, of record; Paulsen et al. “Cysteine-mediated redox signaling: chemistry, biology, and tools for discovery,” Chemical Reviews 113:4633-4679, 2013, of record; and Handa et al. (US 2019/0039910, published February 7, 2019, of record) as applied to claims 1-6, 9, 11, 13 and 15-19 above, and further in view of Bommer et al. (US 2003/0050296, published March 13, 2003) and Fan et al. (US 8,871,926, published October 28, 2014).
The teachings of Wang, Ramírez-Jiménez, Paulsen and Handa have been described supra.
They do not teach the porphyrin is not 5,10,15,20-tetra(4-pyridyl)-21H,23H-porphine as required by claims 38, 41.
They do not teach the porphyrin does not include a transition metal as required by claims 39, 42.
They do not teach the porphyrin does not include zinc as required by claims 40, 43.
These deficiencies are made up for in the teachings of Bommer and Fan.
Bommer teaches photodynamic porphyrin antimicrobial agents (title; abstract; claims; Figure 1):
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(not 5,10,15,20-tetra(4-pyridyl)-21H,23H-porphine, does not include a transition metal / zinc) which exhibit a markedly increased efficiency in photosensitizing bacteria, causing death at much lower concentrations and shorter irradiation times, as required by instant claims 38-43. The porphyrin is (optionally) metal / zinc chelated (claims 4-6).
Fan teaches self-assembled porphyrin nanostructures (title; abstract; claims; paragraph bridging columns 7 and 8). The porphyrin may be coordinated to a metal such as zinc (claims 12, 13; Figure 2b) or not coordinated to a metal (claim 15; Figure 2a). Self-assembly is not limited to metalated porphyrins (column 16, lines 7-31).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the porphyrin nanoparticles of Wang in view of Ramírez-Jiménez, Paulsen and Handa to comprise additional populations of nanoparticles prepared with different porphyrins inclusive of those taught by Bommer in order to adjust / optimize the efficiency in photosensitizing bacteria. There would be a reasonable expectation of success because Fan evidences self-assembly according to the process of Wang is a property of porphyrins per se and is not limited to metalated porphyrins or to the specific porphyrin exemplified by Wang.
Response to Arguments: Claim Rejections - 35 USC § 103
Applicant’s arguments have been fully considered but they are not persuasive.
Applicant’s argument at page 9 of the Remarks that the nanoparticles of Wang differ from those instantly claimed is acknowledged but not found persuasive because the nanoparticles of Wang fall within the scope of the instant claims. That is, the instant claims expressly embrace metal chelated porphyrins (e.g., claim 5) and the instant claims do not exclude the presence of sorbed nitric oxide. Because Wang already directs the skilled artisan to incorporate nitric oxide, modifications of porphyrin nanoparticles to comprise nitric oxide according to methods known in the art are prima facie obvious as evidenced by the additional references.
Applicant’s argument at page 10 that modifying Wang to comprise glutathione would result in a complex that differs from Wang is unpersuasive because Wang expressly teaches the nanoparticles thereof are prepared using known surfactant templating methods (e.g., see Fan et al. (US 8,871,926)).
Applicant’s citation to Dastgheyb at pages 10-11 for the proposition that modifying Wang to comprise glutathione would not enhance antibacterial activity is noted but is unpersuasive because the proposed modification is to comprise glutathione and additional sources of nitric oxide. As such, the proposed modification is not credited as rendering Wang unsatisfactory.
Applicant’s citation to new claims 38-43 which attempt to exclude the porphyrin of Wang are acknowledged. New grounds of rejection are applied supra to meet these claims.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Li et al. (WO 2018/232334) teaches drug – porphyrin conjugates and nanoparticles of the conjugates (title; abstract; claims).
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 ALISSA PROSSER whose telephone number is (571)272-5164. The examiner can normally be reached M - Th, 10 am - 6 pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, DAVID BLANCHARD can be reached on (571)272-0827. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALISSA PROSSER/
Examiner, Art Unit 1619
/BENNETT M CELSA/Primary Examiner, Art Unit 1600
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